Arabian Journal of Chemistry (2013) xxx, xxx–xxx
King Saud University
Arabian Journal of Chemistry
www.ksu.edu.sawww.sciencedirect.com
ORIGINAL ARTICLE
Fabrication, characterization, thermal stability and
nanoassemblies of novel pullulan-aspirin conjugates
Muhammad A. Hussain a,*, Khawar Abbas a,1, Bilal A. Lodhi a,1,
Muhammad Sher a, Muhammad Ali a, Muhammad N. Tahir b, Wolfgang Tremel b,
Saima Iqbal b
a Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistanb Institute of Inorganic & Analytical Chemistry, Johannes Guttenberg University, Duesbergweg 10-14, 55128 Mainz, Germany
Received 30 September 2012; accepted 2 June 2013
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KEYWORDS
Biopolymers;
Pullulan-aspirin conjugates;
Nanoparticles;
Thermal properties;
Aspirin;
Esterification
Corresponding author. Tel.
-mail address: majaz172@y
These authors contributed
er review under responsibilit
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Abstract Present study deals with homogeneous and one-pot synthesis of novel macromolecular
prodrugs (MPDs) of aspirin onto naturally occurring hydrophilic biopolymer pullulan. Pullulan-
aspirin conjugates were synthesized by using green carboxylic acid activating reagent 1,10-carbon-
yldiimidazole (CDI). The aspirin was first reacted with CDI to prepare aspirin-imidazolide at RT
for 24 h which in situ reacted with pre-dissolved pullulan and the reaction preceded further for
24 h at 80 �C under nitrogen. Degree of substitution (DS 0.32–0.40) of aspirin onto pullulan was
calculated from 1H NMR spectroscopy. Spectroscopic techniques confirmed the high covalent drug
loading and purity. Thermal analysis has revealed that new MPDs of aspirin are thermally more
stable than pure aspirin. The activation energy, order and frequency factor of the degradation reac-
tions were calculated using Broido, Friedman and Chang models. The amphiphilic pullulan-aspirin
conjugates self-assembled in nanoparticles without further structural modifications at solvent inter-
face in the range of 500–680 nm as examined by transmission electron microscopy. These novel
pullulan-aspirin conjugates with masked COOH functional group could be potentially safe pro-
drugs for the stomach.ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University.
68614959.
(M.A. Hussain).
this work.
Saud University.
g by Elsevier
ng by Elsevier B.V. on behalf of K
6.001
Hussain, M.A. et al., Fabricatirabian Journal of Chemistry
1. Introduction
Hydrophilic biopolymers, especially, glycopolymers are gettinggreater attention nowadays for the formation of macromolec-ular prodrugs (MPDs). Polysaccharides based MPD design iswidely accepted and proved for better pharmaceutical and
pharmacological properties (Callant and Schacht, 1990;Hussain et al., 2011a,b; Vinsova and Vaverikova, 2008; Jainet al., 2007). Almost all of the polysaccharides used for the
purpose are nontoxic, biocompatible and cheaper drug careers.
ing Saud University.
on, characterization, thermal stability and nanoassemblies of(2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.001
2 M.A. Hussain et al.
A number of non-steroidal anti-inflammatory drugs (NSA-IDs), antibiotics (Kumar et al., 2013; Sharma and Sharma,2008) and anticancer agents (Duncan et al., 2001) have been
reported as polyglucan based prodrugs. By this approach,some useful properties can be easily achieved, e.g., better phar-macokinetic profile, increased tolerance and reduction in dose
frequency. Additionally, MPD design reduces work load onthe kidney, provides wider drug distribution and sustained/de-layed drug release (Sharma and Sharma, 2008).
Polysaccharide based prodrug design can be achieved bysimple conversion of hydroxyl groups to esters and amides afterreactions with drugs (Pappas et al., 2006; Sandrine et al., 2005;Takakura, 1996). By these reactions, carboxylic acids or car-
boxylic acid containing drugs, e.g., NSAIDs can be attachedwith the polymer backbones (Kim and Na, 2010; Park et al.,2012; Babazadeh, 2006; Hussain et al., 2009, 2011a,b). Previ-
ously, acid chlorides and anhydrides (Hussain et al., 2010b,a)of the drug molecules containing carboxylic acid and sulfonicacid catalyzed products were allowed to react with hydroxyls
of polysaccharides. However, nowadays homogenous reactionmethodologies (Glasser et al., 2000; Shimoda et al., 2012; Lie-bert et al., 2011) alongwith the use of in situ carboxylic acid acti-
vating reagents are the prodrug design strategies. Weak andsensitive carboxylic acid containing drugs toward esterificationreactions are first activated with RCOOH acid activating re-agents (Hussain and Heinze, 2008; Liebert et al., 2006) that in-
clude p-toluenesulfonyl chloride (Hussain et al., 2013), 1,10-carbonyldiimidazole (CDI) (Hussain et al.,2004b), and iminiumchlorides (Hussain et al., 2004a), etc. CDI is one of the powerful
and safest reagents as imidazole generated in situ acts as a baseto neutralize acidic impurities. Themacromolecular drