Review ArticleA Critical Appraisal of Solubility EnhancementTechniques of Polyphenols
Harkiran Kaur and Gurpreet Kaur
Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala Punjab 147002 India
Correspondence should be addressed to Gurpreet Kaur kaurgptgmailcom
Received 6 December 2013 Accepted 23 January 2014 Published 3 March 2014
Academic Editor Grzegorz Grynkiewicz
Copyright copy 2014 H Kaur and G KaurThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Polyphenols constitute a family of natural substances distributed widely in plant kingdom These are produced as secondarymetabolites by plants and so far 8000 representatives of this family have been identified Recently there is an increased interestin the polyphenols because of the evidence of their role in prevention of degenerative diseases such as neurodegenerative diseasescancer and cardiovascular diseases Although a large number of drugs are available in the market for treatment of these diseaseshowever the emphasis these days is on the exploitation of natural principles derived fromplantsMost polyphenols show low in vivobioavailability thus limiting their application for oral drug delivery This low bioavailability could be associated with low aqueoussolubility first pass effect metabolism in GIT or irreversible binding to cellular DNA and proteins Therefore there is a need todevise strategies to improve oral bioavailability of polyphenols Various approaches like nanosizing self-microemulsifying drugdelivery systems (SMEDDS) microencapsulation complexation and solid dispersion can be used to increase the bioavailabilityThis paper will highlight the various methods that have been employed till date for the solubility enhancement of variouspolyphenols so that a suitable drug delivery system can be formulated
1 Introduction
Naturally occurring activemoieties have been used in therapysince ages Currently 80 of the worldrsquos population uses plantderived principles either directly or indirectly [1] Certainexamples of plant derived products employed as therapeuticagents are tannins alkaloids polyphenols polysaccharidesessential oils various extracts and exudates Lately muchresearch has been envisaged on polyphenols due to twomain reasons Firstly these possess high spectrum of bio-logical activities including antioxidant anti-inflammatoryantibacterial and antiviral and secondly they are presentin abundance in diet [2] Polyphenols are found in manycomponents of the human food including peanuts darkchocolate green and black tea and turmeric Extensiveresearch in the past years and collected data shed light oncertain physiological properties of plant polyphenols Thesecan slow the progression of certain cancers neurodegen-erative diseases and diabetes and can reduce the risks ofcardiovascular disease thus highlighting the importance ofthe use of plant polyphenols as potential chemopreventive
and anticancer agents in humans [3] Many medicinal plantsconstitute polyphenols as active substances that modulate theactivity of a wide range of enzymes and cell receptors [4]However the concentrations of polyphenols which appeareffective in vitro are often of an order ofmagnitude lower thanthat required to elicit response in vivo thus indicating theirlow bioavailability [5] The bioavailability of polyphenolsfollowing oral administration is governed by many factorssuch as gastric residence time permeability andor solubilitywithin the gut Further the conditions encountered in foodprocessing and storage (temperature oxygen and light) orin the gastrointestinal tract (pH enzymes and presence ofother nutrients) may also influence the stability of polyphe-nols Poor aqueous solubility and low dissolution rates ofpolyphenols contribute to their insufficient bioavailability [6]There are two parameters that are useful for identifying apoorly soluble drug the aqueous solubility and the dosesolubility ratio A drug is classified as poorly soluble if it hasless than 100 120583gmL solubility Dose solubility ratio is definedas volume of gastrointestinal fluids necessary to dissolvethe administered dose [7] The majority of polyphenols
Hindawi Publishing CorporationJournal of PharmaceuticsVolume 2014 Article ID 180845 14 pageshttpdxdoiorg1011552014180845
belong to class II (low solubility and high permeability)and class IV (low solubility and low permeability) BCSclasses thus limiting activity and potential health benefitsof polyphenols The bioavailability of class II and class IVsubstances may be enhanced by increasing the solubilityand dissolution rate of the drug in the gastrointestinal fluidTable 1 depicts solubility and pharmacokinetic propertiesof some commonly used polyphenols [8ndash15] The solubilityof polyphenols can be enhanced by various techniquesTechniques used for improving solubility include inclusioncomplexes micronization solid dispersion nanosuspensionsolid lipid nanoparticles nanostructured lipid carrier lipo-somes self- emulsifying drug delivery systems (SEDDS)and gel based systems Table 2 depicts some of commonlyemployed methods for increasing the solubility [16ndash23] Thepresent review discusses the various methods used till date to
improve the bioavailability of polyphenols by enhancing theirsolubility
2 Polyphenols Types and Method forSolubility Enhancement
Several higher plants and some edible plants comprehendthousand molecules having a polyphenol structure (ie sev-eral hydroxyl groups on aromatic rings)These molecules arereleased as defense against ultraviolet radiation or aggressionby pathogens and are a kind of secondary metabolites Thepolyphenols are classified on the basis of the number ofphenol rings that they contain and of the structural elementsthat bind these rings to one another These are hence catego-rized into phenolic acids flavonoids stilbenes and lignansFigure 1 depicts the chemical structure of polyphenols
Journal of Pharmaceutics 3
Table2Strategies
toim
proves
olub
ilityof
polyph
enols
Metho
dProcedure
Advantages
Disa
dvantages
Exam
ple
Reference
Nanop
articles
[16ndash
18]
Evaporativep
recipitatio
ninto
aqueou
ssolution
Spraying
ofdrug
solutio
nthroug
han
atom
izer
into
anaqueou
ssolutioncontaining
stabilizer
athigh
temperature
Highdissolutionratehigh
surfa
ceareaenh
anced
wettability
Requ
iresta
bilizerslack
ofcontrolledreleaseno
tsuitable
fortherm
olabile
drugs
Nanosuspension
ofqu
ercetin
[45]
Highpressure
homogenization
Precipitatio
nof
drug
byadditio
nof
antisolvent
inthe
drug
solutio
nleadingto
form
ationof
unstableform
ofdrug
which
issta
bilized
bymeans
ofsin
glerepeated
applicationof
high
energy
follo
wed
bythermal
relaxatio
n(ann
ealin
g)
Redu
cedparticlesiz
eenhanced
dissolution
nocrystalgrowth
Long
processin
gtim
eintro
ductionof
impu
rities
high
energy
requ
irements
chem
icaldegradation
Nanosuspension
ofqu
ercetin
[45]
Antiso
lventm
etho
d
Antiso
lvent
precipitatio
nusing
asyringe
pump
Additio
nof
antisolvent
toas
olutionof
drug
and
solventata
particular
flowrateun
derc
onsta
ntstirr
ing
leadingto
precipitatio
nof
drug
which
isthen
filteredto
collectnano
particles
Redu
cedparticlesiz
ehigh
dissolutionratehighsurfa
ceareareduced
crystallinityfaster
onseto
faction
Con
taminationdu
eto
filtration
Nanop
articleso
fhesperetin
[65]
Evaporative
precipitatio
nof
nano
suspensio
n
Mixingof
awater
misc
iblesolventcon
tainingdrug
with
anantisolvent
follo
wed
byevaporationof
solvents
Decreased
particlesiz
eenhanced
surfa
ceareaimproved
dissolution
Particlegrow
thdu
eto
remaining
organics
olvent
insuspensio
n
Curcum
innano
particles
[92]
Supercritical
antisolvent
metho
d
Precipitatio
nof
drug
from
drug
solutio
nby
mixingit
with
acom
pressedflu
idatits
supercriticalcond
ition
sDiffusionof
solventintoantisolvent
phaseleads
todrug
precipitatio
ndu
etolowsolubilityo
fdruginantisolvent
Highprod
uctp
uritycon
trolled
crystalp
olym
orph
ismpossib
leprocessin
gof
thermolabile
moleculessingles
tepprocess
Toxicityandflammabilityof
solvents
poor
controlof
particlemorph
olog
yincompleter
emovalof
resid
ualsolvent
Apigenin
nano
crystals
[55]
Solid
dispersio
nFo
rmationof
eutecticmixtureso
fdrugs
with
hydrop
hilic
carriersby
meltingtheirp
hysic
almixtures
Particlesiz
ereductio
nim
proved
wettabilityenhanced
dissolution
high
erpo
rosity
Decreaseindissolutionon
agingcrystalgrowth
upon
moistu
reabsorptio
ndemixingph
ases
eparation
Solid
dispersio
nof
ellagica
cid
[19ndash
2137]
Self-microem
ulsifying
drug
deliverysyste
ms
Gentle
mixingof
drug
oilsurfa
ctantandcosurfa
ctant
inaqueou
smedialeadingto
form
ationof
ow
microem
ulsio
nof
drug
drop
letswith
meandrop
letsize
lt100n
m
Higherb
ioavailabilityim
proved
absorptio
noraladministratio
nusinggelatin
capsules
Surfa
ctanttoxicitytedious
manufacturin
gmetho
dinteractionwith
capsules
hell
Curcum
in[2223
96]
4 Journal of Pharmaceutics
Table 3 Different methods for solid dispersions of ellagic acid [37]
Acetone ethanol solution was used to dissolve mixtures ofEApolymer followed by spray drying of the resultantdispersion under operating conditions of 90∘C inlettemperature 57ndash60∘C outlet temperature 9mLmin feedrate and 350 Lh nitrogen flow
EA PVP and CAAdP were dissolved inacetonitrile ethanol solution followed by concentratingthe solution with rotary evaporation
21 Phenolic Acids They are plant derived phenolic com-pounds which are produced via shikimic acid throughphenylpropanoid pathway and have a unique chemical struc-ture of C
6ndashC3 Some phenolic acids are also of microbial
origin containing C6ndashC1linkage These are further classified
into two categories derivatives of cinnamic acid (hydroxycin-namic acids) and derivatives of benzoic acid (hydroxybenzoicacids)
211 The Hydroxycinnamic Acids (Figure 1(b)) They aremore common than the hydroxybenzoic acids and consistmainly of p-coumaric acid caffeic acid ferulic acid andsinapic acid These acids are found in glycosylated forms asderivatives of shikimic acid quinic acid and tartaric acidCaffeic acid combines with quinic acid to form chlorogenicacid (Figure 1(c)) It is found in high concentrations incoffee a single cup may contain 70ndash350mg chlorogenic acid[24] Caffeic acid is the most abundant phenolic acid andrepresents between 75 and 100of the total hydroxycinnamicacid content of most of the fruit All parts of the fruitcontain hydrocinnamic acid but the highest concentrationsare seen in the outer parts of ripe fruit Cereal grains aredietary source of ferulic acid Wheat grains may contain 08ndash2 gkg dry weight of ferulic acid which represents up to 90of total polyphenols [25 26] Since hydroxybenzoic acidspossess sufficient aqueous solubility their absorption is notdissolution limited
212 Hydroxybenzoic Acids (Figure 1(a)) Salient examplesof hydroxybenzoic acids are gallic acid protocatechuic acidellagic acid (EA) and vanillic acid Edible plants for examplered fruits black radish onions and green tea are richin hydroxybenzoic acid content [27] Tea is an importantsource of gallic acid and tea leaves may contain up to45 gkg fresh wt of leaves [24 28] Dietary sources ofEA include walnuts pomegranates and berries [29] EApossesses several health benefits against many diseases suchas breast cancer [30] prostate cancer [31] lung cancer[32] colon cancer [33] cardiovascular disease [34] andneurodegenerative diseases [35] EA was found to possessmaximum solubility of 93 120583gmL [36] This low solubilitywas attributed to high crystallinity of EA due to its planarand symmetrical structure and extensive hydrogen-bonding
resulting in low bioavailability of EA Solid dispersions of EAhave been employed to enhance the solubility of EA Li et al[37] formulated solid dispersions of EA by three differentmethods Table 3 depicted the methods and compositionsof these investigational formulations Fourier transforminfrared spectroscopy (FTIR) studies confirmed the presenceof H-bonding between EA and polymers Scanning electronmicroscope (SEM) studies indicated that EA was present inamorphous form in the solid dispersions The in vitro dis-solution studies revealed that the nature of polymer directlyinfluences the solubility of EA The polymer with morehydrophilic character resulted in higher swelling and fasterrelease of EA Thus the release profile of EA from EAPVPmatrix was 92 (1 h) followed by EAHPMCAS (35 05 h)EACMCAB (18 1 h) and EACAAdP (15ndash17 1 h) Incor-poration of CAAdP in EAPVP solid dispersion led to adecrease in release of EA (62 05 h) EA has been reportedto deteriorate in the solution form due to crystallization andchemical degradation The amount of EA remaining after24 h in solution is only 18 and 80 due to crystallizationand chemical degradation respectively However the soliddispersions were found to significantly enhance the stabilityof EA against crystallization and chemical degradation Fur-ther it was found that HPMCAS amorphous solid dispersionprovided maximum stability to EA [37]
22 Flavonoids These are benzo-120574-pyrone derivatives ofphenolic and pyran rings [38] On the basis of substitutionson three rings flavonoids are classified as flavonols flavonesisoflavones flavanones flavanols and anthocyanidins whichare biotransformed in body by methylation sulfation andglucuronidation of hydroxyl groups Flavonoids predomi-nantly exist as 3-O-glycosides and polymers [39] Chemicalstructure of flavonoids is illustrated in Figure 2
221 Flavonols Among flavonoids flavonols are the mostubiquitous in foods The main representatives of flavonolsare quercetin and kaempferol (Figure 2(f1))The flavonols areprimarily found in onions (up to 12 gkg fresh wt) curlykale leeks broccoli and blueberries Red wine and tea alsocontain up to 45mgL flavonols In nature flavonols arepresent in glycosylated forms in plants The sugar moietyassociated with flavonols is mainly glucose or rhamnose
Figure 2 Classification and chemical structure of flavonoids
but other sugars like galactose arabinose and xylose mayalso be involved Each fruit contains around 5ndash10 differentflavonol glycosides [40] The biosynthesis of flavonols isstimulated by light so these tend to accumulate in theouter and aerial tissues Depending on exposure to sunlightdifferences in concentration exist between fruits on thesame tree and even between different sides of a single fruit[41]
Quercetin It is a naturally occurring polyphenol whichbelongs to a group of plant pigments known as flavonoidsresponsible for the colour of vegetables fruits and flowers[42] Quercetin is a flavonol whose chemical structure isderived from flavone Chemically quercetin is known as334101584057-pentahydroxyflavone Quercetin exhibits variousproperties such as anti-inflammatory antioxidant antihis-tamine and antiarthritis [42] The primary dietary sourcesof quercetin are citrus fruits apple onions parsley sage teaand redwine [43]However despite having all these beneficialactivities poor water solubility (03120583gmL) restricts its usethus highlighting the importance of increasing the solubilityof quercetin [44] Gao et al [45] reported the formationof nanosuspension of quercetin by two techniques Thefirst technique is comprised of evaporative precipitationof quercetin into aqueous solution (EPAS) The organicsolution of quercetin in ethanol was poured slowly into anaqueous solution containing Pluronic F68 (075 wv) andlecithin (025 wv) stabilizers The solution was contin-uously stirred under vacuum Finally ethanol was evapo-rated and EPAS nanosuspension was collected The secondtechnique involved high pressure homogenization (HPH)of quercetin dispersion in Pluronic F68 (075 wv) and
lecithin (025wv) A piston gap high pressure homogenizerwas used to circulate the suspension for two cycles at thepressure of 200 bar and five cycles at 500 bar followed by20 more cycles at 1500 bar resulting in HPH suspensionThe mean particle size polydispersity index (PI) and solu-bility profile of quercetin nanosuspension produced by EPASmethod and HPHmethod were found to be 2826 plusmn 503 nm023 plusmn 008 4224 120583gmL and 2136 plusmn 293 nm 021 plusmn 0102786120583gmL respectively X-ray powder diffraction (XRPD)measurements revealed a crystalline to amorphous phasetransition in EPAS process which was not observed in HPHThis formed the basis for higher increase in solubility ofquercetin in case of EPAS [46]
A solid dispersion of quercetin employing CMCABHPMCAS and CAAdP as polymers has been reported by Liet al [47] Quercetin and polymer mixtures were prepared indifferent ratios of 1 9 1 3 1 1 3 1 and 9 1 Acetone ethanol(1 4) solution was used to dissolve the above mixtures toform 2 wv solution The solutions were spray-dried usinginlet temperature 90∘C outlet temperature 57ndash60∘C feed rate9mLmin and nitrogen flow rate 350 Lh XRPD studiesof the formulations revealed that while quercetinCMCABhad identical crystallinity quercetinCAAdp showed amor-phous character and quercetinHPMCAS displayed par-tial crystalline character with respect to crude quercetinFTIR spectra of the formulations showed broadening ofpeak at 3300ndash3500 cmminus1 which was attributed to the pres-ence of intermolecular H-bonding between quercetin andmatrix polymer further decreasing crystalline structure ofquercetin A comparison of release profiles of quercetinsolid dispersion with quercetin powder indicated that thesolid dispersions quercetinHPMCA quercetinCMCAB
6 Journal of Pharmaceutics
using low temperaturethermostat bath
Compressionof liquefied Preheating of CO
crystallization vesselthrough metal filter screen
recovered insolvent
recovery kettle
through rotameter
Washing outresidualDMSO
DMSO
Collection ofnanoparticles
High pressurepump Preheater
high pressure infusion pumpFlow of
into vessel
Depressurizationto atmospheric
pressure
2
CO2
supercritical CO2
CO2
Liquefaction of CO2
Apigenin dissolved in DMSO (20 mgmL)a
Infusion rate = 05 mLminb
Delivery of CO
CO2 exhausted out
Apigen in DMSO solutiona
Supercritical conditions of COc2 = 145MPa 35∘C
COc2 to
pumpedd into vessel through
Figure 3 Steps involved in SAS method for preparation of nanoparticles [55]
and quercetinCAAdp showed 14 release after 05 hwhereasthe dissolution of quercetin powder was found to be 07even after 1 h
Inclusion complexes of quercetin have also been reportedfor increasing solubility of quercetin [48] An inclusioncomplex of quercetin was made with 120573-cyclodextrin (120573CD)hydroxypropyl-120573-cyclodextrin (HP-120573CD) and sulfobutylether-120573-cyclodextrin (SBE-120573CD) (ranging from 0 to 001M)The 1 1 complex between quercetin and cyclodextrins led toincreased solubility of quercetin in the order of 120573CD lt HP-120573CD lt SBE-120573CD [49]
222 Flavones They are much less prevalent than flavonolsin fruit and vegetables Flavones primarily contain glycosidesof luteolin and apigenin (Figure 2(f2)) The important savorysources of flavones are parsley and celery C-glycosides offlavones are encompassed in cereals such as millet and wheat[50 51]
Apigenin (AP) It is a naturally occurring flavone chemicallyknown as 4101584057-trihydroxyflavone The most prevalent nat-ural sources of AP are parsley celery and chamomile tea[52] AP belongs to BCS class IIwith poor aqueous solubilityand high permeability in intestine AP was found to possessmaximum solubility 216 120583gmL at pH 75 resulting in lowdissolution and poor bioavailability [53] Various formulationstrategies have been devised to overcome this problem Highshear mixing for preparation of AP smart crystals has beenreported by Al Shaal et al [54] for solubility enhancement ofAP
Smart crystal technology comprehends combination ofdifferent processes pretreatment of poorly soluble drug fol-lowed by high pressure homogenization A macrosuspensionof AP powder and surfactant solution (Plantacare 2000 UP1ww) was formed by high shearmixing (Ultra-Turrax T2510000 rpm) This was followed by seven passages through
bead milling (Buhler PML-2) The formed nanosuspensionwas then subjected to high pressure homogenization (AvestinC50 300 barcycle) The pretreatment step was included toaccelerate nanocrystals production by reducing homogeniza-tion cycles and to decrease particle sizeMillingmediumusedwas zirkonia and yttriawas employed as a stabilizerThemeanparticle size of AP was found to be 439 plusmn 20 nm with a lowPI of 0283 plusmn 0040 Light microscopy studies also presentedevidence supporting the use of surfactant by showing animage with uniform crystal distribution with no signs oflarge crystals and aggregates in the presence of surfactantA zeta potential of minus38mV was reported which indicated awell charged surface and related stability AP coarse powderand nanoparticles showed identical X-ray diffraction (XRD)pattern indicating no decrease in crystallinity DPPH (22-diphenyl-1-picrylhydrazyl) radical scavenging test showed a2-fold increase in antioxidant activity of AP nanoparticles ascompared to AP macrosuspension
Another method for improvement in solubility of AP hasbeen reported by Zhang et al [55] The study incorporatedpreparation of AP nanocrystals via supercritical antisolventmethod (SAS) Figure 3 depicts a schematic representationof preparation of nanoparticles Photon correlation spec-troscopy (PCS) studies revealed the particle size to be 5625 plusmn56 nm with a PI value of 092 plusmn 021 Reduced degree ofcrystallinity was represented in XRPD diagram Differentialscanning calorimetry (DSC) curves of AP coarse powder andAP nanocrystals were studied and compared A decrease inmelting point of AP was observed with nanoparticles whichcould be attributed to particle size reduction to nanometerrange FTIR patterns were identical for both coarse powderand nanoparticles thus indicating the chemical stability of APduring SAS process AP nanocrystals exhibited more rapiddissolution rate with much higher cumulative amount ofdissolved AP than AP coarse powder The higher dissolutionof AP nanocrystals could be due to the enhanced saturated
Journal of Pharmaceutics 7
solubility resulting from a significant decrease of particle size[56] In vivo studies showed 36 and 34 fold enhancement in119862max and AUC of AP respectively after oral administrationof AP nanocrystals The absolute bioavailability of AP coarsepowder was found to be 20 whereas nanoparticles exhib-ited 69 absolute bioavailability Thus improved solubilitydissolution rate and bioavailability depict the usefulnessof these methods for delivery of such BCS class secondcompounds
223 Flavanones They are natural compounds of restrictedoccurrence and are sometimes termed as minor flavonoidsThe cardinal aglycones are naringenin hesperetin and erio-dictyol (Figure 2(f4)) Glycosylation of flavanones is generallyattained by a disaccharide at position 7 which is eithera neohesperidose that imparts a bitter taste (such as tonaringin in grapefruit) or a rutinose which is flavorlessCitrus fruits contain considerable amount of flavanonesTomatoes and certain aromatic plants such as mint alsoconstitute flavanones Hesperidin and narirutin are presentin orange juice at a concentration of 200ndash600mgL and 15ndash85mgL respectively A single glass of orange juice maycontain between 40 and 140mg of flavanone glycosides [57]However very high flavanone content is found to be presentin the solid parts of orange fruit particularly the albedo (thewhite spongy portion) and the membranes separating thesegments Thus an orange fruit may comprise up to 5 timesas much as a glass of orange juice
(1) Hesperetin It is a naturally occurring flavonoid chemicallyknown as 3101584057-trihydroxy-4-methoxyflavanone Hesperetinis found almost exclusively in citrus fruits [58] Studiesrevealed that hesperetin can avert colon [59] urinary bladder[60] and chemically induced mammary carcinogenesis [61]Other biological activities of hesperetin include antioxidant[62] and anti-inflammatory [63] Aqueous solubility of hes-peretin was found to be 14 120583gmL [64] Nanoparticles ofhesperetin by two different methods namely APSP and EPNhave been have been reported to enhance the solubility anddissolution rate [65]
APSP The solvent and antisolvent used in this methodwere ethanol and deionized water respectively The methodcomprised of dissolution of hesperetin in solvent followed byinjection of drug solution into an antisolvent with the help ofsyringe The solution was constantly stirred using magneticstirrer (200ndash1000 rpm) and the flow rate was varied from 2 to10mLmin
EPN Nanoparticles in this method were formed by quickaddition of drug solution containing hesperetin and ethanolinto antisolvent Hexane was used as antisolvent Vacuumdrying was carried out for quick evaporation of solventleading to formation of nanosuspension
Figures 4(a) and 4(b) depict the effect of various param-eters on particle size and solubility of hesperetin by APSPand EPN methods The formulation containing 5mgmLdrug concentration 10mLmin flow rate stirring speed of1000 rpm and solvent antisolvent ratio of 1 20 depicted
highest solubility (988 120583gmL) This was attributed to adecrease in particle size from 34 120583m to 075120583m (revealed bySEM) In case of EPN highest solubility (1117 120583gmL) wasseen in formulation containing 5 120583gmL drug concentrationand 1 20 solvent antisolvent ratioThe DSC studies revealedthat the melting point of nanoparticles prepared by bothmethods was identical to crude hesperetin but enthalpyof fusion was reduced due to reduction in crystallinity ofnanoparticles of hesperetin
(2) Naringenin (NRG) It is a kind of flavanone (4101584057-trihydroxyflvanone) found extremely in tomatoes [66]cherries [67] grape fruit and citrus fruits [58] In addi-tion to antioxidant property [68] NRG also possess anti-inflammatory [69] antitumour [70] and hepatoprotectiveeffects [71] However clinical applicability of NRG is limitedby its low solubility and bioavailability NRG possesses lowaqueous solubility (45 120583gmL) [72] therefore measures weretaken to investigate methods for enhancing solubility ofNRG Transglycosylation of hesperetin leads to an increasein solubility of hesperetin [73] This formed the basis forpreparing spray-dried particles of NRG with 120572-Glucosylhesperidin (Hsp-G) in order to enhance its solubility [72]Different loading ratios of NRGHsp-G (1 1 to 1 20 ww)were dissolved in ethanol water (8 2 vv) solution Theresultant suspension was then subjected to spray drying atthe rate of 10mLmin employing a spray nozzle of diameter406 120583m and pressure of 013MPa The inlet and outlet tem-peratures of drying chamber were 120∘C and 70∘C respec-tively SEM images of NRGHsp-G samples showed sphericalshaped aggregates with average particle size of 3-4 120583mThe resultant spray-dried particles of NRG showed 60-foldimprovement in solubility when loading ratio of NRGHsp-Gwas 1 20
224 Isoflavones They have structural similarities to estro-gens as they have hydroxyl groups in positions 7 and 41015840 ina configuration analogous to that of the hydroxyls in theestradiol molecule (Figure 2(f3)) Although isoflavones arenot steroids they have potential estrogenic activityThis illus-trates their ability to bind to estrogen receptors They possesspseudohormonal properties and are consequently classifiedas phytoestrogens [2] Leguminous plants are the exclusivesource of isoflavones The main source of isoflavones in thehuman diet is soya and its processed products Isoflavonesprincipally contain 3 compounds genistein daidzein andglycitein (concentration ratio of 1 1 02) Factors such asgeographic zone growing conditions and processing of soyaand its manufactured products greatly affect their isoflavonecontent Isoflavone content of soybeans is 580ndash3800mgkgand of soymilk is 30ndash175mgL [74 75]
Genistein It is a naturally occurring plant flavonoid Soyproducts are the richest sources of genistein [76] Chemicalstructure of genistein (4101584057-trihydroxyisoflavone) containsan isoflavone backbone Genistein has beneficial effects inareas of cancer [77] cardiovascular diseases [78] and post-menopausal symptoms [79] Aqueous solubility of genisteinis very poor approximately 081 120583gmL [80] which leads to
8 Journal of Pharmaceutics
205167
121086 075
695 701
815
966 988
0
1
2
3
4
5
6
7
8
9
10
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
Flow rate(mLmin)
210101010
Stirring speed(rpm)
200200
100010001000
S AS
1 101 101 101 201 20
Drug concentration(mgmL)
555
105
(a)
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
S AS
1 101 151 201 201 20
Drug concentration(mgmL)
55
15105
089 072 06 054 045
965
1082 1097 1113 1117
0
2
4
6
8
10
12
(b)
Figure 4 (a) Depicting the effect of various parameters on particle size and solubility of hesperetin by APSP method [65] (b) Depicting theeffect of various parameters on particle size and solubility of hesperetin by EPN method [65]
low bioavailability of the drug A solid dispersion of genisteinin Pluronic F127 polymeric micelles has been reported forsolubility enhancement by Kwon et al [80] An ethanolicsolution of Pluronic F127 was used to dissolve genisteinby constant stirring at 37∘C for 30min The solution whenevaporated led to formation of clear gel-like matrix Additionof water and constant stirring resulted in formation of poly-meric micelles containing genistein The resulting solutionwas filtered employing 045120583m pore size membrane filter toremove any undissolved genistein followed by lyophilizationat minus80∘C Average particle size of genistein loaded polymericmicelles was found to be 2776 plusmn 046 nm with PI of 026 Invitro drug release showed genistein release 48ndash58 in pH 12mediumand 44ndash82 in pH68mediumwhichwas attributedto higher solubilizing ability of polymeric micelles The invivo pharmacokinetic characterization showed an increasein 119862max from 122 to 568120583gmL and decrease in 119905max from055 to 020 h The polymeric micelles also demonstratedenhanced bioavailability thus confirming enhanced genisteinsolubility and release in gastrointestinal tract
23 Stilbenes Stilbenes encompass a group of biologicallyactive compounds however human diet comprises only few
of these (Figure 1(e)) Examplesmay include trans-resveratroland trans-piceid (its natural glycoside)
231 Resveratrol It belongs to a class of naturally occurringpolyphenols known as stilbenes It is mainly present inthe form of trans-resveratrol (3541015840-trihydroxystilbene) inhuman dietThe dietary sources of resveratrol include peanutbutter dark chocolate blueberries and red wine About23mgL of trans-resveratrol is present in red wine [81]Resveratrol exhibits antiangiogenesis [82] cardioprotective[83] anticarcinogenic and anti-inflammatory activities [84]Aqueous solubility of resveratrol was found to be 30 120583gmLthereby limiting pharmaceutical potential of resveratrol [85]Zhang et al [86] reported a method for enhancing solubilityof resveratrol by formulating nanoparticles of resveratrolusing antisolvent precipitation method The ethanolic solu-tion of resveratrol (solvent) was pouredwith vigorous stirring(9000 rpm) into aqueous solution of polymer (antisolvent)resulting into precipitation of resveratrol after 30 s Fourdifferent polymers that is HPMC PVP PEG 400 and P188were employed The solvent antisolvent ratio was kept con-stant at 1 20 Process parameters employed for spray dryingwere 105∘C inlet temperature 50ndash60∘C outlet temperature
Journal of Pharmaceutics 9
Antisolvent precipitationusing a syringe pump
(APSP)
Evaporative precipitationof nanosuspension (EPN)
20 mL of above solution wasfilled in syringe
Magneticstirring
(200ndash1000) rpm
Flow rate (2ndash10 mLmin)
Solution was injected into deionized
Formed nanoparticles were filteredand vacuum-dried
Hexane was added quickly toform nanosuspension
Vacuum drying of nanoparticles
Vacuum appliedusing rotaryevaporator
Conc of curcumin in ethanolmdash5ndash15 mgmLa
Solvent to antisolvent ratiomdash1 10ndash1 20 (vv)b
Curcumin was dissolved in ethanolaCurcumin was dissolved in ethanola
Evaporation of ethanol and hexaneb
waterb
Figure 5 APSP and EPN techniques for nanoparticle formulation of curcumin [92]
1mLmin spray flow rate and 065MPa atomization airpressure The particle size obtained with HPMC PVP PEG400 and P188 was found to be 161 plusmn 3 1156 plusmn 78 2168plusmn 26 and 1644 plusmn 47 nm respectively Dissolution studiesrepresented complete dissolution of resveratrol nanodisper-sion in less than 45min whereas raw resveratrol did notdissolve completely even after 120min indicating increasedwater solubility of resveratrol by using polymers
24 Miscellaneous
241 Curcumin It is a naturally occurring polyphenol whichis extracted from the plants of Curcuma longa Curcumalonga (turmeric) has been used to treat ailments since a longtime ago It is also employed as a spice in Indian cuisineCurcumin exhibits a variety of pharmacological actions suchas antitumor [87] anti-HIV [88] antioxidant and anti-inflammatory [89] However the goodness of curcuminhas not been able to reach up to its potential yet Themaximum solubility of curcumin in plain aqueous bufferpH 50 has been reported to be 11 ngmL [90] and the oraldose of curcumin for treating advanced colorectal cancer wasfound to be 36 gday [91] Therefore there is need to devisestrategies to increase solubility of curcumin Nanoparticlesof curcumin employing antisolvent precipitation method
have been reported by Kakran et al [92] The antisolventprecipitation involved two methods namely antisolvent pre-cipitation using a syringe pump (APSP) and evaporative pre-cipitation of nanosuspension (EPN) In first method ethanolwas used as solvent and deionized water as antisolvent InEPN method solvent was same but antisolvent employedwas hexane Figure 5 depicts a schematic representation oftechniques employed for formulation of nanoparticles Theeffect of process variables such as stirring speed flow ratesolvent antisolvent (S AS) ratio and drug concentrationwas studied on particle size and solubility
An increase in the stirring speed from 200 to 1000 rpmin APSP leads to a decrease in particle size from 550 to500 nm An increase in stirring speed led to intensificationof micromixing between multiphases resulting in decrease inparticle size Similar results were observed with a variationin flow rate of curcumin solution An increase in the flowrate from 2 to 10mLmin led to decrease in length ofcurcumin particles from 2560 to 1860 nm since an increasein flow rate resulted in rapid mixing Further an inverserelationship was reported between amount of antisolventin SAS ratios and particle size With an increase in S ASratio 1 20 from 1 10 a decrease in length and diameter ofcurcumin particles from 1860 and 490 nm to 930 and 340 nmrespectively was reported The drug concentration exhibited
10 Journal of Pharmaceutics
Polystyrenebeads
(467 g)
Curcumin(8820 mg)
Stainlesssteel
chamber(100 mL)
02 mgmLSDS
441 mL ofHPC-SL (5
mgmL)
Curcumincolloidal
suspension
Micronization(3600 rpm
90 min)Collection
ofcurcumin
suspension
Freezedrying
Preparation of nanocrystal solid dispersion
Preparation of amorphous solid dispersion
Curcumin
curcuminof curcumin
Curcumin
90 (vv)dioxane solution Freeze drying
Sieving with twodifferent meshsizes of sieves
dissolved insolvent
Sonicationat room
temp
Formation ofprimary
emulsion ofAddition of
Mixing
aqueousmedium
Formation offine dispersion
HPMC-AS(800 mg)
(200 mg)
Preparation of nanoemulsion formulation
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
belong to class II (low solubility and high permeability)and class IV (low solubility and low permeability) BCSclasses thus limiting activity and potential health benefitsof polyphenols The bioavailability of class II and class IVsubstances may be enhanced by increasing the solubilityand dissolution rate of the drug in the gastrointestinal fluidTable 1 depicts solubility and pharmacokinetic propertiesof some commonly used polyphenols [8ndash15] The solubilityof polyphenols can be enhanced by various techniquesTechniques used for improving solubility include inclusioncomplexes micronization solid dispersion nanosuspensionsolid lipid nanoparticles nanostructured lipid carrier lipo-somes self- emulsifying drug delivery systems (SEDDS)and gel based systems Table 2 depicts some of commonlyemployed methods for increasing the solubility [16ndash23] Thepresent review discusses the various methods used till date to
improve the bioavailability of polyphenols by enhancing theirsolubility
2 Polyphenols Types and Method forSolubility Enhancement
Several higher plants and some edible plants comprehendthousand molecules having a polyphenol structure (ie sev-eral hydroxyl groups on aromatic rings)These molecules arereleased as defense against ultraviolet radiation or aggressionby pathogens and are a kind of secondary metabolites Thepolyphenols are classified on the basis of the number ofphenol rings that they contain and of the structural elementsthat bind these rings to one another These are hence catego-rized into phenolic acids flavonoids stilbenes and lignansFigure 1 depicts the chemical structure of polyphenols
Journal of Pharmaceutics 3
Table2Strategies
toim
proves
olub
ilityof
polyph
enols
Metho
dProcedure
Advantages
Disa
dvantages
Exam
ple
Reference
Nanop
articles
[16ndash
18]
Evaporativep
recipitatio
ninto
aqueou
ssolution
Spraying
ofdrug
solutio
nthroug
han
atom
izer
into
anaqueou
ssolutioncontaining
stabilizer
athigh
temperature
Highdissolutionratehigh
surfa
ceareaenh
anced
wettability
Requ
iresta
bilizerslack
ofcontrolledreleaseno
tsuitable
fortherm
olabile
drugs
Nanosuspension
ofqu
ercetin
[45]
Highpressure
homogenization
Precipitatio
nof
drug
byadditio
nof
antisolvent
inthe
drug
solutio
nleadingto
form
ationof
unstableform
ofdrug
which
issta
bilized
bymeans
ofsin
glerepeated
applicationof
high
energy
follo
wed
bythermal
relaxatio
n(ann
ealin
g)
Redu
cedparticlesiz
eenhanced
dissolution
nocrystalgrowth
Long
processin
gtim
eintro
ductionof
impu
rities
high
energy
requ
irements
chem
icaldegradation
Nanosuspension
ofqu
ercetin
[45]
Antiso
lventm
etho
d
Antiso
lvent
precipitatio
nusing
asyringe
pump
Additio
nof
antisolvent
toas
olutionof
drug
and
solventata
particular
flowrateun
derc
onsta
ntstirr
ing
leadingto
precipitatio
nof
drug
which
isthen
filteredto
collectnano
particles
Redu
cedparticlesiz
ehigh
dissolutionratehighsurfa
ceareareduced
crystallinityfaster
onseto
faction
Con
taminationdu
eto
filtration
Nanop
articleso
fhesperetin
[65]
Evaporative
precipitatio
nof
nano
suspensio
n
Mixingof
awater
misc
iblesolventcon
tainingdrug
with
anantisolvent
follo
wed
byevaporationof
solvents
Decreased
particlesiz
eenhanced
surfa
ceareaimproved
dissolution
Particlegrow
thdu
eto
remaining
organics
olvent
insuspensio
n
Curcum
innano
particles
[92]
Supercritical
antisolvent
metho
d
Precipitatio
nof
drug
from
drug
solutio
nby
mixingit
with
acom
pressedflu
idatits
supercriticalcond
ition
sDiffusionof
solventintoantisolvent
phaseleads
todrug
precipitatio
ndu
etolowsolubilityo
fdruginantisolvent
Highprod
uctp
uritycon
trolled
crystalp
olym
orph
ismpossib
leprocessin
gof
thermolabile
moleculessingles
tepprocess
Toxicityandflammabilityof
solvents
poor
controlof
particlemorph
olog
yincompleter
emovalof
resid
ualsolvent
Apigenin
nano
crystals
[55]
Solid
dispersio
nFo
rmationof
eutecticmixtureso
fdrugs
with
hydrop
hilic
carriersby
meltingtheirp
hysic
almixtures
Particlesiz
ereductio
nim
proved
wettabilityenhanced
dissolution
high
erpo
rosity
Decreaseindissolutionon
agingcrystalgrowth
upon
moistu
reabsorptio
ndemixingph
ases
eparation
Solid
dispersio
nof
ellagica
cid
[19ndash
2137]
Self-microem
ulsifying
drug
deliverysyste
ms
Gentle
mixingof
drug
oilsurfa
ctantandcosurfa
ctant
inaqueou
smedialeadingto
form
ationof
ow
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drug
drop
letswith
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letsize
lt100n
m
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ioavailabilityim
proved
absorptio
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nusinggelatin
capsules
Surfa
ctanttoxicitytedious
manufacturin
gmetho
dinteractionwith
capsules
hell
Curcum
in[2223
96]
4 Journal of Pharmaceutics
Table 3 Different methods for solid dispersions of ellagic acid [37]
Acetone ethanol solution was used to dissolve mixtures ofEApolymer followed by spray drying of the resultantdispersion under operating conditions of 90∘C inlettemperature 57ndash60∘C outlet temperature 9mLmin feedrate and 350 Lh nitrogen flow
EA PVP and CAAdP were dissolved inacetonitrile ethanol solution followed by concentratingthe solution with rotary evaporation
21 Phenolic Acids They are plant derived phenolic com-pounds which are produced via shikimic acid throughphenylpropanoid pathway and have a unique chemical struc-ture of C
6ndashC3 Some phenolic acids are also of microbial
origin containing C6ndashC1linkage These are further classified
into two categories derivatives of cinnamic acid (hydroxycin-namic acids) and derivatives of benzoic acid (hydroxybenzoicacids)
211 The Hydroxycinnamic Acids (Figure 1(b)) They aremore common than the hydroxybenzoic acids and consistmainly of p-coumaric acid caffeic acid ferulic acid andsinapic acid These acids are found in glycosylated forms asderivatives of shikimic acid quinic acid and tartaric acidCaffeic acid combines with quinic acid to form chlorogenicacid (Figure 1(c)) It is found in high concentrations incoffee a single cup may contain 70ndash350mg chlorogenic acid[24] Caffeic acid is the most abundant phenolic acid andrepresents between 75 and 100of the total hydroxycinnamicacid content of most of the fruit All parts of the fruitcontain hydrocinnamic acid but the highest concentrationsare seen in the outer parts of ripe fruit Cereal grains aredietary source of ferulic acid Wheat grains may contain 08ndash2 gkg dry weight of ferulic acid which represents up to 90of total polyphenols [25 26] Since hydroxybenzoic acidspossess sufficient aqueous solubility their absorption is notdissolution limited
212 Hydroxybenzoic Acids (Figure 1(a)) Salient examplesof hydroxybenzoic acids are gallic acid protocatechuic acidellagic acid (EA) and vanillic acid Edible plants for examplered fruits black radish onions and green tea are richin hydroxybenzoic acid content [27] Tea is an importantsource of gallic acid and tea leaves may contain up to45 gkg fresh wt of leaves [24 28] Dietary sources ofEA include walnuts pomegranates and berries [29] EApossesses several health benefits against many diseases suchas breast cancer [30] prostate cancer [31] lung cancer[32] colon cancer [33] cardiovascular disease [34] andneurodegenerative diseases [35] EA was found to possessmaximum solubility of 93 120583gmL [36] This low solubilitywas attributed to high crystallinity of EA due to its planarand symmetrical structure and extensive hydrogen-bonding
resulting in low bioavailability of EA Solid dispersions of EAhave been employed to enhance the solubility of EA Li et al[37] formulated solid dispersions of EA by three differentmethods Table 3 depicted the methods and compositionsof these investigational formulations Fourier transforminfrared spectroscopy (FTIR) studies confirmed the presenceof H-bonding between EA and polymers Scanning electronmicroscope (SEM) studies indicated that EA was present inamorphous form in the solid dispersions The in vitro dis-solution studies revealed that the nature of polymer directlyinfluences the solubility of EA The polymer with morehydrophilic character resulted in higher swelling and fasterrelease of EA Thus the release profile of EA from EAPVPmatrix was 92 (1 h) followed by EAHPMCAS (35 05 h)EACMCAB (18 1 h) and EACAAdP (15ndash17 1 h) Incor-poration of CAAdP in EAPVP solid dispersion led to adecrease in release of EA (62 05 h) EA has been reportedto deteriorate in the solution form due to crystallization andchemical degradation The amount of EA remaining after24 h in solution is only 18 and 80 due to crystallizationand chemical degradation respectively However the soliddispersions were found to significantly enhance the stabilityof EA against crystallization and chemical degradation Fur-ther it was found that HPMCAS amorphous solid dispersionprovided maximum stability to EA [37]
22 Flavonoids These are benzo-120574-pyrone derivatives ofphenolic and pyran rings [38] On the basis of substitutionson three rings flavonoids are classified as flavonols flavonesisoflavones flavanones flavanols and anthocyanidins whichare biotransformed in body by methylation sulfation andglucuronidation of hydroxyl groups Flavonoids predomi-nantly exist as 3-O-glycosides and polymers [39] Chemicalstructure of flavonoids is illustrated in Figure 2
221 Flavonols Among flavonoids flavonols are the mostubiquitous in foods The main representatives of flavonolsare quercetin and kaempferol (Figure 2(f1))The flavonols areprimarily found in onions (up to 12 gkg fresh wt) curlykale leeks broccoli and blueberries Red wine and tea alsocontain up to 45mgL flavonols In nature flavonols arepresent in glycosylated forms in plants The sugar moietyassociated with flavonols is mainly glucose or rhamnose
Figure 2 Classification and chemical structure of flavonoids
but other sugars like galactose arabinose and xylose mayalso be involved Each fruit contains around 5ndash10 differentflavonol glycosides [40] The biosynthesis of flavonols isstimulated by light so these tend to accumulate in theouter and aerial tissues Depending on exposure to sunlightdifferences in concentration exist between fruits on thesame tree and even between different sides of a single fruit[41]
Quercetin It is a naturally occurring polyphenol whichbelongs to a group of plant pigments known as flavonoidsresponsible for the colour of vegetables fruits and flowers[42] Quercetin is a flavonol whose chemical structure isderived from flavone Chemically quercetin is known as334101584057-pentahydroxyflavone Quercetin exhibits variousproperties such as anti-inflammatory antioxidant antihis-tamine and antiarthritis [42] The primary dietary sourcesof quercetin are citrus fruits apple onions parsley sage teaand redwine [43]However despite having all these beneficialactivities poor water solubility (03120583gmL) restricts its usethus highlighting the importance of increasing the solubilityof quercetin [44] Gao et al [45] reported the formationof nanosuspension of quercetin by two techniques Thefirst technique is comprised of evaporative precipitationof quercetin into aqueous solution (EPAS) The organicsolution of quercetin in ethanol was poured slowly into anaqueous solution containing Pluronic F68 (075 wv) andlecithin (025 wv) stabilizers The solution was contin-uously stirred under vacuum Finally ethanol was evapo-rated and EPAS nanosuspension was collected The secondtechnique involved high pressure homogenization (HPH)of quercetin dispersion in Pluronic F68 (075 wv) and
lecithin (025wv) A piston gap high pressure homogenizerwas used to circulate the suspension for two cycles at thepressure of 200 bar and five cycles at 500 bar followed by20 more cycles at 1500 bar resulting in HPH suspensionThe mean particle size polydispersity index (PI) and solu-bility profile of quercetin nanosuspension produced by EPASmethod and HPHmethod were found to be 2826 plusmn 503 nm023 plusmn 008 4224 120583gmL and 2136 plusmn 293 nm 021 plusmn 0102786120583gmL respectively X-ray powder diffraction (XRPD)measurements revealed a crystalline to amorphous phasetransition in EPAS process which was not observed in HPHThis formed the basis for higher increase in solubility ofquercetin in case of EPAS [46]
A solid dispersion of quercetin employing CMCABHPMCAS and CAAdP as polymers has been reported by Liet al [47] Quercetin and polymer mixtures were prepared indifferent ratios of 1 9 1 3 1 1 3 1 and 9 1 Acetone ethanol(1 4) solution was used to dissolve the above mixtures toform 2 wv solution The solutions were spray-dried usinginlet temperature 90∘C outlet temperature 57ndash60∘C feed rate9mLmin and nitrogen flow rate 350 Lh XRPD studiesof the formulations revealed that while quercetinCMCABhad identical crystallinity quercetinCAAdp showed amor-phous character and quercetinHPMCAS displayed par-tial crystalline character with respect to crude quercetinFTIR spectra of the formulations showed broadening ofpeak at 3300ndash3500 cmminus1 which was attributed to the pres-ence of intermolecular H-bonding between quercetin andmatrix polymer further decreasing crystalline structure ofquercetin A comparison of release profiles of quercetinsolid dispersion with quercetin powder indicated that thesolid dispersions quercetinHPMCA quercetinCMCAB
6 Journal of Pharmaceutics
using low temperaturethermostat bath
Compressionof liquefied Preheating of CO
crystallization vesselthrough metal filter screen
recovered insolvent
recovery kettle
through rotameter
Washing outresidualDMSO
DMSO
Collection ofnanoparticles
High pressurepump Preheater
high pressure infusion pumpFlow of
into vessel
Depressurizationto atmospheric
pressure
2
CO2
supercritical CO2
CO2
Liquefaction of CO2
Apigenin dissolved in DMSO (20 mgmL)a
Infusion rate = 05 mLminb
Delivery of CO
CO2 exhausted out
Apigen in DMSO solutiona
Supercritical conditions of COc2 = 145MPa 35∘C
COc2 to
pumpedd into vessel through
Figure 3 Steps involved in SAS method for preparation of nanoparticles [55]
and quercetinCAAdp showed 14 release after 05 hwhereasthe dissolution of quercetin powder was found to be 07even after 1 h
Inclusion complexes of quercetin have also been reportedfor increasing solubility of quercetin [48] An inclusioncomplex of quercetin was made with 120573-cyclodextrin (120573CD)hydroxypropyl-120573-cyclodextrin (HP-120573CD) and sulfobutylether-120573-cyclodextrin (SBE-120573CD) (ranging from 0 to 001M)The 1 1 complex between quercetin and cyclodextrins led toincreased solubility of quercetin in the order of 120573CD lt HP-120573CD lt SBE-120573CD [49]
222 Flavones They are much less prevalent than flavonolsin fruit and vegetables Flavones primarily contain glycosidesof luteolin and apigenin (Figure 2(f2)) The important savorysources of flavones are parsley and celery C-glycosides offlavones are encompassed in cereals such as millet and wheat[50 51]
Apigenin (AP) It is a naturally occurring flavone chemicallyknown as 4101584057-trihydroxyflavone The most prevalent nat-ural sources of AP are parsley celery and chamomile tea[52] AP belongs to BCS class IIwith poor aqueous solubilityand high permeability in intestine AP was found to possessmaximum solubility 216 120583gmL at pH 75 resulting in lowdissolution and poor bioavailability [53] Various formulationstrategies have been devised to overcome this problem Highshear mixing for preparation of AP smart crystals has beenreported by Al Shaal et al [54] for solubility enhancement ofAP
Smart crystal technology comprehends combination ofdifferent processes pretreatment of poorly soluble drug fol-lowed by high pressure homogenization A macrosuspensionof AP powder and surfactant solution (Plantacare 2000 UP1ww) was formed by high shearmixing (Ultra-Turrax T2510000 rpm) This was followed by seven passages through
bead milling (Buhler PML-2) The formed nanosuspensionwas then subjected to high pressure homogenization (AvestinC50 300 barcycle) The pretreatment step was included toaccelerate nanocrystals production by reducing homogeniza-tion cycles and to decrease particle sizeMillingmediumusedwas zirkonia and yttriawas employed as a stabilizerThemeanparticle size of AP was found to be 439 plusmn 20 nm with a lowPI of 0283 plusmn 0040 Light microscopy studies also presentedevidence supporting the use of surfactant by showing animage with uniform crystal distribution with no signs oflarge crystals and aggregates in the presence of surfactantA zeta potential of minus38mV was reported which indicated awell charged surface and related stability AP coarse powderand nanoparticles showed identical X-ray diffraction (XRD)pattern indicating no decrease in crystallinity DPPH (22-diphenyl-1-picrylhydrazyl) radical scavenging test showed a2-fold increase in antioxidant activity of AP nanoparticles ascompared to AP macrosuspension
Another method for improvement in solubility of AP hasbeen reported by Zhang et al [55] The study incorporatedpreparation of AP nanocrystals via supercritical antisolventmethod (SAS) Figure 3 depicts a schematic representationof preparation of nanoparticles Photon correlation spec-troscopy (PCS) studies revealed the particle size to be 5625 plusmn56 nm with a PI value of 092 plusmn 021 Reduced degree ofcrystallinity was represented in XRPD diagram Differentialscanning calorimetry (DSC) curves of AP coarse powder andAP nanocrystals were studied and compared A decrease inmelting point of AP was observed with nanoparticles whichcould be attributed to particle size reduction to nanometerrange FTIR patterns were identical for both coarse powderand nanoparticles thus indicating the chemical stability of APduring SAS process AP nanocrystals exhibited more rapiddissolution rate with much higher cumulative amount ofdissolved AP than AP coarse powder The higher dissolutionof AP nanocrystals could be due to the enhanced saturated
Journal of Pharmaceutics 7
solubility resulting from a significant decrease of particle size[56] In vivo studies showed 36 and 34 fold enhancement in119862max and AUC of AP respectively after oral administrationof AP nanocrystals The absolute bioavailability of AP coarsepowder was found to be 20 whereas nanoparticles exhib-ited 69 absolute bioavailability Thus improved solubilitydissolution rate and bioavailability depict the usefulnessof these methods for delivery of such BCS class secondcompounds
223 Flavanones They are natural compounds of restrictedoccurrence and are sometimes termed as minor flavonoidsThe cardinal aglycones are naringenin hesperetin and erio-dictyol (Figure 2(f4)) Glycosylation of flavanones is generallyattained by a disaccharide at position 7 which is eithera neohesperidose that imparts a bitter taste (such as tonaringin in grapefruit) or a rutinose which is flavorlessCitrus fruits contain considerable amount of flavanonesTomatoes and certain aromatic plants such as mint alsoconstitute flavanones Hesperidin and narirutin are presentin orange juice at a concentration of 200ndash600mgL and 15ndash85mgL respectively A single glass of orange juice maycontain between 40 and 140mg of flavanone glycosides [57]However very high flavanone content is found to be presentin the solid parts of orange fruit particularly the albedo (thewhite spongy portion) and the membranes separating thesegments Thus an orange fruit may comprise up to 5 timesas much as a glass of orange juice
(1) Hesperetin It is a naturally occurring flavonoid chemicallyknown as 3101584057-trihydroxy-4-methoxyflavanone Hesperetinis found almost exclusively in citrus fruits [58] Studiesrevealed that hesperetin can avert colon [59] urinary bladder[60] and chemically induced mammary carcinogenesis [61]Other biological activities of hesperetin include antioxidant[62] and anti-inflammatory [63] Aqueous solubility of hes-peretin was found to be 14 120583gmL [64] Nanoparticles ofhesperetin by two different methods namely APSP and EPNhave been have been reported to enhance the solubility anddissolution rate [65]
APSP The solvent and antisolvent used in this methodwere ethanol and deionized water respectively The methodcomprised of dissolution of hesperetin in solvent followed byinjection of drug solution into an antisolvent with the help ofsyringe The solution was constantly stirred using magneticstirrer (200ndash1000 rpm) and the flow rate was varied from 2 to10mLmin
EPN Nanoparticles in this method were formed by quickaddition of drug solution containing hesperetin and ethanolinto antisolvent Hexane was used as antisolvent Vacuumdrying was carried out for quick evaporation of solventleading to formation of nanosuspension
Figures 4(a) and 4(b) depict the effect of various param-eters on particle size and solubility of hesperetin by APSPand EPN methods The formulation containing 5mgmLdrug concentration 10mLmin flow rate stirring speed of1000 rpm and solvent antisolvent ratio of 1 20 depicted
highest solubility (988 120583gmL) This was attributed to adecrease in particle size from 34 120583m to 075120583m (revealed bySEM) In case of EPN highest solubility (1117 120583gmL) wasseen in formulation containing 5 120583gmL drug concentrationand 1 20 solvent antisolvent ratioThe DSC studies revealedthat the melting point of nanoparticles prepared by bothmethods was identical to crude hesperetin but enthalpyof fusion was reduced due to reduction in crystallinity ofnanoparticles of hesperetin
(2) Naringenin (NRG) It is a kind of flavanone (4101584057-trihydroxyflvanone) found extremely in tomatoes [66]cherries [67] grape fruit and citrus fruits [58] In addi-tion to antioxidant property [68] NRG also possess anti-inflammatory [69] antitumour [70] and hepatoprotectiveeffects [71] However clinical applicability of NRG is limitedby its low solubility and bioavailability NRG possesses lowaqueous solubility (45 120583gmL) [72] therefore measures weretaken to investigate methods for enhancing solubility ofNRG Transglycosylation of hesperetin leads to an increasein solubility of hesperetin [73] This formed the basis forpreparing spray-dried particles of NRG with 120572-Glucosylhesperidin (Hsp-G) in order to enhance its solubility [72]Different loading ratios of NRGHsp-G (1 1 to 1 20 ww)were dissolved in ethanol water (8 2 vv) solution Theresultant suspension was then subjected to spray drying atthe rate of 10mLmin employing a spray nozzle of diameter406 120583m and pressure of 013MPa The inlet and outlet tem-peratures of drying chamber were 120∘C and 70∘C respec-tively SEM images of NRGHsp-G samples showed sphericalshaped aggregates with average particle size of 3-4 120583mThe resultant spray-dried particles of NRG showed 60-foldimprovement in solubility when loading ratio of NRGHsp-Gwas 1 20
224 Isoflavones They have structural similarities to estro-gens as they have hydroxyl groups in positions 7 and 41015840 ina configuration analogous to that of the hydroxyls in theestradiol molecule (Figure 2(f3)) Although isoflavones arenot steroids they have potential estrogenic activityThis illus-trates their ability to bind to estrogen receptors They possesspseudohormonal properties and are consequently classifiedas phytoestrogens [2] Leguminous plants are the exclusivesource of isoflavones The main source of isoflavones in thehuman diet is soya and its processed products Isoflavonesprincipally contain 3 compounds genistein daidzein andglycitein (concentration ratio of 1 1 02) Factors such asgeographic zone growing conditions and processing of soyaand its manufactured products greatly affect their isoflavonecontent Isoflavone content of soybeans is 580ndash3800mgkgand of soymilk is 30ndash175mgL [74 75]
Genistein It is a naturally occurring plant flavonoid Soyproducts are the richest sources of genistein [76] Chemicalstructure of genistein (4101584057-trihydroxyisoflavone) containsan isoflavone backbone Genistein has beneficial effects inareas of cancer [77] cardiovascular diseases [78] and post-menopausal symptoms [79] Aqueous solubility of genisteinis very poor approximately 081 120583gmL [80] which leads to
8 Journal of Pharmaceutics
205167
121086 075
695 701
815
966 988
0
1
2
3
4
5
6
7
8
9
10
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
Flow rate(mLmin)
210101010
Stirring speed(rpm)
200200
100010001000
S AS
1 101 101 101 201 20
Drug concentration(mgmL)
555
105
(a)
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
S AS
1 101 151 201 201 20
Drug concentration(mgmL)
55
15105
089 072 06 054 045
965
1082 1097 1113 1117
0
2
4
6
8
10
12
(b)
Figure 4 (a) Depicting the effect of various parameters on particle size and solubility of hesperetin by APSP method [65] (b) Depicting theeffect of various parameters on particle size and solubility of hesperetin by EPN method [65]
low bioavailability of the drug A solid dispersion of genisteinin Pluronic F127 polymeric micelles has been reported forsolubility enhancement by Kwon et al [80] An ethanolicsolution of Pluronic F127 was used to dissolve genisteinby constant stirring at 37∘C for 30min The solution whenevaporated led to formation of clear gel-like matrix Additionof water and constant stirring resulted in formation of poly-meric micelles containing genistein The resulting solutionwas filtered employing 045120583m pore size membrane filter toremove any undissolved genistein followed by lyophilizationat minus80∘C Average particle size of genistein loaded polymericmicelles was found to be 2776 plusmn 046 nm with PI of 026 Invitro drug release showed genistein release 48ndash58 in pH 12mediumand 44ndash82 in pH68mediumwhichwas attributedto higher solubilizing ability of polymeric micelles The invivo pharmacokinetic characterization showed an increasein 119862max from 122 to 568120583gmL and decrease in 119905max from055 to 020 h The polymeric micelles also demonstratedenhanced bioavailability thus confirming enhanced genisteinsolubility and release in gastrointestinal tract
23 Stilbenes Stilbenes encompass a group of biologicallyactive compounds however human diet comprises only few
of these (Figure 1(e)) Examplesmay include trans-resveratroland trans-piceid (its natural glycoside)
231 Resveratrol It belongs to a class of naturally occurringpolyphenols known as stilbenes It is mainly present inthe form of trans-resveratrol (3541015840-trihydroxystilbene) inhuman dietThe dietary sources of resveratrol include peanutbutter dark chocolate blueberries and red wine About23mgL of trans-resveratrol is present in red wine [81]Resveratrol exhibits antiangiogenesis [82] cardioprotective[83] anticarcinogenic and anti-inflammatory activities [84]Aqueous solubility of resveratrol was found to be 30 120583gmLthereby limiting pharmaceutical potential of resveratrol [85]Zhang et al [86] reported a method for enhancing solubilityof resveratrol by formulating nanoparticles of resveratrolusing antisolvent precipitation method The ethanolic solu-tion of resveratrol (solvent) was pouredwith vigorous stirring(9000 rpm) into aqueous solution of polymer (antisolvent)resulting into precipitation of resveratrol after 30 s Fourdifferent polymers that is HPMC PVP PEG 400 and P188were employed The solvent antisolvent ratio was kept con-stant at 1 20 Process parameters employed for spray dryingwere 105∘C inlet temperature 50ndash60∘C outlet temperature
Journal of Pharmaceutics 9
Antisolvent precipitationusing a syringe pump
(APSP)
Evaporative precipitationof nanosuspension (EPN)
20 mL of above solution wasfilled in syringe
Magneticstirring
(200ndash1000) rpm
Flow rate (2ndash10 mLmin)
Solution was injected into deionized
Formed nanoparticles were filteredand vacuum-dried
Hexane was added quickly toform nanosuspension
Vacuum drying of nanoparticles
Vacuum appliedusing rotaryevaporator
Conc of curcumin in ethanolmdash5ndash15 mgmLa
Solvent to antisolvent ratiomdash1 10ndash1 20 (vv)b
Curcumin was dissolved in ethanolaCurcumin was dissolved in ethanola
Evaporation of ethanol and hexaneb
waterb
Figure 5 APSP and EPN techniques for nanoparticle formulation of curcumin [92]
1mLmin spray flow rate and 065MPa atomization airpressure The particle size obtained with HPMC PVP PEG400 and P188 was found to be 161 plusmn 3 1156 plusmn 78 2168plusmn 26 and 1644 plusmn 47 nm respectively Dissolution studiesrepresented complete dissolution of resveratrol nanodisper-sion in less than 45min whereas raw resveratrol did notdissolve completely even after 120min indicating increasedwater solubility of resveratrol by using polymers
24 Miscellaneous
241 Curcumin It is a naturally occurring polyphenol whichis extracted from the plants of Curcuma longa Curcumalonga (turmeric) has been used to treat ailments since a longtime ago It is also employed as a spice in Indian cuisineCurcumin exhibits a variety of pharmacological actions suchas antitumor [87] anti-HIV [88] antioxidant and anti-inflammatory [89] However the goodness of curcuminhas not been able to reach up to its potential yet Themaximum solubility of curcumin in plain aqueous bufferpH 50 has been reported to be 11 ngmL [90] and the oraldose of curcumin for treating advanced colorectal cancer wasfound to be 36 gday [91] Therefore there is need to devisestrategies to increase solubility of curcumin Nanoparticlesof curcumin employing antisolvent precipitation method
have been reported by Kakran et al [92] The antisolventprecipitation involved two methods namely antisolvent pre-cipitation using a syringe pump (APSP) and evaporative pre-cipitation of nanosuspension (EPN) In first method ethanolwas used as solvent and deionized water as antisolvent InEPN method solvent was same but antisolvent employedwas hexane Figure 5 depicts a schematic representation oftechniques employed for formulation of nanoparticles Theeffect of process variables such as stirring speed flow ratesolvent antisolvent (S AS) ratio and drug concentrationwas studied on particle size and solubility
An increase in the stirring speed from 200 to 1000 rpmin APSP leads to a decrease in particle size from 550 to500 nm An increase in stirring speed led to intensificationof micromixing between multiphases resulting in decrease inparticle size Similar results were observed with a variationin flow rate of curcumin solution An increase in the flowrate from 2 to 10mLmin led to decrease in length ofcurcumin particles from 2560 to 1860 nm since an increasein flow rate resulted in rapid mixing Further an inverserelationship was reported between amount of antisolventin SAS ratios and particle size With an increase in S ASratio 1 20 from 1 10 a decrease in length and diameter ofcurcumin particles from 1860 and 490 nm to 930 and 340 nmrespectively was reported The drug concentration exhibited
10 Journal of Pharmaceutics
Polystyrenebeads
(467 g)
Curcumin(8820 mg)
Stainlesssteel
chamber(100 mL)
02 mgmLSDS
441 mL ofHPC-SL (5
mgmL)
Curcumincolloidal
suspension
Micronization(3600 rpm
90 min)Collection
ofcurcumin
suspension
Freezedrying
Preparation of nanocrystal solid dispersion
Preparation of amorphous solid dispersion
Curcumin
curcuminof curcumin
Curcumin
90 (vv)dioxane solution Freeze drying
Sieving with twodifferent meshsizes of sieves
dissolved insolvent
Sonicationat room
temp
Formation ofprimary
emulsion ofAddition of
Mixing
aqueousmedium
Formation offine dispersion
HPMC-AS(800 mg)
(200 mg)
Preparation of nanoemulsion formulation
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Acetone ethanol solution was used to dissolve mixtures ofEApolymer followed by spray drying of the resultantdispersion under operating conditions of 90∘C inlettemperature 57ndash60∘C outlet temperature 9mLmin feedrate and 350 Lh nitrogen flow
EA PVP and CAAdP were dissolved inacetonitrile ethanol solution followed by concentratingthe solution with rotary evaporation
21 Phenolic Acids They are plant derived phenolic com-pounds which are produced via shikimic acid throughphenylpropanoid pathway and have a unique chemical struc-ture of C
6ndashC3 Some phenolic acids are also of microbial
origin containing C6ndashC1linkage These are further classified
into two categories derivatives of cinnamic acid (hydroxycin-namic acids) and derivatives of benzoic acid (hydroxybenzoicacids)
211 The Hydroxycinnamic Acids (Figure 1(b)) They aremore common than the hydroxybenzoic acids and consistmainly of p-coumaric acid caffeic acid ferulic acid andsinapic acid These acids are found in glycosylated forms asderivatives of shikimic acid quinic acid and tartaric acidCaffeic acid combines with quinic acid to form chlorogenicacid (Figure 1(c)) It is found in high concentrations incoffee a single cup may contain 70ndash350mg chlorogenic acid[24] Caffeic acid is the most abundant phenolic acid andrepresents between 75 and 100of the total hydroxycinnamicacid content of most of the fruit All parts of the fruitcontain hydrocinnamic acid but the highest concentrationsare seen in the outer parts of ripe fruit Cereal grains aredietary source of ferulic acid Wheat grains may contain 08ndash2 gkg dry weight of ferulic acid which represents up to 90of total polyphenols [25 26] Since hydroxybenzoic acidspossess sufficient aqueous solubility their absorption is notdissolution limited
212 Hydroxybenzoic Acids (Figure 1(a)) Salient examplesof hydroxybenzoic acids are gallic acid protocatechuic acidellagic acid (EA) and vanillic acid Edible plants for examplered fruits black radish onions and green tea are richin hydroxybenzoic acid content [27] Tea is an importantsource of gallic acid and tea leaves may contain up to45 gkg fresh wt of leaves [24 28] Dietary sources ofEA include walnuts pomegranates and berries [29] EApossesses several health benefits against many diseases suchas breast cancer [30] prostate cancer [31] lung cancer[32] colon cancer [33] cardiovascular disease [34] andneurodegenerative diseases [35] EA was found to possessmaximum solubility of 93 120583gmL [36] This low solubilitywas attributed to high crystallinity of EA due to its planarand symmetrical structure and extensive hydrogen-bonding
resulting in low bioavailability of EA Solid dispersions of EAhave been employed to enhance the solubility of EA Li et al[37] formulated solid dispersions of EA by three differentmethods Table 3 depicted the methods and compositionsof these investigational formulations Fourier transforminfrared spectroscopy (FTIR) studies confirmed the presenceof H-bonding between EA and polymers Scanning electronmicroscope (SEM) studies indicated that EA was present inamorphous form in the solid dispersions The in vitro dis-solution studies revealed that the nature of polymer directlyinfluences the solubility of EA The polymer with morehydrophilic character resulted in higher swelling and fasterrelease of EA Thus the release profile of EA from EAPVPmatrix was 92 (1 h) followed by EAHPMCAS (35 05 h)EACMCAB (18 1 h) and EACAAdP (15ndash17 1 h) Incor-poration of CAAdP in EAPVP solid dispersion led to adecrease in release of EA (62 05 h) EA has been reportedto deteriorate in the solution form due to crystallization andchemical degradation The amount of EA remaining after24 h in solution is only 18 and 80 due to crystallizationand chemical degradation respectively However the soliddispersions were found to significantly enhance the stabilityof EA against crystallization and chemical degradation Fur-ther it was found that HPMCAS amorphous solid dispersionprovided maximum stability to EA [37]
22 Flavonoids These are benzo-120574-pyrone derivatives ofphenolic and pyran rings [38] On the basis of substitutionson three rings flavonoids are classified as flavonols flavonesisoflavones flavanones flavanols and anthocyanidins whichare biotransformed in body by methylation sulfation andglucuronidation of hydroxyl groups Flavonoids predomi-nantly exist as 3-O-glycosides and polymers [39] Chemicalstructure of flavonoids is illustrated in Figure 2
221 Flavonols Among flavonoids flavonols are the mostubiquitous in foods The main representatives of flavonolsare quercetin and kaempferol (Figure 2(f1))The flavonols areprimarily found in onions (up to 12 gkg fresh wt) curlykale leeks broccoli and blueberries Red wine and tea alsocontain up to 45mgL flavonols In nature flavonols arepresent in glycosylated forms in plants The sugar moietyassociated with flavonols is mainly glucose or rhamnose
Figure 2 Classification and chemical structure of flavonoids
but other sugars like galactose arabinose and xylose mayalso be involved Each fruit contains around 5ndash10 differentflavonol glycosides [40] The biosynthesis of flavonols isstimulated by light so these tend to accumulate in theouter and aerial tissues Depending on exposure to sunlightdifferences in concentration exist between fruits on thesame tree and even between different sides of a single fruit[41]
Quercetin It is a naturally occurring polyphenol whichbelongs to a group of plant pigments known as flavonoidsresponsible for the colour of vegetables fruits and flowers[42] Quercetin is a flavonol whose chemical structure isderived from flavone Chemically quercetin is known as334101584057-pentahydroxyflavone Quercetin exhibits variousproperties such as anti-inflammatory antioxidant antihis-tamine and antiarthritis [42] The primary dietary sourcesof quercetin are citrus fruits apple onions parsley sage teaand redwine [43]However despite having all these beneficialactivities poor water solubility (03120583gmL) restricts its usethus highlighting the importance of increasing the solubilityof quercetin [44] Gao et al [45] reported the formationof nanosuspension of quercetin by two techniques Thefirst technique is comprised of evaporative precipitationof quercetin into aqueous solution (EPAS) The organicsolution of quercetin in ethanol was poured slowly into anaqueous solution containing Pluronic F68 (075 wv) andlecithin (025 wv) stabilizers The solution was contin-uously stirred under vacuum Finally ethanol was evapo-rated and EPAS nanosuspension was collected The secondtechnique involved high pressure homogenization (HPH)of quercetin dispersion in Pluronic F68 (075 wv) and
lecithin (025wv) A piston gap high pressure homogenizerwas used to circulate the suspension for two cycles at thepressure of 200 bar and five cycles at 500 bar followed by20 more cycles at 1500 bar resulting in HPH suspensionThe mean particle size polydispersity index (PI) and solu-bility profile of quercetin nanosuspension produced by EPASmethod and HPHmethod were found to be 2826 plusmn 503 nm023 plusmn 008 4224 120583gmL and 2136 plusmn 293 nm 021 plusmn 0102786120583gmL respectively X-ray powder diffraction (XRPD)measurements revealed a crystalline to amorphous phasetransition in EPAS process which was not observed in HPHThis formed the basis for higher increase in solubility ofquercetin in case of EPAS [46]
A solid dispersion of quercetin employing CMCABHPMCAS and CAAdP as polymers has been reported by Liet al [47] Quercetin and polymer mixtures were prepared indifferent ratios of 1 9 1 3 1 1 3 1 and 9 1 Acetone ethanol(1 4) solution was used to dissolve the above mixtures toform 2 wv solution The solutions were spray-dried usinginlet temperature 90∘C outlet temperature 57ndash60∘C feed rate9mLmin and nitrogen flow rate 350 Lh XRPD studiesof the formulations revealed that while quercetinCMCABhad identical crystallinity quercetinCAAdp showed amor-phous character and quercetinHPMCAS displayed par-tial crystalline character with respect to crude quercetinFTIR spectra of the formulations showed broadening ofpeak at 3300ndash3500 cmminus1 which was attributed to the pres-ence of intermolecular H-bonding between quercetin andmatrix polymer further decreasing crystalline structure ofquercetin A comparison of release profiles of quercetinsolid dispersion with quercetin powder indicated that thesolid dispersions quercetinHPMCA quercetinCMCAB
6 Journal of Pharmaceutics
using low temperaturethermostat bath
Compressionof liquefied Preheating of CO
crystallization vesselthrough metal filter screen
recovered insolvent
recovery kettle
through rotameter
Washing outresidualDMSO
DMSO
Collection ofnanoparticles
High pressurepump Preheater
high pressure infusion pumpFlow of
into vessel
Depressurizationto atmospheric
pressure
2
CO2
supercritical CO2
CO2
Liquefaction of CO2
Apigenin dissolved in DMSO (20 mgmL)a
Infusion rate = 05 mLminb
Delivery of CO
CO2 exhausted out
Apigen in DMSO solutiona
Supercritical conditions of COc2 = 145MPa 35∘C
COc2 to
pumpedd into vessel through
Figure 3 Steps involved in SAS method for preparation of nanoparticles [55]
and quercetinCAAdp showed 14 release after 05 hwhereasthe dissolution of quercetin powder was found to be 07even after 1 h
Inclusion complexes of quercetin have also been reportedfor increasing solubility of quercetin [48] An inclusioncomplex of quercetin was made with 120573-cyclodextrin (120573CD)hydroxypropyl-120573-cyclodextrin (HP-120573CD) and sulfobutylether-120573-cyclodextrin (SBE-120573CD) (ranging from 0 to 001M)The 1 1 complex between quercetin and cyclodextrins led toincreased solubility of quercetin in the order of 120573CD lt HP-120573CD lt SBE-120573CD [49]
222 Flavones They are much less prevalent than flavonolsin fruit and vegetables Flavones primarily contain glycosidesof luteolin and apigenin (Figure 2(f2)) The important savorysources of flavones are parsley and celery C-glycosides offlavones are encompassed in cereals such as millet and wheat[50 51]
Apigenin (AP) It is a naturally occurring flavone chemicallyknown as 4101584057-trihydroxyflavone The most prevalent nat-ural sources of AP are parsley celery and chamomile tea[52] AP belongs to BCS class IIwith poor aqueous solubilityand high permeability in intestine AP was found to possessmaximum solubility 216 120583gmL at pH 75 resulting in lowdissolution and poor bioavailability [53] Various formulationstrategies have been devised to overcome this problem Highshear mixing for preparation of AP smart crystals has beenreported by Al Shaal et al [54] for solubility enhancement ofAP
Smart crystal technology comprehends combination ofdifferent processes pretreatment of poorly soluble drug fol-lowed by high pressure homogenization A macrosuspensionof AP powder and surfactant solution (Plantacare 2000 UP1ww) was formed by high shearmixing (Ultra-Turrax T2510000 rpm) This was followed by seven passages through
bead milling (Buhler PML-2) The formed nanosuspensionwas then subjected to high pressure homogenization (AvestinC50 300 barcycle) The pretreatment step was included toaccelerate nanocrystals production by reducing homogeniza-tion cycles and to decrease particle sizeMillingmediumusedwas zirkonia and yttriawas employed as a stabilizerThemeanparticle size of AP was found to be 439 plusmn 20 nm with a lowPI of 0283 plusmn 0040 Light microscopy studies also presentedevidence supporting the use of surfactant by showing animage with uniform crystal distribution with no signs oflarge crystals and aggregates in the presence of surfactantA zeta potential of minus38mV was reported which indicated awell charged surface and related stability AP coarse powderand nanoparticles showed identical X-ray diffraction (XRD)pattern indicating no decrease in crystallinity DPPH (22-diphenyl-1-picrylhydrazyl) radical scavenging test showed a2-fold increase in antioxidant activity of AP nanoparticles ascompared to AP macrosuspension
Another method for improvement in solubility of AP hasbeen reported by Zhang et al [55] The study incorporatedpreparation of AP nanocrystals via supercritical antisolventmethod (SAS) Figure 3 depicts a schematic representationof preparation of nanoparticles Photon correlation spec-troscopy (PCS) studies revealed the particle size to be 5625 plusmn56 nm with a PI value of 092 plusmn 021 Reduced degree ofcrystallinity was represented in XRPD diagram Differentialscanning calorimetry (DSC) curves of AP coarse powder andAP nanocrystals were studied and compared A decrease inmelting point of AP was observed with nanoparticles whichcould be attributed to particle size reduction to nanometerrange FTIR patterns were identical for both coarse powderand nanoparticles thus indicating the chemical stability of APduring SAS process AP nanocrystals exhibited more rapiddissolution rate with much higher cumulative amount ofdissolved AP than AP coarse powder The higher dissolutionof AP nanocrystals could be due to the enhanced saturated
Journal of Pharmaceutics 7
solubility resulting from a significant decrease of particle size[56] In vivo studies showed 36 and 34 fold enhancement in119862max and AUC of AP respectively after oral administrationof AP nanocrystals The absolute bioavailability of AP coarsepowder was found to be 20 whereas nanoparticles exhib-ited 69 absolute bioavailability Thus improved solubilitydissolution rate and bioavailability depict the usefulnessof these methods for delivery of such BCS class secondcompounds
223 Flavanones They are natural compounds of restrictedoccurrence and are sometimes termed as minor flavonoidsThe cardinal aglycones are naringenin hesperetin and erio-dictyol (Figure 2(f4)) Glycosylation of flavanones is generallyattained by a disaccharide at position 7 which is eithera neohesperidose that imparts a bitter taste (such as tonaringin in grapefruit) or a rutinose which is flavorlessCitrus fruits contain considerable amount of flavanonesTomatoes and certain aromatic plants such as mint alsoconstitute flavanones Hesperidin and narirutin are presentin orange juice at a concentration of 200ndash600mgL and 15ndash85mgL respectively A single glass of orange juice maycontain between 40 and 140mg of flavanone glycosides [57]However very high flavanone content is found to be presentin the solid parts of orange fruit particularly the albedo (thewhite spongy portion) and the membranes separating thesegments Thus an orange fruit may comprise up to 5 timesas much as a glass of orange juice
(1) Hesperetin It is a naturally occurring flavonoid chemicallyknown as 3101584057-trihydroxy-4-methoxyflavanone Hesperetinis found almost exclusively in citrus fruits [58] Studiesrevealed that hesperetin can avert colon [59] urinary bladder[60] and chemically induced mammary carcinogenesis [61]Other biological activities of hesperetin include antioxidant[62] and anti-inflammatory [63] Aqueous solubility of hes-peretin was found to be 14 120583gmL [64] Nanoparticles ofhesperetin by two different methods namely APSP and EPNhave been have been reported to enhance the solubility anddissolution rate [65]
APSP The solvent and antisolvent used in this methodwere ethanol and deionized water respectively The methodcomprised of dissolution of hesperetin in solvent followed byinjection of drug solution into an antisolvent with the help ofsyringe The solution was constantly stirred using magneticstirrer (200ndash1000 rpm) and the flow rate was varied from 2 to10mLmin
EPN Nanoparticles in this method were formed by quickaddition of drug solution containing hesperetin and ethanolinto antisolvent Hexane was used as antisolvent Vacuumdrying was carried out for quick evaporation of solventleading to formation of nanosuspension
Figures 4(a) and 4(b) depict the effect of various param-eters on particle size and solubility of hesperetin by APSPand EPN methods The formulation containing 5mgmLdrug concentration 10mLmin flow rate stirring speed of1000 rpm and solvent antisolvent ratio of 1 20 depicted
highest solubility (988 120583gmL) This was attributed to adecrease in particle size from 34 120583m to 075120583m (revealed bySEM) In case of EPN highest solubility (1117 120583gmL) wasseen in formulation containing 5 120583gmL drug concentrationand 1 20 solvent antisolvent ratioThe DSC studies revealedthat the melting point of nanoparticles prepared by bothmethods was identical to crude hesperetin but enthalpyof fusion was reduced due to reduction in crystallinity ofnanoparticles of hesperetin
(2) Naringenin (NRG) It is a kind of flavanone (4101584057-trihydroxyflvanone) found extremely in tomatoes [66]cherries [67] grape fruit and citrus fruits [58] In addi-tion to antioxidant property [68] NRG also possess anti-inflammatory [69] antitumour [70] and hepatoprotectiveeffects [71] However clinical applicability of NRG is limitedby its low solubility and bioavailability NRG possesses lowaqueous solubility (45 120583gmL) [72] therefore measures weretaken to investigate methods for enhancing solubility ofNRG Transglycosylation of hesperetin leads to an increasein solubility of hesperetin [73] This formed the basis forpreparing spray-dried particles of NRG with 120572-Glucosylhesperidin (Hsp-G) in order to enhance its solubility [72]Different loading ratios of NRGHsp-G (1 1 to 1 20 ww)were dissolved in ethanol water (8 2 vv) solution Theresultant suspension was then subjected to spray drying atthe rate of 10mLmin employing a spray nozzle of diameter406 120583m and pressure of 013MPa The inlet and outlet tem-peratures of drying chamber were 120∘C and 70∘C respec-tively SEM images of NRGHsp-G samples showed sphericalshaped aggregates with average particle size of 3-4 120583mThe resultant spray-dried particles of NRG showed 60-foldimprovement in solubility when loading ratio of NRGHsp-Gwas 1 20
224 Isoflavones They have structural similarities to estro-gens as they have hydroxyl groups in positions 7 and 41015840 ina configuration analogous to that of the hydroxyls in theestradiol molecule (Figure 2(f3)) Although isoflavones arenot steroids they have potential estrogenic activityThis illus-trates their ability to bind to estrogen receptors They possesspseudohormonal properties and are consequently classifiedas phytoestrogens [2] Leguminous plants are the exclusivesource of isoflavones The main source of isoflavones in thehuman diet is soya and its processed products Isoflavonesprincipally contain 3 compounds genistein daidzein andglycitein (concentration ratio of 1 1 02) Factors such asgeographic zone growing conditions and processing of soyaand its manufactured products greatly affect their isoflavonecontent Isoflavone content of soybeans is 580ndash3800mgkgand of soymilk is 30ndash175mgL [74 75]
Genistein It is a naturally occurring plant flavonoid Soyproducts are the richest sources of genistein [76] Chemicalstructure of genistein (4101584057-trihydroxyisoflavone) containsan isoflavone backbone Genistein has beneficial effects inareas of cancer [77] cardiovascular diseases [78] and post-menopausal symptoms [79] Aqueous solubility of genisteinis very poor approximately 081 120583gmL [80] which leads to
8 Journal of Pharmaceutics
205167
121086 075
695 701
815
966 988
0
1
2
3
4
5
6
7
8
9
10
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
Flow rate(mLmin)
210101010
Stirring speed(rpm)
200200
100010001000
S AS
1 101 101 101 201 20
Drug concentration(mgmL)
555
105
(a)
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
S AS
1 101 151 201 201 20
Drug concentration(mgmL)
55
15105
089 072 06 054 045
965
1082 1097 1113 1117
0
2
4
6
8
10
12
(b)
Figure 4 (a) Depicting the effect of various parameters on particle size and solubility of hesperetin by APSP method [65] (b) Depicting theeffect of various parameters on particle size and solubility of hesperetin by EPN method [65]
low bioavailability of the drug A solid dispersion of genisteinin Pluronic F127 polymeric micelles has been reported forsolubility enhancement by Kwon et al [80] An ethanolicsolution of Pluronic F127 was used to dissolve genisteinby constant stirring at 37∘C for 30min The solution whenevaporated led to formation of clear gel-like matrix Additionof water and constant stirring resulted in formation of poly-meric micelles containing genistein The resulting solutionwas filtered employing 045120583m pore size membrane filter toremove any undissolved genistein followed by lyophilizationat minus80∘C Average particle size of genistein loaded polymericmicelles was found to be 2776 plusmn 046 nm with PI of 026 Invitro drug release showed genistein release 48ndash58 in pH 12mediumand 44ndash82 in pH68mediumwhichwas attributedto higher solubilizing ability of polymeric micelles The invivo pharmacokinetic characterization showed an increasein 119862max from 122 to 568120583gmL and decrease in 119905max from055 to 020 h The polymeric micelles also demonstratedenhanced bioavailability thus confirming enhanced genisteinsolubility and release in gastrointestinal tract
23 Stilbenes Stilbenes encompass a group of biologicallyactive compounds however human diet comprises only few
of these (Figure 1(e)) Examplesmay include trans-resveratroland trans-piceid (its natural glycoside)
231 Resveratrol It belongs to a class of naturally occurringpolyphenols known as stilbenes It is mainly present inthe form of trans-resveratrol (3541015840-trihydroxystilbene) inhuman dietThe dietary sources of resveratrol include peanutbutter dark chocolate blueberries and red wine About23mgL of trans-resveratrol is present in red wine [81]Resveratrol exhibits antiangiogenesis [82] cardioprotective[83] anticarcinogenic and anti-inflammatory activities [84]Aqueous solubility of resveratrol was found to be 30 120583gmLthereby limiting pharmaceutical potential of resveratrol [85]Zhang et al [86] reported a method for enhancing solubilityof resveratrol by formulating nanoparticles of resveratrolusing antisolvent precipitation method The ethanolic solu-tion of resveratrol (solvent) was pouredwith vigorous stirring(9000 rpm) into aqueous solution of polymer (antisolvent)resulting into precipitation of resveratrol after 30 s Fourdifferent polymers that is HPMC PVP PEG 400 and P188were employed The solvent antisolvent ratio was kept con-stant at 1 20 Process parameters employed for spray dryingwere 105∘C inlet temperature 50ndash60∘C outlet temperature
Journal of Pharmaceutics 9
Antisolvent precipitationusing a syringe pump
(APSP)
Evaporative precipitationof nanosuspension (EPN)
20 mL of above solution wasfilled in syringe
Magneticstirring
(200ndash1000) rpm
Flow rate (2ndash10 mLmin)
Solution was injected into deionized
Formed nanoparticles were filteredand vacuum-dried
Hexane was added quickly toform nanosuspension
Vacuum drying of nanoparticles
Vacuum appliedusing rotaryevaporator
Conc of curcumin in ethanolmdash5ndash15 mgmLa
Solvent to antisolvent ratiomdash1 10ndash1 20 (vv)b
Curcumin was dissolved in ethanolaCurcumin was dissolved in ethanola
Evaporation of ethanol and hexaneb
waterb
Figure 5 APSP and EPN techniques for nanoparticle formulation of curcumin [92]
1mLmin spray flow rate and 065MPa atomization airpressure The particle size obtained with HPMC PVP PEG400 and P188 was found to be 161 plusmn 3 1156 plusmn 78 2168plusmn 26 and 1644 plusmn 47 nm respectively Dissolution studiesrepresented complete dissolution of resveratrol nanodisper-sion in less than 45min whereas raw resveratrol did notdissolve completely even after 120min indicating increasedwater solubility of resveratrol by using polymers
24 Miscellaneous
241 Curcumin It is a naturally occurring polyphenol whichis extracted from the plants of Curcuma longa Curcumalonga (turmeric) has been used to treat ailments since a longtime ago It is also employed as a spice in Indian cuisineCurcumin exhibits a variety of pharmacological actions suchas antitumor [87] anti-HIV [88] antioxidant and anti-inflammatory [89] However the goodness of curcuminhas not been able to reach up to its potential yet Themaximum solubility of curcumin in plain aqueous bufferpH 50 has been reported to be 11 ngmL [90] and the oraldose of curcumin for treating advanced colorectal cancer wasfound to be 36 gday [91] Therefore there is need to devisestrategies to increase solubility of curcumin Nanoparticlesof curcumin employing antisolvent precipitation method
have been reported by Kakran et al [92] The antisolventprecipitation involved two methods namely antisolvent pre-cipitation using a syringe pump (APSP) and evaporative pre-cipitation of nanosuspension (EPN) In first method ethanolwas used as solvent and deionized water as antisolvent InEPN method solvent was same but antisolvent employedwas hexane Figure 5 depicts a schematic representation oftechniques employed for formulation of nanoparticles Theeffect of process variables such as stirring speed flow ratesolvent antisolvent (S AS) ratio and drug concentrationwas studied on particle size and solubility
An increase in the stirring speed from 200 to 1000 rpmin APSP leads to a decrease in particle size from 550 to500 nm An increase in stirring speed led to intensificationof micromixing between multiphases resulting in decrease inparticle size Similar results were observed with a variationin flow rate of curcumin solution An increase in the flowrate from 2 to 10mLmin led to decrease in length ofcurcumin particles from 2560 to 1860 nm since an increasein flow rate resulted in rapid mixing Further an inverserelationship was reported between amount of antisolventin SAS ratios and particle size With an increase in S ASratio 1 20 from 1 10 a decrease in length and diameter ofcurcumin particles from 1860 and 490 nm to 930 and 340 nmrespectively was reported The drug concentration exhibited
10 Journal of Pharmaceutics
Polystyrenebeads
(467 g)
Curcumin(8820 mg)
Stainlesssteel
chamber(100 mL)
02 mgmLSDS
441 mL ofHPC-SL (5
mgmL)
Curcumincolloidal
suspension
Micronization(3600 rpm
90 min)Collection
ofcurcumin
suspension
Freezedrying
Preparation of nanocrystal solid dispersion
Preparation of amorphous solid dispersion
Curcumin
curcuminof curcumin
Curcumin
90 (vv)dioxane solution Freeze drying
Sieving with twodifferent meshsizes of sieves
dissolved insolvent
Sonicationat room
temp
Formation ofprimary
emulsion ofAddition of
Mixing
aqueousmedium
Formation offine dispersion
HPMC-AS(800 mg)
(200 mg)
Preparation of nanoemulsion formulation
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Acetone ethanol solution was used to dissolve mixtures ofEApolymer followed by spray drying of the resultantdispersion under operating conditions of 90∘C inlettemperature 57ndash60∘C outlet temperature 9mLmin feedrate and 350 Lh nitrogen flow
EA PVP and CAAdP were dissolved inacetonitrile ethanol solution followed by concentratingthe solution with rotary evaporation
21 Phenolic Acids They are plant derived phenolic com-pounds which are produced via shikimic acid throughphenylpropanoid pathway and have a unique chemical struc-ture of C
6ndashC3 Some phenolic acids are also of microbial
origin containing C6ndashC1linkage These are further classified
into two categories derivatives of cinnamic acid (hydroxycin-namic acids) and derivatives of benzoic acid (hydroxybenzoicacids)
211 The Hydroxycinnamic Acids (Figure 1(b)) They aremore common than the hydroxybenzoic acids and consistmainly of p-coumaric acid caffeic acid ferulic acid andsinapic acid These acids are found in glycosylated forms asderivatives of shikimic acid quinic acid and tartaric acidCaffeic acid combines with quinic acid to form chlorogenicacid (Figure 1(c)) It is found in high concentrations incoffee a single cup may contain 70ndash350mg chlorogenic acid[24] Caffeic acid is the most abundant phenolic acid andrepresents between 75 and 100of the total hydroxycinnamicacid content of most of the fruit All parts of the fruitcontain hydrocinnamic acid but the highest concentrationsare seen in the outer parts of ripe fruit Cereal grains aredietary source of ferulic acid Wheat grains may contain 08ndash2 gkg dry weight of ferulic acid which represents up to 90of total polyphenols [25 26] Since hydroxybenzoic acidspossess sufficient aqueous solubility their absorption is notdissolution limited
212 Hydroxybenzoic Acids (Figure 1(a)) Salient examplesof hydroxybenzoic acids are gallic acid protocatechuic acidellagic acid (EA) and vanillic acid Edible plants for examplered fruits black radish onions and green tea are richin hydroxybenzoic acid content [27] Tea is an importantsource of gallic acid and tea leaves may contain up to45 gkg fresh wt of leaves [24 28] Dietary sources ofEA include walnuts pomegranates and berries [29] EApossesses several health benefits against many diseases suchas breast cancer [30] prostate cancer [31] lung cancer[32] colon cancer [33] cardiovascular disease [34] andneurodegenerative diseases [35] EA was found to possessmaximum solubility of 93 120583gmL [36] This low solubilitywas attributed to high crystallinity of EA due to its planarand symmetrical structure and extensive hydrogen-bonding
resulting in low bioavailability of EA Solid dispersions of EAhave been employed to enhance the solubility of EA Li et al[37] formulated solid dispersions of EA by three differentmethods Table 3 depicted the methods and compositionsof these investigational formulations Fourier transforminfrared spectroscopy (FTIR) studies confirmed the presenceof H-bonding between EA and polymers Scanning electronmicroscope (SEM) studies indicated that EA was present inamorphous form in the solid dispersions The in vitro dis-solution studies revealed that the nature of polymer directlyinfluences the solubility of EA The polymer with morehydrophilic character resulted in higher swelling and fasterrelease of EA Thus the release profile of EA from EAPVPmatrix was 92 (1 h) followed by EAHPMCAS (35 05 h)EACMCAB (18 1 h) and EACAAdP (15ndash17 1 h) Incor-poration of CAAdP in EAPVP solid dispersion led to adecrease in release of EA (62 05 h) EA has been reportedto deteriorate in the solution form due to crystallization andchemical degradation The amount of EA remaining after24 h in solution is only 18 and 80 due to crystallizationand chemical degradation respectively However the soliddispersions were found to significantly enhance the stabilityof EA against crystallization and chemical degradation Fur-ther it was found that HPMCAS amorphous solid dispersionprovided maximum stability to EA [37]
22 Flavonoids These are benzo-120574-pyrone derivatives ofphenolic and pyran rings [38] On the basis of substitutionson three rings flavonoids are classified as flavonols flavonesisoflavones flavanones flavanols and anthocyanidins whichare biotransformed in body by methylation sulfation andglucuronidation of hydroxyl groups Flavonoids predomi-nantly exist as 3-O-glycosides and polymers [39] Chemicalstructure of flavonoids is illustrated in Figure 2
221 Flavonols Among flavonoids flavonols are the mostubiquitous in foods The main representatives of flavonolsare quercetin and kaempferol (Figure 2(f1))The flavonols areprimarily found in onions (up to 12 gkg fresh wt) curlykale leeks broccoli and blueberries Red wine and tea alsocontain up to 45mgL flavonols In nature flavonols arepresent in glycosylated forms in plants The sugar moietyassociated with flavonols is mainly glucose or rhamnose
Figure 2 Classification and chemical structure of flavonoids
but other sugars like galactose arabinose and xylose mayalso be involved Each fruit contains around 5ndash10 differentflavonol glycosides [40] The biosynthesis of flavonols isstimulated by light so these tend to accumulate in theouter and aerial tissues Depending on exposure to sunlightdifferences in concentration exist between fruits on thesame tree and even between different sides of a single fruit[41]
Quercetin It is a naturally occurring polyphenol whichbelongs to a group of plant pigments known as flavonoidsresponsible for the colour of vegetables fruits and flowers[42] Quercetin is a flavonol whose chemical structure isderived from flavone Chemically quercetin is known as334101584057-pentahydroxyflavone Quercetin exhibits variousproperties such as anti-inflammatory antioxidant antihis-tamine and antiarthritis [42] The primary dietary sourcesof quercetin are citrus fruits apple onions parsley sage teaand redwine [43]However despite having all these beneficialactivities poor water solubility (03120583gmL) restricts its usethus highlighting the importance of increasing the solubilityof quercetin [44] Gao et al [45] reported the formationof nanosuspension of quercetin by two techniques Thefirst technique is comprised of evaporative precipitationof quercetin into aqueous solution (EPAS) The organicsolution of quercetin in ethanol was poured slowly into anaqueous solution containing Pluronic F68 (075 wv) andlecithin (025 wv) stabilizers The solution was contin-uously stirred under vacuum Finally ethanol was evapo-rated and EPAS nanosuspension was collected The secondtechnique involved high pressure homogenization (HPH)of quercetin dispersion in Pluronic F68 (075 wv) and
lecithin (025wv) A piston gap high pressure homogenizerwas used to circulate the suspension for two cycles at thepressure of 200 bar and five cycles at 500 bar followed by20 more cycles at 1500 bar resulting in HPH suspensionThe mean particle size polydispersity index (PI) and solu-bility profile of quercetin nanosuspension produced by EPASmethod and HPHmethod were found to be 2826 plusmn 503 nm023 plusmn 008 4224 120583gmL and 2136 plusmn 293 nm 021 plusmn 0102786120583gmL respectively X-ray powder diffraction (XRPD)measurements revealed a crystalline to amorphous phasetransition in EPAS process which was not observed in HPHThis formed the basis for higher increase in solubility ofquercetin in case of EPAS [46]
A solid dispersion of quercetin employing CMCABHPMCAS and CAAdP as polymers has been reported by Liet al [47] Quercetin and polymer mixtures were prepared indifferent ratios of 1 9 1 3 1 1 3 1 and 9 1 Acetone ethanol(1 4) solution was used to dissolve the above mixtures toform 2 wv solution The solutions were spray-dried usinginlet temperature 90∘C outlet temperature 57ndash60∘C feed rate9mLmin and nitrogen flow rate 350 Lh XRPD studiesof the formulations revealed that while quercetinCMCABhad identical crystallinity quercetinCAAdp showed amor-phous character and quercetinHPMCAS displayed par-tial crystalline character with respect to crude quercetinFTIR spectra of the formulations showed broadening ofpeak at 3300ndash3500 cmminus1 which was attributed to the pres-ence of intermolecular H-bonding between quercetin andmatrix polymer further decreasing crystalline structure ofquercetin A comparison of release profiles of quercetinsolid dispersion with quercetin powder indicated that thesolid dispersions quercetinHPMCA quercetinCMCAB
6 Journal of Pharmaceutics
using low temperaturethermostat bath
Compressionof liquefied Preheating of CO
crystallization vesselthrough metal filter screen
recovered insolvent
recovery kettle
through rotameter
Washing outresidualDMSO
DMSO
Collection ofnanoparticles
High pressurepump Preheater
high pressure infusion pumpFlow of
into vessel
Depressurizationto atmospheric
pressure
2
CO2
supercritical CO2
CO2
Liquefaction of CO2
Apigenin dissolved in DMSO (20 mgmL)a
Infusion rate = 05 mLminb
Delivery of CO
CO2 exhausted out
Apigen in DMSO solutiona
Supercritical conditions of COc2 = 145MPa 35∘C
COc2 to
pumpedd into vessel through
Figure 3 Steps involved in SAS method for preparation of nanoparticles [55]
and quercetinCAAdp showed 14 release after 05 hwhereasthe dissolution of quercetin powder was found to be 07even after 1 h
Inclusion complexes of quercetin have also been reportedfor increasing solubility of quercetin [48] An inclusioncomplex of quercetin was made with 120573-cyclodextrin (120573CD)hydroxypropyl-120573-cyclodextrin (HP-120573CD) and sulfobutylether-120573-cyclodextrin (SBE-120573CD) (ranging from 0 to 001M)The 1 1 complex between quercetin and cyclodextrins led toincreased solubility of quercetin in the order of 120573CD lt HP-120573CD lt SBE-120573CD [49]
222 Flavones They are much less prevalent than flavonolsin fruit and vegetables Flavones primarily contain glycosidesof luteolin and apigenin (Figure 2(f2)) The important savorysources of flavones are parsley and celery C-glycosides offlavones are encompassed in cereals such as millet and wheat[50 51]
Apigenin (AP) It is a naturally occurring flavone chemicallyknown as 4101584057-trihydroxyflavone The most prevalent nat-ural sources of AP are parsley celery and chamomile tea[52] AP belongs to BCS class IIwith poor aqueous solubilityand high permeability in intestine AP was found to possessmaximum solubility 216 120583gmL at pH 75 resulting in lowdissolution and poor bioavailability [53] Various formulationstrategies have been devised to overcome this problem Highshear mixing for preparation of AP smart crystals has beenreported by Al Shaal et al [54] for solubility enhancement ofAP
Smart crystal technology comprehends combination ofdifferent processes pretreatment of poorly soluble drug fol-lowed by high pressure homogenization A macrosuspensionof AP powder and surfactant solution (Plantacare 2000 UP1ww) was formed by high shearmixing (Ultra-Turrax T2510000 rpm) This was followed by seven passages through
bead milling (Buhler PML-2) The formed nanosuspensionwas then subjected to high pressure homogenization (AvestinC50 300 barcycle) The pretreatment step was included toaccelerate nanocrystals production by reducing homogeniza-tion cycles and to decrease particle sizeMillingmediumusedwas zirkonia and yttriawas employed as a stabilizerThemeanparticle size of AP was found to be 439 plusmn 20 nm with a lowPI of 0283 plusmn 0040 Light microscopy studies also presentedevidence supporting the use of surfactant by showing animage with uniform crystal distribution with no signs oflarge crystals and aggregates in the presence of surfactantA zeta potential of minus38mV was reported which indicated awell charged surface and related stability AP coarse powderand nanoparticles showed identical X-ray diffraction (XRD)pattern indicating no decrease in crystallinity DPPH (22-diphenyl-1-picrylhydrazyl) radical scavenging test showed a2-fold increase in antioxidant activity of AP nanoparticles ascompared to AP macrosuspension
Another method for improvement in solubility of AP hasbeen reported by Zhang et al [55] The study incorporatedpreparation of AP nanocrystals via supercritical antisolventmethod (SAS) Figure 3 depicts a schematic representationof preparation of nanoparticles Photon correlation spec-troscopy (PCS) studies revealed the particle size to be 5625 plusmn56 nm with a PI value of 092 plusmn 021 Reduced degree ofcrystallinity was represented in XRPD diagram Differentialscanning calorimetry (DSC) curves of AP coarse powder andAP nanocrystals were studied and compared A decrease inmelting point of AP was observed with nanoparticles whichcould be attributed to particle size reduction to nanometerrange FTIR patterns were identical for both coarse powderand nanoparticles thus indicating the chemical stability of APduring SAS process AP nanocrystals exhibited more rapiddissolution rate with much higher cumulative amount ofdissolved AP than AP coarse powder The higher dissolutionof AP nanocrystals could be due to the enhanced saturated
Journal of Pharmaceutics 7
solubility resulting from a significant decrease of particle size[56] In vivo studies showed 36 and 34 fold enhancement in119862max and AUC of AP respectively after oral administrationof AP nanocrystals The absolute bioavailability of AP coarsepowder was found to be 20 whereas nanoparticles exhib-ited 69 absolute bioavailability Thus improved solubilitydissolution rate and bioavailability depict the usefulnessof these methods for delivery of such BCS class secondcompounds
223 Flavanones They are natural compounds of restrictedoccurrence and are sometimes termed as minor flavonoidsThe cardinal aglycones are naringenin hesperetin and erio-dictyol (Figure 2(f4)) Glycosylation of flavanones is generallyattained by a disaccharide at position 7 which is eithera neohesperidose that imparts a bitter taste (such as tonaringin in grapefruit) or a rutinose which is flavorlessCitrus fruits contain considerable amount of flavanonesTomatoes and certain aromatic plants such as mint alsoconstitute flavanones Hesperidin and narirutin are presentin orange juice at a concentration of 200ndash600mgL and 15ndash85mgL respectively A single glass of orange juice maycontain between 40 and 140mg of flavanone glycosides [57]However very high flavanone content is found to be presentin the solid parts of orange fruit particularly the albedo (thewhite spongy portion) and the membranes separating thesegments Thus an orange fruit may comprise up to 5 timesas much as a glass of orange juice
(1) Hesperetin It is a naturally occurring flavonoid chemicallyknown as 3101584057-trihydroxy-4-methoxyflavanone Hesperetinis found almost exclusively in citrus fruits [58] Studiesrevealed that hesperetin can avert colon [59] urinary bladder[60] and chemically induced mammary carcinogenesis [61]Other biological activities of hesperetin include antioxidant[62] and anti-inflammatory [63] Aqueous solubility of hes-peretin was found to be 14 120583gmL [64] Nanoparticles ofhesperetin by two different methods namely APSP and EPNhave been have been reported to enhance the solubility anddissolution rate [65]
APSP The solvent and antisolvent used in this methodwere ethanol and deionized water respectively The methodcomprised of dissolution of hesperetin in solvent followed byinjection of drug solution into an antisolvent with the help ofsyringe The solution was constantly stirred using magneticstirrer (200ndash1000 rpm) and the flow rate was varied from 2 to10mLmin
EPN Nanoparticles in this method were formed by quickaddition of drug solution containing hesperetin and ethanolinto antisolvent Hexane was used as antisolvent Vacuumdrying was carried out for quick evaporation of solventleading to formation of nanosuspension
Figures 4(a) and 4(b) depict the effect of various param-eters on particle size and solubility of hesperetin by APSPand EPN methods The formulation containing 5mgmLdrug concentration 10mLmin flow rate stirring speed of1000 rpm and solvent antisolvent ratio of 1 20 depicted
highest solubility (988 120583gmL) This was attributed to adecrease in particle size from 34 120583m to 075120583m (revealed bySEM) In case of EPN highest solubility (1117 120583gmL) wasseen in formulation containing 5 120583gmL drug concentrationand 1 20 solvent antisolvent ratioThe DSC studies revealedthat the melting point of nanoparticles prepared by bothmethods was identical to crude hesperetin but enthalpyof fusion was reduced due to reduction in crystallinity ofnanoparticles of hesperetin
(2) Naringenin (NRG) It is a kind of flavanone (4101584057-trihydroxyflvanone) found extremely in tomatoes [66]cherries [67] grape fruit and citrus fruits [58] In addi-tion to antioxidant property [68] NRG also possess anti-inflammatory [69] antitumour [70] and hepatoprotectiveeffects [71] However clinical applicability of NRG is limitedby its low solubility and bioavailability NRG possesses lowaqueous solubility (45 120583gmL) [72] therefore measures weretaken to investigate methods for enhancing solubility ofNRG Transglycosylation of hesperetin leads to an increasein solubility of hesperetin [73] This formed the basis forpreparing spray-dried particles of NRG with 120572-Glucosylhesperidin (Hsp-G) in order to enhance its solubility [72]Different loading ratios of NRGHsp-G (1 1 to 1 20 ww)were dissolved in ethanol water (8 2 vv) solution Theresultant suspension was then subjected to spray drying atthe rate of 10mLmin employing a spray nozzle of diameter406 120583m and pressure of 013MPa The inlet and outlet tem-peratures of drying chamber were 120∘C and 70∘C respec-tively SEM images of NRGHsp-G samples showed sphericalshaped aggregates with average particle size of 3-4 120583mThe resultant spray-dried particles of NRG showed 60-foldimprovement in solubility when loading ratio of NRGHsp-Gwas 1 20
224 Isoflavones They have structural similarities to estro-gens as they have hydroxyl groups in positions 7 and 41015840 ina configuration analogous to that of the hydroxyls in theestradiol molecule (Figure 2(f3)) Although isoflavones arenot steroids they have potential estrogenic activityThis illus-trates their ability to bind to estrogen receptors They possesspseudohormonal properties and are consequently classifiedas phytoestrogens [2] Leguminous plants are the exclusivesource of isoflavones The main source of isoflavones in thehuman diet is soya and its processed products Isoflavonesprincipally contain 3 compounds genistein daidzein andglycitein (concentration ratio of 1 1 02) Factors such asgeographic zone growing conditions and processing of soyaand its manufactured products greatly affect their isoflavonecontent Isoflavone content of soybeans is 580ndash3800mgkgand of soymilk is 30ndash175mgL [74 75]
Genistein It is a naturally occurring plant flavonoid Soyproducts are the richest sources of genistein [76] Chemicalstructure of genistein (4101584057-trihydroxyisoflavone) containsan isoflavone backbone Genistein has beneficial effects inareas of cancer [77] cardiovascular diseases [78] and post-menopausal symptoms [79] Aqueous solubility of genisteinis very poor approximately 081 120583gmL [80] which leads to
8 Journal of Pharmaceutics
205167
121086 075
695 701
815
966 988
0
1
2
3
4
5
6
7
8
9
10
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
Flow rate(mLmin)
210101010
Stirring speed(rpm)
200200
100010001000
S AS
1 101 101 101 201 20
Drug concentration(mgmL)
555
105
(a)
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
S AS
1 101 151 201 201 20
Drug concentration(mgmL)
55
15105
089 072 06 054 045
965
1082 1097 1113 1117
0
2
4
6
8
10
12
(b)
Figure 4 (a) Depicting the effect of various parameters on particle size and solubility of hesperetin by APSP method [65] (b) Depicting theeffect of various parameters on particle size and solubility of hesperetin by EPN method [65]
low bioavailability of the drug A solid dispersion of genisteinin Pluronic F127 polymeric micelles has been reported forsolubility enhancement by Kwon et al [80] An ethanolicsolution of Pluronic F127 was used to dissolve genisteinby constant stirring at 37∘C for 30min The solution whenevaporated led to formation of clear gel-like matrix Additionof water and constant stirring resulted in formation of poly-meric micelles containing genistein The resulting solutionwas filtered employing 045120583m pore size membrane filter toremove any undissolved genistein followed by lyophilizationat minus80∘C Average particle size of genistein loaded polymericmicelles was found to be 2776 plusmn 046 nm with PI of 026 Invitro drug release showed genistein release 48ndash58 in pH 12mediumand 44ndash82 in pH68mediumwhichwas attributedto higher solubilizing ability of polymeric micelles The invivo pharmacokinetic characterization showed an increasein 119862max from 122 to 568120583gmL and decrease in 119905max from055 to 020 h The polymeric micelles also demonstratedenhanced bioavailability thus confirming enhanced genisteinsolubility and release in gastrointestinal tract
23 Stilbenes Stilbenes encompass a group of biologicallyactive compounds however human diet comprises only few
of these (Figure 1(e)) Examplesmay include trans-resveratroland trans-piceid (its natural glycoside)
231 Resveratrol It belongs to a class of naturally occurringpolyphenols known as stilbenes It is mainly present inthe form of trans-resveratrol (3541015840-trihydroxystilbene) inhuman dietThe dietary sources of resveratrol include peanutbutter dark chocolate blueberries and red wine About23mgL of trans-resveratrol is present in red wine [81]Resveratrol exhibits antiangiogenesis [82] cardioprotective[83] anticarcinogenic and anti-inflammatory activities [84]Aqueous solubility of resveratrol was found to be 30 120583gmLthereby limiting pharmaceutical potential of resveratrol [85]Zhang et al [86] reported a method for enhancing solubilityof resveratrol by formulating nanoparticles of resveratrolusing antisolvent precipitation method The ethanolic solu-tion of resveratrol (solvent) was pouredwith vigorous stirring(9000 rpm) into aqueous solution of polymer (antisolvent)resulting into precipitation of resveratrol after 30 s Fourdifferent polymers that is HPMC PVP PEG 400 and P188were employed The solvent antisolvent ratio was kept con-stant at 1 20 Process parameters employed for spray dryingwere 105∘C inlet temperature 50ndash60∘C outlet temperature
Journal of Pharmaceutics 9
Antisolvent precipitationusing a syringe pump
(APSP)
Evaporative precipitationof nanosuspension (EPN)
20 mL of above solution wasfilled in syringe
Magneticstirring
(200ndash1000) rpm
Flow rate (2ndash10 mLmin)
Solution was injected into deionized
Formed nanoparticles were filteredand vacuum-dried
Hexane was added quickly toform nanosuspension
Vacuum drying of nanoparticles
Vacuum appliedusing rotaryevaporator
Conc of curcumin in ethanolmdash5ndash15 mgmLa
Solvent to antisolvent ratiomdash1 10ndash1 20 (vv)b
Curcumin was dissolved in ethanolaCurcumin was dissolved in ethanola
Evaporation of ethanol and hexaneb
waterb
Figure 5 APSP and EPN techniques for nanoparticle formulation of curcumin [92]
1mLmin spray flow rate and 065MPa atomization airpressure The particle size obtained with HPMC PVP PEG400 and P188 was found to be 161 plusmn 3 1156 plusmn 78 2168plusmn 26 and 1644 plusmn 47 nm respectively Dissolution studiesrepresented complete dissolution of resveratrol nanodisper-sion in less than 45min whereas raw resveratrol did notdissolve completely even after 120min indicating increasedwater solubility of resveratrol by using polymers
24 Miscellaneous
241 Curcumin It is a naturally occurring polyphenol whichis extracted from the plants of Curcuma longa Curcumalonga (turmeric) has been used to treat ailments since a longtime ago It is also employed as a spice in Indian cuisineCurcumin exhibits a variety of pharmacological actions suchas antitumor [87] anti-HIV [88] antioxidant and anti-inflammatory [89] However the goodness of curcuminhas not been able to reach up to its potential yet Themaximum solubility of curcumin in plain aqueous bufferpH 50 has been reported to be 11 ngmL [90] and the oraldose of curcumin for treating advanced colorectal cancer wasfound to be 36 gday [91] Therefore there is need to devisestrategies to increase solubility of curcumin Nanoparticlesof curcumin employing antisolvent precipitation method
have been reported by Kakran et al [92] The antisolventprecipitation involved two methods namely antisolvent pre-cipitation using a syringe pump (APSP) and evaporative pre-cipitation of nanosuspension (EPN) In first method ethanolwas used as solvent and deionized water as antisolvent InEPN method solvent was same but antisolvent employedwas hexane Figure 5 depicts a schematic representation oftechniques employed for formulation of nanoparticles Theeffect of process variables such as stirring speed flow ratesolvent antisolvent (S AS) ratio and drug concentrationwas studied on particle size and solubility
An increase in the stirring speed from 200 to 1000 rpmin APSP leads to a decrease in particle size from 550 to500 nm An increase in stirring speed led to intensificationof micromixing between multiphases resulting in decrease inparticle size Similar results were observed with a variationin flow rate of curcumin solution An increase in the flowrate from 2 to 10mLmin led to decrease in length ofcurcumin particles from 2560 to 1860 nm since an increasein flow rate resulted in rapid mixing Further an inverserelationship was reported between amount of antisolventin SAS ratios and particle size With an increase in S ASratio 1 20 from 1 10 a decrease in length and diameter ofcurcumin particles from 1860 and 490 nm to 930 and 340 nmrespectively was reported The drug concentration exhibited
10 Journal of Pharmaceutics
Polystyrenebeads
(467 g)
Curcumin(8820 mg)
Stainlesssteel
chamber(100 mL)
02 mgmLSDS
441 mL ofHPC-SL (5
mgmL)
Curcumincolloidal
suspension
Micronization(3600 rpm
90 min)Collection
ofcurcumin
suspension
Freezedrying
Preparation of nanocrystal solid dispersion
Preparation of amorphous solid dispersion
Curcumin
curcuminof curcumin
Curcumin
90 (vv)dioxane solution Freeze drying
Sieving with twodifferent meshsizes of sieves
dissolved insolvent
Sonicationat room
temp
Formation ofprimary
emulsion ofAddition of
Mixing
aqueousmedium
Formation offine dispersion
HPMC-AS(800 mg)
(200 mg)
Preparation of nanoemulsion formulation
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 2 Classification and chemical structure of flavonoids
but other sugars like galactose arabinose and xylose mayalso be involved Each fruit contains around 5ndash10 differentflavonol glycosides [40] The biosynthesis of flavonols isstimulated by light so these tend to accumulate in theouter and aerial tissues Depending on exposure to sunlightdifferences in concentration exist between fruits on thesame tree and even between different sides of a single fruit[41]
Quercetin It is a naturally occurring polyphenol whichbelongs to a group of plant pigments known as flavonoidsresponsible for the colour of vegetables fruits and flowers[42] Quercetin is a flavonol whose chemical structure isderived from flavone Chemically quercetin is known as334101584057-pentahydroxyflavone Quercetin exhibits variousproperties such as anti-inflammatory antioxidant antihis-tamine and antiarthritis [42] The primary dietary sourcesof quercetin are citrus fruits apple onions parsley sage teaand redwine [43]However despite having all these beneficialactivities poor water solubility (03120583gmL) restricts its usethus highlighting the importance of increasing the solubilityof quercetin [44] Gao et al [45] reported the formationof nanosuspension of quercetin by two techniques Thefirst technique is comprised of evaporative precipitationof quercetin into aqueous solution (EPAS) The organicsolution of quercetin in ethanol was poured slowly into anaqueous solution containing Pluronic F68 (075 wv) andlecithin (025 wv) stabilizers The solution was contin-uously stirred under vacuum Finally ethanol was evapo-rated and EPAS nanosuspension was collected The secondtechnique involved high pressure homogenization (HPH)of quercetin dispersion in Pluronic F68 (075 wv) and
lecithin (025wv) A piston gap high pressure homogenizerwas used to circulate the suspension for two cycles at thepressure of 200 bar and five cycles at 500 bar followed by20 more cycles at 1500 bar resulting in HPH suspensionThe mean particle size polydispersity index (PI) and solu-bility profile of quercetin nanosuspension produced by EPASmethod and HPHmethod were found to be 2826 plusmn 503 nm023 plusmn 008 4224 120583gmL and 2136 plusmn 293 nm 021 plusmn 0102786120583gmL respectively X-ray powder diffraction (XRPD)measurements revealed a crystalline to amorphous phasetransition in EPAS process which was not observed in HPHThis formed the basis for higher increase in solubility ofquercetin in case of EPAS [46]
A solid dispersion of quercetin employing CMCABHPMCAS and CAAdP as polymers has been reported by Liet al [47] Quercetin and polymer mixtures were prepared indifferent ratios of 1 9 1 3 1 1 3 1 and 9 1 Acetone ethanol(1 4) solution was used to dissolve the above mixtures toform 2 wv solution The solutions were spray-dried usinginlet temperature 90∘C outlet temperature 57ndash60∘C feed rate9mLmin and nitrogen flow rate 350 Lh XRPD studiesof the formulations revealed that while quercetinCMCABhad identical crystallinity quercetinCAAdp showed amor-phous character and quercetinHPMCAS displayed par-tial crystalline character with respect to crude quercetinFTIR spectra of the formulations showed broadening ofpeak at 3300ndash3500 cmminus1 which was attributed to the pres-ence of intermolecular H-bonding between quercetin andmatrix polymer further decreasing crystalline structure ofquercetin A comparison of release profiles of quercetinsolid dispersion with quercetin powder indicated that thesolid dispersions quercetinHPMCA quercetinCMCAB
6 Journal of Pharmaceutics
using low temperaturethermostat bath
Compressionof liquefied Preheating of CO
crystallization vesselthrough metal filter screen
recovered insolvent
recovery kettle
through rotameter
Washing outresidualDMSO
DMSO
Collection ofnanoparticles
High pressurepump Preheater
high pressure infusion pumpFlow of
into vessel
Depressurizationto atmospheric
pressure
2
CO2
supercritical CO2
CO2
Liquefaction of CO2
Apigenin dissolved in DMSO (20 mgmL)a
Infusion rate = 05 mLminb
Delivery of CO
CO2 exhausted out
Apigen in DMSO solutiona
Supercritical conditions of COc2 = 145MPa 35∘C
COc2 to
pumpedd into vessel through
Figure 3 Steps involved in SAS method for preparation of nanoparticles [55]
and quercetinCAAdp showed 14 release after 05 hwhereasthe dissolution of quercetin powder was found to be 07even after 1 h
Inclusion complexes of quercetin have also been reportedfor increasing solubility of quercetin [48] An inclusioncomplex of quercetin was made with 120573-cyclodextrin (120573CD)hydroxypropyl-120573-cyclodextrin (HP-120573CD) and sulfobutylether-120573-cyclodextrin (SBE-120573CD) (ranging from 0 to 001M)The 1 1 complex between quercetin and cyclodextrins led toincreased solubility of quercetin in the order of 120573CD lt HP-120573CD lt SBE-120573CD [49]
222 Flavones They are much less prevalent than flavonolsin fruit and vegetables Flavones primarily contain glycosidesof luteolin and apigenin (Figure 2(f2)) The important savorysources of flavones are parsley and celery C-glycosides offlavones are encompassed in cereals such as millet and wheat[50 51]
Apigenin (AP) It is a naturally occurring flavone chemicallyknown as 4101584057-trihydroxyflavone The most prevalent nat-ural sources of AP are parsley celery and chamomile tea[52] AP belongs to BCS class IIwith poor aqueous solubilityand high permeability in intestine AP was found to possessmaximum solubility 216 120583gmL at pH 75 resulting in lowdissolution and poor bioavailability [53] Various formulationstrategies have been devised to overcome this problem Highshear mixing for preparation of AP smart crystals has beenreported by Al Shaal et al [54] for solubility enhancement ofAP
Smart crystal technology comprehends combination ofdifferent processes pretreatment of poorly soluble drug fol-lowed by high pressure homogenization A macrosuspensionof AP powder and surfactant solution (Plantacare 2000 UP1ww) was formed by high shearmixing (Ultra-Turrax T2510000 rpm) This was followed by seven passages through
bead milling (Buhler PML-2) The formed nanosuspensionwas then subjected to high pressure homogenization (AvestinC50 300 barcycle) The pretreatment step was included toaccelerate nanocrystals production by reducing homogeniza-tion cycles and to decrease particle sizeMillingmediumusedwas zirkonia and yttriawas employed as a stabilizerThemeanparticle size of AP was found to be 439 plusmn 20 nm with a lowPI of 0283 plusmn 0040 Light microscopy studies also presentedevidence supporting the use of surfactant by showing animage with uniform crystal distribution with no signs oflarge crystals and aggregates in the presence of surfactantA zeta potential of minus38mV was reported which indicated awell charged surface and related stability AP coarse powderand nanoparticles showed identical X-ray diffraction (XRD)pattern indicating no decrease in crystallinity DPPH (22-diphenyl-1-picrylhydrazyl) radical scavenging test showed a2-fold increase in antioxidant activity of AP nanoparticles ascompared to AP macrosuspension
Another method for improvement in solubility of AP hasbeen reported by Zhang et al [55] The study incorporatedpreparation of AP nanocrystals via supercritical antisolventmethod (SAS) Figure 3 depicts a schematic representationof preparation of nanoparticles Photon correlation spec-troscopy (PCS) studies revealed the particle size to be 5625 plusmn56 nm with a PI value of 092 plusmn 021 Reduced degree ofcrystallinity was represented in XRPD diagram Differentialscanning calorimetry (DSC) curves of AP coarse powder andAP nanocrystals were studied and compared A decrease inmelting point of AP was observed with nanoparticles whichcould be attributed to particle size reduction to nanometerrange FTIR patterns were identical for both coarse powderand nanoparticles thus indicating the chemical stability of APduring SAS process AP nanocrystals exhibited more rapiddissolution rate with much higher cumulative amount ofdissolved AP than AP coarse powder The higher dissolutionof AP nanocrystals could be due to the enhanced saturated
Journal of Pharmaceutics 7
solubility resulting from a significant decrease of particle size[56] In vivo studies showed 36 and 34 fold enhancement in119862max and AUC of AP respectively after oral administrationof AP nanocrystals The absolute bioavailability of AP coarsepowder was found to be 20 whereas nanoparticles exhib-ited 69 absolute bioavailability Thus improved solubilitydissolution rate and bioavailability depict the usefulnessof these methods for delivery of such BCS class secondcompounds
223 Flavanones They are natural compounds of restrictedoccurrence and are sometimes termed as minor flavonoidsThe cardinal aglycones are naringenin hesperetin and erio-dictyol (Figure 2(f4)) Glycosylation of flavanones is generallyattained by a disaccharide at position 7 which is eithera neohesperidose that imparts a bitter taste (such as tonaringin in grapefruit) or a rutinose which is flavorlessCitrus fruits contain considerable amount of flavanonesTomatoes and certain aromatic plants such as mint alsoconstitute flavanones Hesperidin and narirutin are presentin orange juice at a concentration of 200ndash600mgL and 15ndash85mgL respectively A single glass of orange juice maycontain between 40 and 140mg of flavanone glycosides [57]However very high flavanone content is found to be presentin the solid parts of orange fruit particularly the albedo (thewhite spongy portion) and the membranes separating thesegments Thus an orange fruit may comprise up to 5 timesas much as a glass of orange juice
(1) Hesperetin It is a naturally occurring flavonoid chemicallyknown as 3101584057-trihydroxy-4-methoxyflavanone Hesperetinis found almost exclusively in citrus fruits [58] Studiesrevealed that hesperetin can avert colon [59] urinary bladder[60] and chemically induced mammary carcinogenesis [61]Other biological activities of hesperetin include antioxidant[62] and anti-inflammatory [63] Aqueous solubility of hes-peretin was found to be 14 120583gmL [64] Nanoparticles ofhesperetin by two different methods namely APSP and EPNhave been have been reported to enhance the solubility anddissolution rate [65]
APSP The solvent and antisolvent used in this methodwere ethanol and deionized water respectively The methodcomprised of dissolution of hesperetin in solvent followed byinjection of drug solution into an antisolvent with the help ofsyringe The solution was constantly stirred using magneticstirrer (200ndash1000 rpm) and the flow rate was varied from 2 to10mLmin
EPN Nanoparticles in this method were formed by quickaddition of drug solution containing hesperetin and ethanolinto antisolvent Hexane was used as antisolvent Vacuumdrying was carried out for quick evaporation of solventleading to formation of nanosuspension
Figures 4(a) and 4(b) depict the effect of various param-eters on particle size and solubility of hesperetin by APSPand EPN methods The formulation containing 5mgmLdrug concentration 10mLmin flow rate stirring speed of1000 rpm and solvent antisolvent ratio of 1 20 depicted
highest solubility (988 120583gmL) This was attributed to adecrease in particle size from 34 120583m to 075120583m (revealed bySEM) In case of EPN highest solubility (1117 120583gmL) wasseen in formulation containing 5 120583gmL drug concentrationand 1 20 solvent antisolvent ratioThe DSC studies revealedthat the melting point of nanoparticles prepared by bothmethods was identical to crude hesperetin but enthalpyof fusion was reduced due to reduction in crystallinity ofnanoparticles of hesperetin
(2) Naringenin (NRG) It is a kind of flavanone (4101584057-trihydroxyflvanone) found extremely in tomatoes [66]cherries [67] grape fruit and citrus fruits [58] In addi-tion to antioxidant property [68] NRG also possess anti-inflammatory [69] antitumour [70] and hepatoprotectiveeffects [71] However clinical applicability of NRG is limitedby its low solubility and bioavailability NRG possesses lowaqueous solubility (45 120583gmL) [72] therefore measures weretaken to investigate methods for enhancing solubility ofNRG Transglycosylation of hesperetin leads to an increasein solubility of hesperetin [73] This formed the basis forpreparing spray-dried particles of NRG with 120572-Glucosylhesperidin (Hsp-G) in order to enhance its solubility [72]Different loading ratios of NRGHsp-G (1 1 to 1 20 ww)were dissolved in ethanol water (8 2 vv) solution Theresultant suspension was then subjected to spray drying atthe rate of 10mLmin employing a spray nozzle of diameter406 120583m and pressure of 013MPa The inlet and outlet tem-peratures of drying chamber were 120∘C and 70∘C respec-tively SEM images of NRGHsp-G samples showed sphericalshaped aggregates with average particle size of 3-4 120583mThe resultant spray-dried particles of NRG showed 60-foldimprovement in solubility when loading ratio of NRGHsp-Gwas 1 20
224 Isoflavones They have structural similarities to estro-gens as they have hydroxyl groups in positions 7 and 41015840 ina configuration analogous to that of the hydroxyls in theestradiol molecule (Figure 2(f3)) Although isoflavones arenot steroids they have potential estrogenic activityThis illus-trates their ability to bind to estrogen receptors They possesspseudohormonal properties and are consequently classifiedas phytoestrogens [2] Leguminous plants are the exclusivesource of isoflavones The main source of isoflavones in thehuman diet is soya and its processed products Isoflavonesprincipally contain 3 compounds genistein daidzein andglycitein (concentration ratio of 1 1 02) Factors such asgeographic zone growing conditions and processing of soyaand its manufactured products greatly affect their isoflavonecontent Isoflavone content of soybeans is 580ndash3800mgkgand of soymilk is 30ndash175mgL [74 75]
Genistein It is a naturally occurring plant flavonoid Soyproducts are the richest sources of genistein [76] Chemicalstructure of genistein (4101584057-trihydroxyisoflavone) containsan isoflavone backbone Genistein has beneficial effects inareas of cancer [77] cardiovascular diseases [78] and post-menopausal symptoms [79] Aqueous solubility of genisteinis very poor approximately 081 120583gmL [80] which leads to
8 Journal of Pharmaceutics
205167
121086 075
695 701
815
966 988
0
1
2
3
4
5
6
7
8
9
10
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
Flow rate(mLmin)
210101010
Stirring speed(rpm)
200200
100010001000
S AS
1 101 101 101 201 20
Drug concentration(mgmL)
555
105
(a)
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
S AS
1 101 151 201 201 20
Drug concentration(mgmL)
55
15105
089 072 06 054 045
965
1082 1097 1113 1117
0
2
4
6
8
10
12
(b)
Figure 4 (a) Depicting the effect of various parameters on particle size and solubility of hesperetin by APSP method [65] (b) Depicting theeffect of various parameters on particle size and solubility of hesperetin by EPN method [65]
low bioavailability of the drug A solid dispersion of genisteinin Pluronic F127 polymeric micelles has been reported forsolubility enhancement by Kwon et al [80] An ethanolicsolution of Pluronic F127 was used to dissolve genisteinby constant stirring at 37∘C for 30min The solution whenevaporated led to formation of clear gel-like matrix Additionof water and constant stirring resulted in formation of poly-meric micelles containing genistein The resulting solutionwas filtered employing 045120583m pore size membrane filter toremove any undissolved genistein followed by lyophilizationat minus80∘C Average particle size of genistein loaded polymericmicelles was found to be 2776 plusmn 046 nm with PI of 026 Invitro drug release showed genistein release 48ndash58 in pH 12mediumand 44ndash82 in pH68mediumwhichwas attributedto higher solubilizing ability of polymeric micelles The invivo pharmacokinetic characterization showed an increasein 119862max from 122 to 568120583gmL and decrease in 119905max from055 to 020 h The polymeric micelles also demonstratedenhanced bioavailability thus confirming enhanced genisteinsolubility and release in gastrointestinal tract
23 Stilbenes Stilbenes encompass a group of biologicallyactive compounds however human diet comprises only few
of these (Figure 1(e)) Examplesmay include trans-resveratroland trans-piceid (its natural glycoside)
231 Resveratrol It belongs to a class of naturally occurringpolyphenols known as stilbenes It is mainly present inthe form of trans-resveratrol (3541015840-trihydroxystilbene) inhuman dietThe dietary sources of resveratrol include peanutbutter dark chocolate blueberries and red wine About23mgL of trans-resveratrol is present in red wine [81]Resveratrol exhibits antiangiogenesis [82] cardioprotective[83] anticarcinogenic and anti-inflammatory activities [84]Aqueous solubility of resveratrol was found to be 30 120583gmLthereby limiting pharmaceutical potential of resveratrol [85]Zhang et al [86] reported a method for enhancing solubilityof resveratrol by formulating nanoparticles of resveratrolusing antisolvent precipitation method The ethanolic solu-tion of resveratrol (solvent) was pouredwith vigorous stirring(9000 rpm) into aqueous solution of polymer (antisolvent)resulting into precipitation of resveratrol after 30 s Fourdifferent polymers that is HPMC PVP PEG 400 and P188were employed The solvent antisolvent ratio was kept con-stant at 1 20 Process parameters employed for spray dryingwere 105∘C inlet temperature 50ndash60∘C outlet temperature
Journal of Pharmaceutics 9
Antisolvent precipitationusing a syringe pump
(APSP)
Evaporative precipitationof nanosuspension (EPN)
20 mL of above solution wasfilled in syringe
Magneticstirring
(200ndash1000) rpm
Flow rate (2ndash10 mLmin)
Solution was injected into deionized
Formed nanoparticles were filteredand vacuum-dried
Hexane was added quickly toform nanosuspension
Vacuum drying of nanoparticles
Vacuum appliedusing rotaryevaporator
Conc of curcumin in ethanolmdash5ndash15 mgmLa
Solvent to antisolvent ratiomdash1 10ndash1 20 (vv)b
Curcumin was dissolved in ethanolaCurcumin was dissolved in ethanola
Evaporation of ethanol and hexaneb
waterb
Figure 5 APSP and EPN techniques for nanoparticle formulation of curcumin [92]
1mLmin spray flow rate and 065MPa atomization airpressure The particle size obtained with HPMC PVP PEG400 and P188 was found to be 161 plusmn 3 1156 plusmn 78 2168plusmn 26 and 1644 plusmn 47 nm respectively Dissolution studiesrepresented complete dissolution of resveratrol nanodisper-sion in less than 45min whereas raw resveratrol did notdissolve completely even after 120min indicating increasedwater solubility of resveratrol by using polymers
24 Miscellaneous
241 Curcumin It is a naturally occurring polyphenol whichis extracted from the plants of Curcuma longa Curcumalonga (turmeric) has been used to treat ailments since a longtime ago It is also employed as a spice in Indian cuisineCurcumin exhibits a variety of pharmacological actions suchas antitumor [87] anti-HIV [88] antioxidant and anti-inflammatory [89] However the goodness of curcuminhas not been able to reach up to its potential yet Themaximum solubility of curcumin in plain aqueous bufferpH 50 has been reported to be 11 ngmL [90] and the oraldose of curcumin for treating advanced colorectal cancer wasfound to be 36 gday [91] Therefore there is need to devisestrategies to increase solubility of curcumin Nanoparticlesof curcumin employing antisolvent precipitation method
have been reported by Kakran et al [92] The antisolventprecipitation involved two methods namely antisolvent pre-cipitation using a syringe pump (APSP) and evaporative pre-cipitation of nanosuspension (EPN) In first method ethanolwas used as solvent and deionized water as antisolvent InEPN method solvent was same but antisolvent employedwas hexane Figure 5 depicts a schematic representation oftechniques employed for formulation of nanoparticles Theeffect of process variables such as stirring speed flow ratesolvent antisolvent (S AS) ratio and drug concentrationwas studied on particle size and solubility
An increase in the stirring speed from 200 to 1000 rpmin APSP leads to a decrease in particle size from 550 to500 nm An increase in stirring speed led to intensificationof micromixing between multiphases resulting in decrease inparticle size Similar results were observed with a variationin flow rate of curcumin solution An increase in the flowrate from 2 to 10mLmin led to decrease in length ofcurcumin particles from 2560 to 1860 nm since an increasein flow rate resulted in rapid mixing Further an inverserelationship was reported between amount of antisolventin SAS ratios and particle size With an increase in S ASratio 1 20 from 1 10 a decrease in length and diameter ofcurcumin particles from 1860 and 490 nm to 930 and 340 nmrespectively was reported The drug concentration exhibited
10 Journal of Pharmaceutics
Polystyrenebeads
(467 g)
Curcumin(8820 mg)
Stainlesssteel
chamber(100 mL)
02 mgmLSDS
441 mL ofHPC-SL (5
mgmL)
Curcumincolloidal
suspension
Micronization(3600 rpm
90 min)Collection
ofcurcumin
suspension
Freezedrying
Preparation of nanocrystal solid dispersion
Preparation of amorphous solid dispersion
Curcumin
curcuminof curcumin
Curcumin
90 (vv)dioxane solution Freeze drying
Sieving with twodifferent meshsizes of sieves
dissolved insolvent
Sonicationat room
temp
Formation ofprimary
emulsion ofAddition of
Mixing
aqueousmedium
Formation offine dispersion
HPMC-AS(800 mg)
(200 mg)
Preparation of nanoemulsion formulation
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 3 Steps involved in SAS method for preparation of nanoparticles [55]
and quercetinCAAdp showed 14 release after 05 hwhereasthe dissolution of quercetin powder was found to be 07even after 1 h
Inclusion complexes of quercetin have also been reportedfor increasing solubility of quercetin [48] An inclusioncomplex of quercetin was made with 120573-cyclodextrin (120573CD)hydroxypropyl-120573-cyclodextrin (HP-120573CD) and sulfobutylether-120573-cyclodextrin (SBE-120573CD) (ranging from 0 to 001M)The 1 1 complex between quercetin and cyclodextrins led toincreased solubility of quercetin in the order of 120573CD lt HP-120573CD lt SBE-120573CD [49]
222 Flavones They are much less prevalent than flavonolsin fruit and vegetables Flavones primarily contain glycosidesof luteolin and apigenin (Figure 2(f2)) The important savorysources of flavones are parsley and celery C-glycosides offlavones are encompassed in cereals such as millet and wheat[50 51]
Apigenin (AP) It is a naturally occurring flavone chemicallyknown as 4101584057-trihydroxyflavone The most prevalent nat-ural sources of AP are parsley celery and chamomile tea[52] AP belongs to BCS class IIwith poor aqueous solubilityand high permeability in intestine AP was found to possessmaximum solubility 216 120583gmL at pH 75 resulting in lowdissolution and poor bioavailability [53] Various formulationstrategies have been devised to overcome this problem Highshear mixing for preparation of AP smart crystals has beenreported by Al Shaal et al [54] for solubility enhancement ofAP
Smart crystal technology comprehends combination ofdifferent processes pretreatment of poorly soluble drug fol-lowed by high pressure homogenization A macrosuspensionof AP powder and surfactant solution (Plantacare 2000 UP1ww) was formed by high shearmixing (Ultra-Turrax T2510000 rpm) This was followed by seven passages through
bead milling (Buhler PML-2) The formed nanosuspensionwas then subjected to high pressure homogenization (AvestinC50 300 barcycle) The pretreatment step was included toaccelerate nanocrystals production by reducing homogeniza-tion cycles and to decrease particle sizeMillingmediumusedwas zirkonia and yttriawas employed as a stabilizerThemeanparticle size of AP was found to be 439 plusmn 20 nm with a lowPI of 0283 plusmn 0040 Light microscopy studies also presentedevidence supporting the use of surfactant by showing animage with uniform crystal distribution with no signs oflarge crystals and aggregates in the presence of surfactantA zeta potential of minus38mV was reported which indicated awell charged surface and related stability AP coarse powderand nanoparticles showed identical X-ray diffraction (XRD)pattern indicating no decrease in crystallinity DPPH (22-diphenyl-1-picrylhydrazyl) radical scavenging test showed a2-fold increase in antioxidant activity of AP nanoparticles ascompared to AP macrosuspension
Another method for improvement in solubility of AP hasbeen reported by Zhang et al [55] The study incorporatedpreparation of AP nanocrystals via supercritical antisolventmethod (SAS) Figure 3 depicts a schematic representationof preparation of nanoparticles Photon correlation spec-troscopy (PCS) studies revealed the particle size to be 5625 plusmn56 nm with a PI value of 092 plusmn 021 Reduced degree ofcrystallinity was represented in XRPD diagram Differentialscanning calorimetry (DSC) curves of AP coarse powder andAP nanocrystals were studied and compared A decrease inmelting point of AP was observed with nanoparticles whichcould be attributed to particle size reduction to nanometerrange FTIR patterns were identical for both coarse powderand nanoparticles thus indicating the chemical stability of APduring SAS process AP nanocrystals exhibited more rapiddissolution rate with much higher cumulative amount ofdissolved AP than AP coarse powder The higher dissolutionof AP nanocrystals could be due to the enhanced saturated
Journal of Pharmaceutics 7
solubility resulting from a significant decrease of particle size[56] In vivo studies showed 36 and 34 fold enhancement in119862max and AUC of AP respectively after oral administrationof AP nanocrystals The absolute bioavailability of AP coarsepowder was found to be 20 whereas nanoparticles exhib-ited 69 absolute bioavailability Thus improved solubilitydissolution rate and bioavailability depict the usefulnessof these methods for delivery of such BCS class secondcompounds
223 Flavanones They are natural compounds of restrictedoccurrence and are sometimes termed as minor flavonoidsThe cardinal aglycones are naringenin hesperetin and erio-dictyol (Figure 2(f4)) Glycosylation of flavanones is generallyattained by a disaccharide at position 7 which is eithera neohesperidose that imparts a bitter taste (such as tonaringin in grapefruit) or a rutinose which is flavorlessCitrus fruits contain considerable amount of flavanonesTomatoes and certain aromatic plants such as mint alsoconstitute flavanones Hesperidin and narirutin are presentin orange juice at a concentration of 200ndash600mgL and 15ndash85mgL respectively A single glass of orange juice maycontain between 40 and 140mg of flavanone glycosides [57]However very high flavanone content is found to be presentin the solid parts of orange fruit particularly the albedo (thewhite spongy portion) and the membranes separating thesegments Thus an orange fruit may comprise up to 5 timesas much as a glass of orange juice
(1) Hesperetin It is a naturally occurring flavonoid chemicallyknown as 3101584057-trihydroxy-4-methoxyflavanone Hesperetinis found almost exclusively in citrus fruits [58] Studiesrevealed that hesperetin can avert colon [59] urinary bladder[60] and chemically induced mammary carcinogenesis [61]Other biological activities of hesperetin include antioxidant[62] and anti-inflammatory [63] Aqueous solubility of hes-peretin was found to be 14 120583gmL [64] Nanoparticles ofhesperetin by two different methods namely APSP and EPNhave been have been reported to enhance the solubility anddissolution rate [65]
APSP The solvent and antisolvent used in this methodwere ethanol and deionized water respectively The methodcomprised of dissolution of hesperetin in solvent followed byinjection of drug solution into an antisolvent with the help ofsyringe The solution was constantly stirred using magneticstirrer (200ndash1000 rpm) and the flow rate was varied from 2 to10mLmin
EPN Nanoparticles in this method were formed by quickaddition of drug solution containing hesperetin and ethanolinto antisolvent Hexane was used as antisolvent Vacuumdrying was carried out for quick evaporation of solventleading to formation of nanosuspension
Figures 4(a) and 4(b) depict the effect of various param-eters on particle size and solubility of hesperetin by APSPand EPN methods The formulation containing 5mgmLdrug concentration 10mLmin flow rate stirring speed of1000 rpm and solvent antisolvent ratio of 1 20 depicted
highest solubility (988 120583gmL) This was attributed to adecrease in particle size from 34 120583m to 075120583m (revealed bySEM) In case of EPN highest solubility (1117 120583gmL) wasseen in formulation containing 5 120583gmL drug concentrationand 1 20 solvent antisolvent ratioThe DSC studies revealedthat the melting point of nanoparticles prepared by bothmethods was identical to crude hesperetin but enthalpyof fusion was reduced due to reduction in crystallinity ofnanoparticles of hesperetin
(2) Naringenin (NRG) It is a kind of flavanone (4101584057-trihydroxyflvanone) found extremely in tomatoes [66]cherries [67] grape fruit and citrus fruits [58] In addi-tion to antioxidant property [68] NRG also possess anti-inflammatory [69] antitumour [70] and hepatoprotectiveeffects [71] However clinical applicability of NRG is limitedby its low solubility and bioavailability NRG possesses lowaqueous solubility (45 120583gmL) [72] therefore measures weretaken to investigate methods for enhancing solubility ofNRG Transglycosylation of hesperetin leads to an increasein solubility of hesperetin [73] This formed the basis forpreparing spray-dried particles of NRG with 120572-Glucosylhesperidin (Hsp-G) in order to enhance its solubility [72]Different loading ratios of NRGHsp-G (1 1 to 1 20 ww)were dissolved in ethanol water (8 2 vv) solution Theresultant suspension was then subjected to spray drying atthe rate of 10mLmin employing a spray nozzle of diameter406 120583m and pressure of 013MPa The inlet and outlet tem-peratures of drying chamber were 120∘C and 70∘C respec-tively SEM images of NRGHsp-G samples showed sphericalshaped aggregates with average particle size of 3-4 120583mThe resultant spray-dried particles of NRG showed 60-foldimprovement in solubility when loading ratio of NRGHsp-Gwas 1 20
224 Isoflavones They have structural similarities to estro-gens as they have hydroxyl groups in positions 7 and 41015840 ina configuration analogous to that of the hydroxyls in theestradiol molecule (Figure 2(f3)) Although isoflavones arenot steroids they have potential estrogenic activityThis illus-trates their ability to bind to estrogen receptors They possesspseudohormonal properties and are consequently classifiedas phytoestrogens [2] Leguminous plants are the exclusivesource of isoflavones The main source of isoflavones in thehuman diet is soya and its processed products Isoflavonesprincipally contain 3 compounds genistein daidzein andglycitein (concentration ratio of 1 1 02) Factors such asgeographic zone growing conditions and processing of soyaand its manufactured products greatly affect their isoflavonecontent Isoflavone content of soybeans is 580ndash3800mgkgand of soymilk is 30ndash175mgL [74 75]
Genistein It is a naturally occurring plant flavonoid Soyproducts are the richest sources of genistein [76] Chemicalstructure of genistein (4101584057-trihydroxyisoflavone) containsan isoflavone backbone Genistein has beneficial effects inareas of cancer [77] cardiovascular diseases [78] and post-menopausal symptoms [79] Aqueous solubility of genisteinis very poor approximately 081 120583gmL [80] which leads to
8 Journal of Pharmaceutics
205167
121086 075
695 701
815
966 988
0
1
2
3
4
5
6
7
8
9
10
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
Flow rate(mLmin)
210101010
Stirring speed(rpm)
200200
100010001000
S AS
1 101 101 101 201 20
Drug concentration(mgmL)
555
105
(a)
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
S AS
1 101 151 201 201 20
Drug concentration(mgmL)
55
15105
089 072 06 054 045
965
1082 1097 1113 1117
0
2
4
6
8
10
12
(b)
Figure 4 (a) Depicting the effect of various parameters on particle size and solubility of hesperetin by APSP method [65] (b) Depicting theeffect of various parameters on particle size and solubility of hesperetin by EPN method [65]
low bioavailability of the drug A solid dispersion of genisteinin Pluronic F127 polymeric micelles has been reported forsolubility enhancement by Kwon et al [80] An ethanolicsolution of Pluronic F127 was used to dissolve genisteinby constant stirring at 37∘C for 30min The solution whenevaporated led to formation of clear gel-like matrix Additionof water and constant stirring resulted in formation of poly-meric micelles containing genistein The resulting solutionwas filtered employing 045120583m pore size membrane filter toremove any undissolved genistein followed by lyophilizationat minus80∘C Average particle size of genistein loaded polymericmicelles was found to be 2776 plusmn 046 nm with PI of 026 Invitro drug release showed genistein release 48ndash58 in pH 12mediumand 44ndash82 in pH68mediumwhichwas attributedto higher solubilizing ability of polymeric micelles The invivo pharmacokinetic characterization showed an increasein 119862max from 122 to 568120583gmL and decrease in 119905max from055 to 020 h The polymeric micelles also demonstratedenhanced bioavailability thus confirming enhanced genisteinsolubility and release in gastrointestinal tract
23 Stilbenes Stilbenes encompass a group of biologicallyactive compounds however human diet comprises only few
of these (Figure 1(e)) Examplesmay include trans-resveratroland trans-piceid (its natural glycoside)
231 Resveratrol It belongs to a class of naturally occurringpolyphenols known as stilbenes It is mainly present inthe form of trans-resveratrol (3541015840-trihydroxystilbene) inhuman dietThe dietary sources of resveratrol include peanutbutter dark chocolate blueberries and red wine About23mgL of trans-resveratrol is present in red wine [81]Resveratrol exhibits antiangiogenesis [82] cardioprotective[83] anticarcinogenic and anti-inflammatory activities [84]Aqueous solubility of resveratrol was found to be 30 120583gmLthereby limiting pharmaceutical potential of resveratrol [85]Zhang et al [86] reported a method for enhancing solubilityof resveratrol by formulating nanoparticles of resveratrolusing antisolvent precipitation method The ethanolic solu-tion of resveratrol (solvent) was pouredwith vigorous stirring(9000 rpm) into aqueous solution of polymer (antisolvent)resulting into precipitation of resveratrol after 30 s Fourdifferent polymers that is HPMC PVP PEG 400 and P188were employed The solvent antisolvent ratio was kept con-stant at 1 20 Process parameters employed for spray dryingwere 105∘C inlet temperature 50ndash60∘C outlet temperature
Journal of Pharmaceutics 9
Antisolvent precipitationusing a syringe pump
(APSP)
Evaporative precipitationof nanosuspension (EPN)
20 mL of above solution wasfilled in syringe
Magneticstirring
(200ndash1000) rpm
Flow rate (2ndash10 mLmin)
Solution was injected into deionized
Formed nanoparticles were filteredand vacuum-dried
Hexane was added quickly toform nanosuspension
Vacuum drying of nanoparticles
Vacuum appliedusing rotaryevaporator
Conc of curcumin in ethanolmdash5ndash15 mgmLa
Solvent to antisolvent ratiomdash1 10ndash1 20 (vv)b
Curcumin was dissolved in ethanolaCurcumin was dissolved in ethanola
Evaporation of ethanol and hexaneb
waterb
Figure 5 APSP and EPN techniques for nanoparticle formulation of curcumin [92]
1mLmin spray flow rate and 065MPa atomization airpressure The particle size obtained with HPMC PVP PEG400 and P188 was found to be 161 plusmn 3 1156 plusmn 78 2168plusmn 26 and 1644 plusmn 47 nm respectively Dissolution studiesrepresented complete dissolution of resveratrol nanodisper-sion in less than 45min whereas raw resveratrol did notdissolve completely even after 120min indicating increasedwater solubility of resveratrol by using polymers
24 Miscellaneous
241 Curcumin It is a naturally occurring polyphenol whichis extracted from the plants of Curcuma longa Curcumalonga (turmeric) has been used to treat ailments since a longtime ago It is also employed as a spice in Indian cuisineCurcumin exhibits a variety of pharmacological actions suchas antitumor [87] anti-HIV [88] antioxidant and anti-inflammatory [89] However the goodness of curcuminhas not been able to reach up to its potential yet Themaximum solubility of curcumin in plain aqueous bufferpH 50 has been reported to be 11 ngmL [90] and the oraldose of curcumin for treating advanced colorectal cancer wasfound to be 36 gday [91] Therefore there is need to devisestrategies to increase solubility of curcumin Nanoparticlesof curcumin employing antisolvent precipitation method
have been reported by Kakran et al [92] The antisolventprecipitation involved two methods namely antisolvent pre-cipitation using a syringe pump (APSP) and evaporative pre-cipitation of nanosuspension (EPN) In first method ethanolwas used as solvent and deionized water as antisolvent InEPN method solvent was same but antisolvent employedwas hexane Figure 5 depicts a schematic representation oftechniques employed for formulation of nanoparticles Theeffect of process variables such as stirring speed flow ratesolvent antisolvent (S AS) ratio and drug concentrationwas studied on particle size and solubility
An increase in the stirring speed from 200 to 1000 rpmin APSP leads to a decrease in particle size from 550 to500 nm An increase in stirring speed led to intensificationof micromixing between multiphases resulting in decrease inparticle size Similar results were observed with a variationin flow rate of curcumin solution An increase in the flowrate from 2 to 10mLmin led to decrease in length ofcurcumin particles from 2560 to 1860 nm since an increasein flow rate resulted in rapid mixing Further an inverserelationship was reported between amount of antisolventin SAS ratios and particle size With an increase in S ASratio 1 20 from 1 10 a decrease in length and diameter ofcurcumin particles from 1860 and 490 nm to 930 and 340 nmrespectively was reported The drug concentration exhibited
10 Journal of Pharmaceutics
Polystyrenebeads
(467 g)
Curcumin(8820 mg)
Stainlesssteel
chamber(100 mL)
02 mgmLSDS
441 mL ofHPC-SL (5
mgmL)
Curcumincolloidal
suspension
Micronization(3600 rpm
90 min)Collection
ofcurcumin
suspension
Freezedrying
Preparation of nanocrystal solid dispersion
Preparation of amorphous solid dispersion
Curcumin
curcuminof curcumin
Curcumin
90 (vv)dioxane solution Freeze drying
Sieving with twodifferent meshsizes of sieves
dissolved insolvent
Sonicationat room
temp
Formation ofprimary
emulsion ofAddition of
Mixing
aqueousmedium
Formation offine dispersion
HPMC-AS(800 mg)
(200 mg)
Preparation of nanoemulsion formulation
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
solubility resulting from a significant decrease of particle size[56] In vivo studies showed 36 and 34 fold enhancement in119862max and AUC of AP respectively after oral administrationof AP nanocrystals The absolute bioavailability of AP coarsepowder was found to be 20 whereas nanoparticles exhib-ited 69 absolute bioavailability Thus improved solubilitydissolution rate and bioavailability depict the usefulnessof these methods for delivery of such BCS class secondcompounds
223 Flavanones They are natural compounds of restrictedoccurrence and are sometimes termed as minor flavonoidsThe cardinal aglycones are naringenin hesperetin and erio-dictyol (Figure 2(f4)) Glycosylation of flavanones is generallyattained by a disaccharide at position 7 which is eithera neohesperidose that imparts a bitter taste (such as tonaringin in grapefruit) or a rutinose which is flavorlessCitrus fruits contain considerable amount of flavanonesTomatoes and certain aromatic plants such as mint alsoconstitute flavanones Hesperidin and narirutin are presentin orange juice at a concentration of 200ndash600mgL and 15ndash85mgL respectively A single glass of orange juice maycontain between 40 and 140mg of flavanone glycosides [57]However very high flavanone content is found to be presentin the solid parts of orange fruit particularly the albedo (thewhite spongy portion) and the membranes separating thesegments Thus an orange fruit may comprise up to 5 timesas much as a glass of orange juice
(1) Hesperetin It is a naturally occurring flavonoid chemicallyknown as 3101584057-trihydroxy-4-methoxyflavanone Hesperetinis found almost exclusively in citrus fruits [58] Studiesrevealed that hesperetin can avert colon [59] urinary bladder[60] and chemically induced mammary carcinogenesis [61]Other biological activities of hesperetin include antioxidant[62] and anti-inflammatory [63] Aqueous solubility of hes-peretin was found to be 14 120583gmL [64] Nanoparticles ofhesperetin by two different methods namely APSP and EPNhave been have been reported to enhance the solubility anddissolution rate [65]
APSP The solvent and antisolvent used in this methodwere ethanol and deionized water respectively The methodcomprised of dissolution of hesperetin in solvent followed byinjection of drug solution into an antisolvent with the help ofsyringe The solution was constantly stirred using magneticstirrer (200ndash1000 rpm) and the flow rate was varied from 2 to10mLmin
EPN Nanoparticles in this method were formed by quickaddition of drug solution containing hesperetin and ethanolinto antisolvent Hexane was used as antisolvent Vacuumdrying was carried out for quick evaporation of solventleading to formation of nanosuspension
Figures 4(a) and 4(b) depict the effect of various param-eters on particle size and solubility of hesperetin by APSPand EPN methods The formulation containing 5mgmLdrug concentration 10mLmin flow rate stirring speed of1000 rpm and solvent antisolvent ratio of 1 20 depicted
highest solubility (988 120583gmL) This was attributed to adecrease in particle size from 34 120583m to 075120583m (revealed bySEM) In case of EPN highest solubility (1117 120583gmL) wasseen in formulation containing 5 120583gmL drug concentrationand 1 20 solvent antisolvent ratioThe DSC studies revealedthat the melting point of nanoparticles prepared by bothmethods was identical to crude hesperetin but enthalpyof fusion was reduced due to reduction in crystallinity ofnanoparticles of hesperetin
(2) Naringenin (NRG) It is a kind of flavanone (4101584057-trihydroxyflvanone) found extremely in tomatoes [66]cherries [67] grape fruit and citrus fruits [58] In addi-tion to antioxidant property [68] NRG also possess anti-inflammatory [69] antitumour [70] and hepatoprotectiveeffects [71] However clinical applicability of NRG is limitedby its low solubility and bioavailability NRG possesses lowaqueous solubility (45 120583gmL) [72] therefore measures weretaken to investigate methods for enhancing solubility ofNRG Transglycosylation of hesperetin leads to an increasein solubility of hesperetin [73] This formed the basis forpreparing spray-dried particles of NRG with 120572-Glucosylhesperidin (Hsp-G) in order to enhance its solubility [72]Different loading ratios of NRGHsp-G (1 1 to 1 20 ww)were dissolved in ethanol water (8 2 vv) solution Theresultant suspension was then subjected to spray drying atthe rate of 10mLmin employing a spray nozzle of diameter406 120583m and pressure of 013MPa The inlet and outlet tem-peratures of drying chamber were 120∘C and 70∘C respec-tively SEM images of NRGHsp-G samples showed sphericalshaped aggregates with average particle size of 3-4 120583mThe resultant spray-dried particles of NRG showed 60-foldimprovement in solubility when loading ratio of NRGHsp-Gwas 1 20
224 Isoflavones They have structural similarities to estro-gens as they have hydroxyl groups in positions 7 and 41015840 ina configuration analogous to that of the hydroxyls in theestradiol molecule (Figure 2(f3)) Although isoflavones arenot steroids they have potential estrogenic activityThis illus-trates their ability to bind to estrogen receptors They possesspseudohormonal properties and are consequently classifiedas phytoestrogens [2] Leguminous plants are the exclusivesource of isoflavones The main source of isoflavones in thehuman diet is soya and its processed products Isoflavonesprincipally contain 3 compounds genistein daidzein andglycitein (concentration ratio of 1 1 02) Factors such asgeographic zone growing conditions and processing of soyaand its manufactured products greatly affect their isoflavonecontent Isoflavone content of soybeans is 580ndash3800mgkgand of soymilk is 30ndash175mgL [74 75]
Genistein It is a naturally occurring plant flavonoid Soyproducts are the richest sources of genistein [76] Chemicalstructure of genistein (4101584057-trihydroxyisoflavone) containsan isoflavone backbone Genistein has beneficial effects inareas of cancer [77] cardiovascular diseases [78] and post-menopausal symptoms [79] Aqueous solubility of genisteinis very poor approximately 081 120583gmL [80] which leads to
8 Journal of Pharmaceutics
205167
121086 075
695 701
815
966 988
0
1
2
3
4
5
6
7
8
9
10
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
Flow rate(mLmin)
210101010
Stirring speed(rpm)
200200
100010001000
S AS
1 101 101 101 201 20
Drug concentration(mgmL)
555
105
(a)
A B C D E
Particle size (120583m)Solubility (120583gmL)
Formulation
ABCDE
S AS
1 101 151 201 201 20
Drug concentration(mgmL)
55
15105
089 072 06 054 045
965
1082 1097 1113 1117
0
2
4
6
8
10
12
(b)
Figure 4 (a) Depicting the effect of various parameters on particle size and solubility of hesperetin by APSP method [65] (b) Depicting theeffect of various parameters on particle size and solubility of hesperetin by EPN method [65]
low bioavailability of the drug A solid dispersion of genisteinin Pluronic F127 polymeric micelles has been reported forsolubility enhancement by Kwon et al [80] An ethanolicsolution of Pluronic F127 was used to dissolve genisteinby constant stirring at 37∘C for 30min The solution whenevaporated led to formation of clear gel-like matrix Additionof water and constant stirring resulted in formation of poly-meric micelles containing genistein The resulting solutionwas filtered employing 045120583m pore size membrane filter toremove any undissolved genistein followed by lyophilizationat minus80∘C Average particle size of genistein loaded polymericmicelles was found to be 2776 plusmn 046 nm with PI of 026 Invitro drug release showed genistein release 48ndash58 in pH 12mediumand 44ndash82 in pH68mediumwhichwas attributedto higher solubilizing ability of polymeric micelles The invivo pharmacokinetic characterization showed an increasein 119862max from 122 to 568120583gmL and decrease in 119905max from055 to 020 h The polymeric micelles also demonstratedenhanced bioavailability thus confirming enhanced genisteinsolubility and release in gastrointestinal tract
23 Stilbenes Stilbenes encompass a group of biologicallyactive compounds however human diet comprises only few
of these (Figure 1(e)) Examplesmay include trans-resveratroland trans-piceid (its natural glycoside)
231 Resveratrol It belongs to a class of naturally occurringpolyphenols known as stilbenes It is mainly present inthe form of trans-resveratrol (3541015840-trihydroxystilbene) inhuman dietThe dietary sources of resveratrol include peanutbutter dark chocolate blueberries and red wine About23mgL of trans-resveratrol is present in red wine [81]Resveratrol exhibits antiangiogenesis [82] cardioprotective[83] anticarcinogenic and anti-inflammatory activities [84]Aqueous solubility of resveratrol was found to be 30 120583gmLthereby limiting pharmaceutical potential of resveratrol [85]Zhang et al [86] reported a method for enhancing solubilityof resveratrol by formulating nanoparticles of resveratrolusing antisolvent precipitation method The ethanolic solu-tion of resveratrol (solvent) was pouredwith vigorous stirring(9000 rpm) into aqueous solution of polymer (antisolvent)resulting into precipitation of resveratrol after 30 s Fourdifferent polymers that is HPMC PVP PEG 400 and P188were employed The solvent antisolvent ratio was kept con-stant at 1 20 Process parameters employed for spray dryingwere 105∘C inlet temperature 50ndash60∘C outlet temperature
Journal of Pharmaceutics 9
Antisolvent precipitationusing a syringe pump
(APSP)
Evaporative precipitationof nanosuspension (EPN)
20 mL of above solution wasfilled in syringe
Magneticstirring
(200ndash1000) rpm
Flow rate (2ndash10 mLmin)
Solution was injected into deionized
Formed nanoparticles were filteredand vacuum-dried
Hexane was added quickly toform nanosuspension
Vacuum drying of nanoparticles
Vacuum appliedusing rotaryevaporator
Conc of curcumin in ethanolmdash5ndash15 mgmLa
Solvent to antisolvent ratiomdash1 10ndash1 20 (vv)b
Curcumin was dissolved in ethanolaCurcumin was dissolved in ethanola
Evaporation of ethanol and hexaneb
waterb
Figure 5 APSP and EPN techniques for nanoparticle formulation of curcumin [92]
1mLmin spray flow rate and 065MPa atomization airpressure The particle size obtained with HPMC PVP PEG400 and P188 was found to be 161 plusmn 3 1156 plusmn 78 2168plusmn 26 and 1644 plusmn 47 nm respectively Dissolution studiesrepresented complete dissolution of resveratrol nanodisper-sion in less than 45min whereas raw resveratrol did notdissolve completely even after 120min indicating increasedwater solubility of resveratrol by using polymers
24 Miscellaneous
241 Curcumin It is a naturally occurring polyphenol whichis extracted from the plants of Curcuma longa Curcumalonga (turmeric) has been used to treat ailments since a longtime ago It is also employed as a spice in Indian cuisineCurcumin exhibits a variety of pharmacological actions suchas antitumor [87] anti-HIV [88] antioxidant and anti-inflammatory [89] However the goodness of curcuminhas not been able to reach up to its potential yet Themaximum solubility of curcumin in plain aqueous bufferpH 50 has been reported to be 11 ngmL [90] and the oraldose of curcumin for treating advanced colorectal cancer wasfound to be 36 gday [91] Therefore there is need to devisestrategies to increase solubility of curcumin Nanoparticlesof curcumin employing antisolvent precipitation method
have been reported by Kakran et al [92] The antisolventprecipitation involved two methods namely antisolvent pre-cipitation using a syringe pump (APSP) and evaporative pre-cipitation of nanosuspension (EPN) In first method ethanolwas used as solvent and deionized water as antisolvent InEPN method solvent was same but antisolvent employedwas hexane Figure 5 depicts a schematic representation oftechniques employed for formulation of nanoparticles Theeffect of process variables such as stirring speed flow ratesolvent antisolvent (S AS) ratio and drug concentrationwas studied on particle size and solubility
An increase in the stirring speed from 200 to 1000 rpmin APSP leads to a decrease in particle size from 550 to500 nm An increase in stirring speed led to intensificationof micromixing between multiphases resulting in decrease inparticle size Similar results were observed with a variationin flow rate of curcumin solution An increase in the flowrate from 2 to 10mLmin led to decrease in length ofcurcumin particles from 2560 to 1860 nm since an increasein flow rate resulted in rapid mixing Further an inverserelationship was reported between amount of antisolventin SAS ratios and particle size With an increase in S ASratio 1 20 from 1 10 a decrease in length and diameter ofcurcumin particles from 1860 and 490 nm to 930 and 340 nmrespectively was reported The drug concentration exhibited
10 Journal of Pharmaceutics
Polystyrenebeads
(467 g)
Curcumin(8820 mg)
Stainlesssteel
chamber(100 mL)
02 mgmLSDS
441 mL ofHPC-SL (5
mgmL)
Curcumincolloidal
suspension
Micronization(3600 rpm
90 min)Collection
ofcurcumin
suspension
Freezedrying
Preparation of nanocrystal solid dispersion
Preparation of amorphous solid dispersion
Curcumin
curcuminof curcumin
Curcumin
90 (vv)dioxane solution Freeze drying
Sieving with twodifferent meshsizes of sieves
dissolved insolvent
Sonicationat room
temp
Formation ofprimary
emulsion ofAddition of
Mixing
aqueousmedium
Formation offine dispersion
HPMC-AS(800 mg)
(200 mg)
Preparation of nanoemulsion formulation
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 4 (a) Depicting the effect of various parameters on particle size and solubility of hesperetin by APSP method [65] (b) Depicting theeffect of various parameters on particle size and solubility of hesperetin by EPN method [65]
low bioavailability of the drug A solid dispersion of genisteinin Pluronic F127 polymeric micelles has been reported forsolubility enhancement by Kwon et al [80] An ethanolicsolution of Pluronic F127 was used to dissolve genisteinby constant stirring at 37∘C for 30min The solution whenevaporated led to formation of clear gel-like matrix Additionof water and constant stirring resulted in formation of poly-meric micelles containing genistein The resulting solutionwas filtered employing 045120583m pore size membrane filter toremove any undissolved genistein followed by lyophilizationat minus80∘C Average particle size of genistein loaded polymericmicelles was found to be 2776 plusmn 046 nm with PI of 026 Invitro drug release showed genistein release 48ndash58 in pH 12mediumand 44ndash82 in pH68mediumwhichwas attributedto higher solubilizing ability of polymeric micelles The invivo pharmacokinetic characterization showed an increasein 119862max from 122 to 568120583gmL and decrease in 119905max from055 to 020 h The polymeric micelles also demonstratedenhanced bioavailability thus confirming enhanced genisteinsolubility and release in gastrointestinal tract
23 Stilbenes Stilbenes encompass a group of biologicallyactive compounds however human diet comprises only few
of these (Figure 1(e)) Examplesmay include trans-resveratroland trans-piceid (its natural glycoside)
231 Resveratrol It belongs to a class of naturally occurringpolyphenols known as stilbenes It is mainly present inthe form of trans-resveratrol (3541015840-trihydroxystilbene) inhuman dietThe dietary sources of resveratrol include peanutbutter dark chocolate blueberries and red wine About23mgL of trans-resveratrol is present in red wine [81]Resveratrol exhibits antiangiogenesis [82] cardioprotective[83] anticarcinogenic and anti-inflammatory activities [84]Aqueous solubility of resveratrol was found to be 30 120583gmLthereby limiting pharmaceutical potential of resveratrol [85]Zhang et al [86] reported a method for enhancing solubilityof resveratrol by formulating nanoparticles of resveratrolusing antisolvent precipitation method The ethanolic solu-tion of resveratrol (solvent) was pouredwith vigorous stirring(9000 rpm) into aqueous solution of polymer (antisolvent)resulting into precipitation of resveratrol after 30 s Fourdifferent polymers that is HPMC PVP PEG 400 and P188were employed The solvent antisolvent ratio was kept con-stant at 1 20 Process parameters employed for spray dryingwere 105∘C inlet temperature 50ndash60∘C outlet temperature
Journal of Pharmaceutics 9
Antisolvent precipitationusing a syringe pump
(APSP)
Evaporative precipitationof nanosuspension (EPN)
20 mL of above solution wasfilled in syringe
Magneticstirring
(200ndash1000) rpm
Flow rate (2ndash10 mLmin)
Solution was injected into deionized
Formed nanoparticles were filteredand vacuum-dried
Hexane was added quickly toform nanosuspension
Vacuum drying of nanoparticles
Vacuum appliedusing rotaryevaporator
Conc of curcumin in ethanolmdash5ndash15 mgmLa
Solvent to antisolvent ratiomdash1 10ndash1 20 (vv)b
Curcumin was dissolved in ethanolaCurcumin was dissolved in ethanola
Evaporation of ethanol and hexaneb
waterb
Figure 5 APSP and EPN techniques for nanoparticle formulation of curcumin [92]
1mLmin spray flow rate and 065MPa atomization airpressure The particle size obtained with HPMC PVP PEG400 and P188 was found to be 161 plusmn 3 1156 plusmn 78 2168plusmn 26 and 1644 plusmn 47 nm respectively Dissolution studiesrepresented complete dissolution of resveratrol nanodisper-sion in less than 45min whereas raw resveratrol did notdissolve completely even after 120min indicating increasedwater solubility of resveratrol by using polymers
24 Miscellaneous
241 Curcumin It is a naturally occurring polyphenol whichis extracted from the plants of Curcuma longa Curcumalonga (turmeric) has been used to treat ailments since a longtime ago It is also employed as a spice in Indian cuisineCurcumin exhibits a variety of pharmacological actions suchas antitumor [87] anti-HIV [88] antioxidant and anti-inflammatory [89] However the goodness of curcuminhas not been able to reach up to its potential yet Themaximum solubility of curcumin in plain aqueous bufferpH 50 has been reported to be 11 ngmL [90] and the oraldose of curcumin for treating advanced colorectal cancer wasfound to be 36 gday [91] Therefore there is need to devisestrategies to increase solubility of curcumin Nanoparticlesof curcumin employing antisolvent precipitation method
have been reported by Kakran et al [92] The antisolventprecipitation involved two methods namely antisolvent pre-cipitation using a syringe pump (APSP) and evaporative pre-cipitation of nanosuspension (EPN) In first method ethanolwas used as solvent and deionized water as antisolvent InEPN method solvent was same but antisolvent employedwas hexane Figure 5 depicts a schematic representation oftechniques employed for formulation of nanoparticles Theeffect of process variables such as stirring speed flow ratesolvent antisolvent (S AS) ratio and drug concentrationwas studied on particle size and solubility
An increase in the stirring speed from 200 to 1000 rpmin APSP leads to a decrease in particle size from 550 to500 nm An increase in stirring speed led to intensificationof micromixing between multiphases resulting in decrease inparticle size Similar results were observed with a variationin flow rate of curcumin solution An increase in the flowrate from 2 to 10mLmin led to decrease in length ofcurcumin particles from 2560 to 1860 nm since an increasein flow rate resulted in rapid mixing Further an inverserelationship was reported between amount of antisolventin SAS ratios and particle size With an increase in S ASratio 1 20 from 1 10 a decrease in length and diameter ofcurcumin particles from 1860 and 490 nm to 930 and 340 nmrespectively was reported The drug concentration exhibited
10 Journal of Pharmaceutics
Polystyrenebeads
(467 g)
Curcumin(8820 mg)
Stainlesssteel
chamber(100 mL)
02 mgmLSDS
441 mL ofHPC-SL (5
mgmL)
Curcumincolloidal
suspension
Micronization(3600 rpm
90 min)Collection
ofcurcumin
suspension
Freezedrying
Preparation of nanocrystal solid dispersion
Preparation of amorphous solid dispersion
Curcumin
curcuminof curcumin
Curcumin
90 (vv)dioxane solution Freeze drying
Sieving with twodifferent meshsizes of sieves
dissolved insolvent
Sonicationat room
temp
Formation ofprimary
emulsion ofAddition of
Mixing
aqueousmedium
Formation offine dispersion
HPMC-AS(800 mg)
(200 mg)
Preparation of nanoemulsion formulation
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Formed nanoparticles were filteredand vacuum-dried
Hexane was added quickly toform nanosuspension
Vacuum drying of nanoparticles
Vacuum appliedusing rotaryevaporator
Conc of curcumin in ethanolmdash5ndash15 mgmLa
Solvent to antisolvent ratiomdash1 10ndash1 20 (vv)b
Curcumin was dissolved in ethanolaCurcumin was dissolved in ethanola
Evaporation of ethanol and hexaneb
waterb
Figure 5 APSP and EPN techniques for nanoparticle formulation of curcumin [92]
1mLmin spray flow rate and 065MPa atomization airpressure The particle size obtained with HPMC PVP PEG400 and P188 was found to be 161 plusmn 3 1156 plusmn 78 2168plusmn 26 and 1644 plusmn 47 nm respectively Dissolution studiesrepresented complete dissolution of resveratrol nanodisper-sion in less than 45min whereas raw resveratrol did notdissolve completely even after 120min indicating increasedwater solubility of resveratrol by using polymers
24 Miscellaneous
241 Curcumin It is a naturally occurring polyphenol whichis extracted from the plants of Curcuma longa Curcumalonga (turmeric) has been used to treat ailments since a longtime ago It is also employed as a spice in Indian cuisineCurcumin exhibits a variety of pharmacological actions suchas antitumor [87] anti-HIV [88] antioxidant and anti-inflammatory [89] However the goodness of curcuminhas not been able to reach up to its potential yet Themaximum solubility of curcumin in plain aqueous bufferpH 50 has been reported to be 11 ngmL [90] and the oraldose of curcumin for treating advanced colorectal cancer wasfound to be 36 gday [91] Therefore there is need to devisestrategies to increase solubility of curcumin Nanoparticlesof curcumin employing antisolvent precipitation method
have been reported by Kakran et al [92] The antisolventprecipitation involved two methods namely antisolvent pre-cipitation using a syringe pump (APSP) and evaporative pre-cipitation of nanosuspension (EPN) In first method ethanolwas used as solvent and deionized water as antisolvent InEPN method solvent was same but antisolvent employedwas hexane Figure 5 depicts a schematic representation oftechniques employed for formulation of nanoparticles Theeffect of process variables such as stirring speed flow ratesolvent antisolvent (S AS) ratio and drug concentrationwas studied on particle size and solubility
An increase in the stirring speed from 200 to 1000 rpmin APSP leads to a decrease in particle size from 550 to500 nm An increase in stirring speed led to intensificationof micromixing between multiphases resulting in decrease inparticle size Similar results were observed with a variationin flow rate of curcumin solution An increase in the flowrate from 2 to 10mLmin led to decrease in length ofcurcumin particles from 2560 to 1860 nm since an increasein flow rate resulted in rapid mixing Further an inverserelationship was reported between amount of antisolventin SAS ratios and particle size With an increase in S ASratio 1 20 from 1 10 a decrease in length and diameter ofcurcumin particles from 1860 and 490 nm to 930 and 340 nmrespectively was reported The drug concentration exhibited
10 Journal of Pharmaceutics
Polystyrenebeads
(467 g)
Curcumin(8820 mg)
Stainlesssteel
chamber(100 mL)
02 mgmLSDS
441 mL ofHPC-SL (5
mgmL)
Curcumincolloidal
suspension
Micronization(3600 rpm
90 min)Collection
ofcurcumin
suspension
Freezedrying
Preparation of nanocrystal solid dispersion
Preparation of amorphous solid dispersion
Curcumin
curcuminof curcumin
Curcumin
90 (vv)dioxane solution Freeze drying
Sieving with twodifferent meshsizes of sieves
dissolved insolvent
Sonicationat room
temp
Formation ofprimary
emulsion ofAddition of
Mixing
aqueousmedium
Formation offine dispersion
HPMC-AS(800 mg)
(200 mg)
Preparation of nanoemulsion formulation
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
PEG 400 100 120583L of propylene glycol50 120583L of ethanol 10 120583L of Tween-80
aSolvent mixture consists of 200 120583L of
mixturea
Figure 6 Formulation of curcumin solid dispersions [94]
a direct relationship with particle size as greater supersatura-tion followed by faster nucleation rate and smaller particleswas observed with an increase in drug concentration Theparticle length increased from 930 to 965 nm with a changein drug concentration from 5 to 15mgmL Further DSCstudies revealed a decrease in curcumin crystallinity owingto decrease in melting enthalpy of nanoparticles althoughmelting point was identical to original curcumin The sol-ubility studies indicated that solubility of curcumin (058 plusmn003 120583gmL) was increased by APSP and EPN methods to748 plusmn 011 120583gmL and 823 plusmn 007 120583gmL respectively whichwas ascribed to a reduced particle size [93] and decreasedcrystallinity [46]
Nanocrystal Solid Dispersions of Curcumin Solid dispersionshave also been demonstrated to increase the bioavailabil-ity of poorly water soluble drugs Onoue et al [94] havereported the formulation of solid dispersions of curcumin toenhance its solubility Three types of curcumin dispersionswere formulated namely nanocrystal solid dispersion (CSD)amorphous solid dispersion (ASD) and nanoemulsion (NE)
Figure 6 shows the schematic representation of preparation ofthree types of solid dispersions Diffraction pattern of CSD-curcumin was identical with crystalline curcumin indicatinghigh crystallinity of curcumin whereas ASD-curcumin wasfound to be amorphous Release rates of amorphous soliddispersion nanocrystal solid dispersion and nanoemulsionformulation were found to be 95 (180min) 80 (180min)and 93 (60min) respectively thus indicating enhancedsolubility of curcumin with solid dispersions
Self-Microemulsifying Drug Delivery Systems of Curcumin(SMEDDS) Use of SMEDDS as one of the approachesto enhance solubility dissolution and oral absorption ofpoorly water soluble drugs has gained interest recently [95]Cui et al [96] employed SMEDDS for enhancing solubilityof curcumin Curcumin loaded SMEDDS were formulatedemploying oil (ethyl oleate) surfactant (the mixtures ofemulsifierOP cremorphor EL-40 1 1 ww) and cosurfactant(PEG 400) Different concentrations of the three componentswere used and evaluated for particle size and solubility Theoptimal concentration of oil surfactant and cosurfactant was
Journal of Pharmaceutics 11
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
found to be 125 575 and 30 respectively Accordingto transmission electron microscopy (TEM) images themean particle size of formulation after dilution with waterwas found to be 21 nm and the solubility of curcumin wasenhanced to 21mgg A rapid dissolution (85 in 10min) wasobserved with SMEDDS whereas crude curcumin showednegligible release even after 60min in both pH 12 and68 buffer solutions In vivo oral absorption of curcuminloaded SMEDDS depicted 38-time increase in absorptionpercentage of SMEDDS
3 Conclusion
Increase in solubility of a therapeutic agent can enhance thebioavailability of that compound Polyphenols are naturallyoccurring active principles with wide variety of physiologicaland biological activities However their therapeutic potentialhas not been exposed widely because of their low solubilitiesThis review discusses the various techniques employed sofar for solubility enhancement of polyphenols The differentstrategies for example antisolvent precipitation evaporativeprecipitation high pressure homogenization or SMEDDSresulted in approximately 15ndash20-fold enhancement in solu-bility and 3ndash5-fold enhancement in bioavailability for somepolyphenols thus suggesting that application potential ofpolyphenols can be enhanced by increasing their solubility
Abbreviations
AP ApigeninAPSP Antisolvent precipitation using a syringe
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] V Atul Bhattaram U Graefe C Kohlert M Veit and HDerendorf ldquoPharmacokinetics and bioavailability of herbalmedicinal productsrdquo Phytomedicine vol 9 no 3 pp 1ndash33 2002
[2] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo The AmericanJournal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004
[3] A Scalbert and G Williamson ldquoDietary intake and bioavail-ability of polyphenolsrdquo Journal of Nutrition vol 130 no 8 pp2073Sndash2085S 2000
[4] E Middleton Jr C Kandaswami and T C Theoharides ldquoTheeffects of plant flavonoids on mammalian cells implicationsfor inflammation heart disease and cancerrdquo PharmacologicalReviews vol 52 no 4 pp 673ndash751 2000
[5] A Scalbert C Manach C Morand C Remesy and L JimenezldquoDietary polyphenols and the prevention of diseasesrdquo CriticalReviews in Food Science and Nutrition vol 45 no 4 pp 287ndash306 2005
[6] G L Amidon H Lennernas V P Shah and J R Crison ldquoAtheoretical basis for a biopharmaceutic drug classification thecorrelation of in vitro drug product dissolution and in vivobioavailabilityrdquo Pharmaceutical Research vol 12 no 3 pp 413ndash420 1995
[7] C M OrsquoDriscoll and B T Griffin ldquoBiopharmaceutical chal-lenges associated with drugs with low aqueous solubility-Thepotential impact of lipid-based formulationsrdquo Advanced DrugDelivery Reviews vol 60 no 6 pp 617ndash624 2008
[8] G D Stoner C Sardo G Apseloff et al ldquoPharmacokinetics ofanthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 daysrdquo Journal of ClinicalPharmacology vol 45 no 10 pp 1153ndash1164 2005
[9] C H Cottart V Nivet-Antoine C Laguillier-Morizot and J LBeaudeux ldquoResveratrol bioavailability and toxicity in humansrdquoMolecular Nutrition and Food Research vol 54 no 1 pp 7ndash162010
[10] P C H Hollman J M P van Trijp M N C P Buysman et alldquoRelative bioavailability of the antioxidant flavonoid quercetinfrom various foods in manrdquo FEBS Letters vol 418 no 1-2 pp152ndash156 1997
[11] HMeyer A BolarinwaGWolfram and J Linseisen ldquoBioavail-ability of apigenin from apiin-rich parsley in humansrdquo Annalsof Nutrition and Metabolism vol 50 no 3 pp 167ndash172 2006
[12] I Erlund E Meririnne G Alfthan and A Aro ldquoHumannutrition and metabolism plasma kinetics and urinary excre-tion of the flavanones naringenin and hesperetin in humansafter ingestion of orange juice and grapefruit juicerdquo Journal ofNutrition vol 131 no 2 pp 235ndash241 2001
[13] H Matsumoto H Inaba M Kishi S Tominaga M Hirayamaand T Tsuda ldquoOrally administered delphinidin 3-rutinosideand cyanidin 3-rutinoside are directly absorbed in rats andhumans and appear in the blood as the intact formsrdquo Journalof Agricultural and Food Chemistry vol 49 no 3 pp 1546ndash15512001
[14] X Xu H J Wang P A Murphy L Cook and S HendrichldquoDaidzein is a more bioavailable soymilk isoflavone than is
12 Journal of Pharmaceutics
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
genistein in adult womenrdquo Journal of Nutrition vol 124 no 6pp 825ndash832 1994
[15] Q Shen X Li D Yuan andW Jia ldquoEnhanced oral bioavailabil-ity of daidzein by self-microemulsifying drug delivery systemrdquoChemical and Pharmaceutical Bulletin vol 58 no 5 pp 639ndash643 2010
[16] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011
[17] R T Bonnecaze and D R Lloyd Nanoparticle engineeringprocesses evaporative precipitation into aqueous solution (EPAS)and antisolvent precipitation to enhance the dissolution rates ofpoorly water soluble drugs [PhD thesis] University of TexasAustin Tex USA 2004
[18] J E Kipp ldquoThe role of solid nanoparticle technology in theparenteral delivery of poorly water-soluble drugsrdquo InternationalJournal of Pharmaceutics vol 284 no 1-2 pp 109ndash122 2004
[19] S K Das S Roy Y Kalimuthu J Khanam and A NandaldquoSolid dispersions an approach to enhance the bioavailabilityof poorly water-soluble drugsrdquo International Journal of Pharma-cology and Pharmaceutical Technology vol 1 no 1 pp 37ndash462012
[20] A T M Serajuddln ldquoSolid dispersion of poorly water-solubledrugs early promises subsequent problems and recent break-throughsrdquo Journal of Pharmaceutical Sciences vol 88 no 10 pp1058ndash1066 1999
[21] B Sinha R H Muller and J P Moschwitzer ldquoBottom-upapproaches for preparing drug nanocrystals formulations andfactors affecting particle sizerdquo International Journal of Pharma-ceutics vol 453 no 1 pp 126ndash141 2013
[22] P Balakrishnan B J Lee D H Oh et al ldquoEnhanced oralbioavailability of dexibuprofen by a novel solid Self-emulsifyingdrug delivery system (SEDDS)rdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 72 no 3 pp 539ndash545 2009
[23] R N Gursoy and S Benita ldquoSelf-emulsifying drug deliverysystems (SEDDS) for improved oral delivery of lipophilicdrugsrdquo Biomedicine and Pharmacotherapy vol 58 no 3 pp173ndash182 2004
[24] M N Clifford ldquoChlorogenic acids and other cinnamatesmdashnature occurrence and dietary burdenrdquo Journal of the Scienceof Food and Agriculture vol 79 no 3 pp 362ndash372 1999
[25] F Sosulski K Krygier and L Hogge ldquoFree esterified andinsoluble-bound phenolic acids 3 composition of phenolicacids in cereal and potato floursrdquo Journal of Agricultural andFood Chemistry vol 30 no 2 pp 337ndash340 1982
[26] I Lempereur X Rouau and J Abecassis ldquoGenetic and agro-nomic variation in arabinoxylan and ferulic acid contentsof durum wheat (Triticum durum L) grain and its millingfractionsrdquo Journal of Cereal Science vol 25 no 2 pp 103ndash1101997
[27] M Naczk and F Shahidi ldquoExtraction and analysis of phenolicsin foodrdquo Journal of Chromatography A vol 1054 no 1-2 pp 95ndash111 2004
[28] L H Yao Y M Jiang J Shi et al ldquoFlavonoids in food and theirhealth benefitsrdquo Plant Foods for Human Nutrition vol 59 no 3pp 113ndash122 2004
[29] S H Hakkinen S O Karenlampi H M Mykkanen I MHeinonen and A R Torronen ldquoEllagic acid content in berriesinfluence of domestic processing and storagerdquo European FoodResearch and Technology vol 212 no 1 pp 75ndash80 2000
[30] N Wang Z Y Wang S L Mo et al ldquoEllagic acid a phenoliccompound exerts anti-angiogenesis effects via VEGFR-2 sig-naling pathway in breast cancerrdquo Breast Cancer Research andTreatment pp 134943ndash3955 2012
[31] C Bell and S Hawthorne ldquoEllagic acid pomegranate andprostate cancermdasha mini reviewrdquo Journal of Pharmacy andPharmacology vol 60 no 2 pp 139ndash144 2008
[32] M Boukharta G Jalbert and A Castonguay ldquoBiodistributionof ellagic acid and dose-related inhibition of lung tumorigenesisin AJ micerdquo Nutrition and Cancer vol 18 no 2 pp 181ndash1891992
[33] A Gonzalez-Sarrıas J C Espın F A Tomas-Barberan andM T Garcıa-Conesa ldquoGene expression cell cycle arrest andMAPK signalling regulation in Caco-2 cells exposed to ellagicacid and itsmetabolites urolithinsrdquoMolecular NutritionampFoodResearch vol 53 no 6 pp 686ndash698 2009
[34] M Larrosa M T Garcıa-Conesa J C Espın and F A Tomas-Barberan ldquoEllagitannins ellagic acid and vascular healthrdquoMolecular Aspects of Medicine vol 31 no 6 pp 513ndash539 2010
[35] Y Porat A Abramowitz and E Gazit ldquoInhibition of amy-loid fibril formation by polyphenols structural similarity andaromatic interactions as a common inhibition mechanismrdquoChemical Biology andDrugDesign vol 67 no 1 pp 27ndash37 2006
[36] I Bala V Bhardwaj S Hariharan and M N V R KumarldquoAnalytical methods for assay of ellagic acid and its solubilitystudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol40 no 1 pp 206ndash210 2006
[37] B Li K Harich LWegiel L S Taylor and K J Edgar ldquoStabilityand solubility enhancement of ellagic acid in cellulose estersolid dispersionsrdquo Carbohydrate Polymers vol 92 no 2 pp1443ndash1450 2012
[38] A Hassig W X Linag H Schwabl and K StampflildquoFlavonoids and tannins plant-based antioxidants with vitamincharacterrdquoMedical Hypotheses vol 52 no 5 pp 479ndash481 1999
[39] J F Hammerstone S A Lazarus andHH Schmitz ldquoProcyani-din content and variation in some commonly consumed foodsrdquoJournal of Nutrition vol 130 no 8 pp 2086Sndash2092S 2000
[40] J Macheix A Fleuriet and J Billot Fruit Phenolics CRC PressBoca Raton Fla USA 1990
[41] S F Price P J Breen M Valladao and B T Watson ldquoClustersun exposure and quercetin in Pinot noir grapes and winerdquoTheAmerican Journal of Enology and Viticulture vol 46 no 2 pp187ndash194 1995
[42] J V Formica ldquoReview of the biology of quercetin and relatedbioflavonoidsrdquo Food and Chemical Toxicology vol 33 no 12 pp1061ndash1080 1995
[43] A T Jan M R Kamli I Murtaza J B Singh A Ali and QM R Haq ldquoDietary flavonoid quercetin and associated healthbenefitsmdashan overviewrdquo Food Reviews International vol 26 no3 pp 302ndash317 2010
[44] P G Cadena M A Pereira R Cordeiro et al ldquoNanoencap-sulation of quercetin and resveratrol into elastic liposomesrdquoBiochimica et Biophysica Acta vol 1828 no 2 pp 309ndash316 2012
[45] L Gao G Liu X Wang F Liu Y Xu and J Ma ldquoPreparationof a chemically stable quercetin formulation using nanosuspen-sion technologyrdquo International Journal of Pharmaceutics vol404 no 1-2 pp 231ndash237 2011
[46] B C Hancock G T Carlson D D Ladipo B A LangdonandM PMullarney ldquoComparison of themechanical propertiesof the crystalline and amorphous forms of a drug substancerdquoInternational Journal of Pharmaceutics vol 241 no 1 pp 73ndash85 2002
Journal of Pharmaceutics 13
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
[47] B Li S Konecke K Harich L Wegiel L S Taylor and KJ Edgar ldquoSolid dispersion of quercetin in cellulose derivativematrices influences both solubility and stabilityrdquo CarbohydratePolymers vol 92 no 2 pp 2033ndash2040 2012
[48] C Jullian L Moyano C Yanez and C Olea-Azar ldquoCom-plexation of quercetin with three kinds of cyclodextrins anantioxidant studyrdquo Spectrochimica Acta A vol 67 no 1 pp 230ndash234 2007
[49] T Higuchi and K A Connors ldquoPhase-solubility techniquesrdquoAdvances inAnaytical Chemistry and Instrumentation vol 4 no2 pp 117ndash212 1965
[50] H King ldquoPhenolic compounds of commercial wheat germrdquoJournal of Food Science vol 27 no 5 pp 446ndash454 1962
[51] Y Feng C McDonald and B Vick ldquoC-glycosylflavones fromhard red spring wheat branrdquo Cereal Chemistry vol 65 no 6pp 452ndash456 1988
[52] D Patel S Shukla and S Gupta ldquoApigenin and cancerchemoprevention progress potential and promise (review)rdquoInternational Journal of Oncology vol 30 no 1 pp 233ndash2452007
[53] J Zhang D Liu Y Huang Y Gao and S Qian ldquoBiopharmaceu-tics classification and intestinal absorption study of apigeninrdquoInternational Journal of Pharmaceutics vol 436 no 1-2 pp 311ndash317 2012
[54] L Al Shaal R Shegokar and R H Muller ldquoProductionand characterization of antioxidant apigenin nanocrystals as anovel UV skin protective formulationrdquo International Journal ofPharmaceutics vol 420 no 1 pp 133ndash140 2011
[55] J Zhang Y Huang D Liu Y Gao and S Qian ldquoPreparationof apigenin nanocrystals using supercritical antisolvent processfor dissolution and bioavailability enhancementrdquo EuropeanJournal of Pharmaceutical Sciences vol 48 no 4 pp 740ndash7472013
[56] G Buckton and A E Beezer ldquoThe relationship between particlesize and solubilityrdquo International Journal of Pharmaceutics vol82 no 3 pp R7ndashR10 1992
[57] F A Tomas-Barberan and M N Clifford ldquoFlavanones chal-cones and dihydrochalcones-nature occurrence and dietaryburdenrdquo Journal of the Science of Food and Agriculture vol 80no 7 pp 1073ndash1080 2000
[58] I Erlund ldquoReview of the flavonoids quercetin hesperetin andnaringenin Dietary sources bioactivities bioavailability andepidemiologyrdquo Nutrition Research vol 24 no 10 pp 851ndash8742004
[59] T Tanaka H Makita K Kawabata et al ldquoChemopreven-tion of azoxymethane-induced rat colon carcinogenesis bythe naturally occurring flavonoids diosmin and hesperidinrdquoCarcinogenesis vol 18 no 5 pp 957ndash965 1997
[60] M Yang T Tanaka Y Hirose T Deguchi H Mori and YKawada ldquoChemopreventive effects of diosmin and hesperidinon N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in MALE ICR micerdquo InternationalJournal of Cancer vol 73 no 5 pp 719ndash724 1997
[61] F V So N Guthrie A F Chambers M Moussa and K KCarroll ldquoInhibition of human breast cancer cell proliferationand delay of mammary tumorigenesis by flavonoids and citrusjuicesrdquo Nutrition and Cancer vol 26 no 2 pp 167ndash181 1996
[62] E M Choi and Y H Kim ldquoHesperetin attenuates the highlyreducing sugar-triggered inhibition of osteoblast differentia-tionrdquo Cell Biology and Toxicology vol 24 no 3 pp 225ndash2312008
[63] E M Galati M T Montforte S Kirjavainen A M ForestieriA Trovato andMM Tripodo ldquoBiological effects of hesperidina citrus flavonoid (note I) antiinflammatory and analgesicactivityrdquo Farmaco vol 49 no 11 pp 709ndash712 1994
[64] P R Mishra L A Shaal R H Muller and C M Keck ldquoPro-duction and characterization of Hesperetin nanosuspensionsfor dermal deliveryrdquo International Journal of Pharmaceutics vol371 no 1-2 pp 182ndash189 2009
[65] M Kakran N G Sahoo and L Li ldquoPrecipitation of poorlywater-soluble antioxidant hesperetin for improved solubilityand dissolutionrdquo in Proceedings of the CHEMECA 2011 Engi-neering a Better World pp 1380ndash1390 Sydney Hilton HotelSydney Australia September 2011
[66] G le Gall M S Dupont F A Mellon et al ldquoCharacterizationand content of flavonoid glycosides in genetically modifiedtomato (Lycopersicon esculentum) fruitsrdquo Journal of Agriculturaland Food Chemistry vol 51 no 9 pp 2438ndash2446 2003
[67] H Wang M G Nair G M Strasburg A M Booren and JI Gray ldquoAntioxidant polyphenols from tart cherries (Prunuscerasus)rdquo Journal of Agricultural and Food Chemistry vol 47 no3 pp 840ndash844 1999
[68] H J Heo D O Kim S C Shin M J Kim B G Kim andD H Shin ldquoEffect of antioxidant flavanone naringenin fromCitrus junos on neuroprotectionrdquo Journal of Agricultural andFood Chemistry vol 52 no 6 pp 1520ndash1525 2004
[69] S Hirai Y I Kim T Goto et al ldquoInhibitory effect of naringeninchalcone on inflammatory changes in the interaction betweenadipocytes and macrophagesrdquo Life Sciences vol 81 no 16 pp1272ndash1279 2007
[70] S I Kanno A Tomizawa T Hiura et al ldquoInhibitory effects ofnaringenin on tumor growth in human cancer cell lines andsarcoma S-180-implanted micerdquo Biological and PharmaceuticalBulletin vol 28 no 3 pp 527ndash530 2005
[71] M H Lee S Yoon and J O Moon ldquoThe flavonoid naringenininhibits dimethylnitrosamine-induced liver damage in ratsrdquoBiological and Pharmaceutical Bulletin vol 27 no 1 pp 72ndash762004
[72] Y Tozuka J Kishi and H Takeuchi ldquoAnomalous dissolutionproperty enhancement of naringenin from spray-dried particleswith 120572-glucosylhesperidinrdquo Advanced Powder Technology vol21 no 3 pp 305ndash309 2010
[73] T Kometani Y Terada T Nishimura H Takii and S OkadaldquoTransglycosylation to hesperidin by cyclodextrin glucan-otransferase from an alkalophilic Bacillus species in alkaline pHand properties of hesperidin glycosidesrdquo Bioscience Biotechnol-ogy and Biochemistry vol 58 no 11 pp 1990ndash1994 1994
[74] A Cassidy B Hanley and R M Lamuela-RaventosldquoIsoflavones lignans and stilbenes-origins metabolismand potential importance to human healthrdquo Journal of theScience of Food and Agriculture vol 80 no 7 pp 1044ndash10622000
[75] K Reinli and G Block ldquoPhytoestrogen content of foodsmdashacompendium of literature valuesrdquoNutrition and Cancer vol 26no 2 pp 123ndash148 1996
[76] J Liggins L J C Bluck S Runswick C Atkinson W ACoward and S A Bingham ldquoDaidzein and genistein contentof fruits and nutsrdquo Journal of Nutritional Biochemistry vol 11no 6 pp 326ndash331 2000
[77] S Banerjee Y Li Z Wang and F H Sarkar ldquoMulti-targetedtherapy of cancer by genisteinrdquo Cancer Letters vol 269 no 2pp 226ndash242 2008
14 Journal of Pharmaceutics
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
[78] M S Anthony T B Clarkson and J K Williams ldquoEffects ofsoy isoflavones on atherosclerosis potential mechanismsrdquo TheAmerican Journal of Clinical Nutrition vol 68 no 6 pp 1390Sndash1393S 1998
[79] T Uesugi Y Fukui and Y Yamori ldquoBeneficial effects of soybeanisoflavone supplementation on bone metabolism and serumlipids in postmenopausal Japanese women a four-week studyrdquoJournal of the American College of Nutrition vol 21 no 2 pp97ndash102 2002
[80] H K Suk Y K Sun W H Kyoung et al ldquoPharmaceutical eval-uation of genistein-loaded pluronic micelles for oral deliveryrdquoArchives of Pharmacal Research vol 30 no 9 pp 1138ndash11432007
[81] X Vitrac J P Monti J Vercauteren G Deffieux and J MMerillon ldquoDirect liquid chromatographic analysis of resveratrolderivatives and flavanonols in wines with absorbance andfluorescence detectionrdquo Analytica Chimica Acta vol 458 no 1pp 103ndash110 2002
[82] KM Kasiotis H Pratsinis D Kletsas and S A HaroutounianldquoResveratrol and related stilbenes their anti-aging and anti-angiogenic propertiesrdquo Food and Chemical Toxicology vol 61pp 112ndash120 2013
[83] B Catalgol S Batirel Y Taga and N K Ozer ldquoResveratrolFrench paradox revisitedrdquo Frontiers in Pharmacology vol 3article 141 2012
[84] C C Udenigwe V R Ramprasath R E Aluko and P JH Jones ldquoPotential of resveratrol in anticancer and anti-inflammatory therapyrdquo Nutrition Reviews vol 66 no 8 pp445ndash454 2008
[85] A Duvuri The formulation of naturally-occurring polyphenolicnutraceutical agents using hot-melt extrusion [MS thesis] Uni-versity of Rhode Island Kingston RI USA 2011
[86] X P Zhang Y Le J X Wang H Zhao and J F ChenldquoResveratrol nanodispersion with high stability and dissolutionraterdquo LWT-Food Science and Technology vol 50 no 2 pp 622ndash628 2012
[87] M L Kuo T S Huang and J K Lin ldquoCurcumin an antiox-idant and anti-tumor promoter induces apoptosis in humanleukemia cellsrdquo Biochimica et Biophysica Acta vol 1317 no 2pp 95ndash100 1996
[88] A Mazumder K Raghavan J Weinstein K W Kohn and YPommier ldquoInhibition of human immunodeficiency virus type-1 integrase by curcuminrdquoBiochemical Pharmacology vol 49 no8 pp 1165ndash1170 1995
[89] V P Menon and A R Sudheer ldquoAntioxidant and anti-inflammatory properties of curcuminrdquoAdvances in Experimen-tal Medicine and Biology vol 595 pp 105ndash125 2007
[90] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002
[91] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004
[92] M Kakran N G Sahoo I L Tan and L Li ldquoPreparationof nanoparticles of poorly water-soluble antioxidant curcuminby antisolvent precipitation methodsrdquo Journal of NanoparticleResearch vol 14 no 3 article 757 2012
[93] M Mosharraf and C Nystrom ldquoThe effect of particle size andshape on the surface specific dissolution rate ofmicrosized prac-tically insoluble drugsrdquo International Journal of Pharmaceuticsvol 122 no 1-2 pp 35ndash47 1995
[94] S Onoue H Takahashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 no 4 pp 1871ndash1881 2010
[95] P Zhang Y Liu N Feng and J Xu ldquoPreparation and evaluationof self-microemulsifying drug delivery system of oridoninrdquoInternational Journal of Pharmaceutics vol 355 no 1-2 pp 269ndash276 2008
[96] J Cui B Yu Y Zhao et al ldquoEnhancement of oral absorptionof curcumin by self-microemulsifying drug delivery systemsrdquoInternational Journal of Pharmaceutics vol 371 no 1-2 pp 148ndash155 2009
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
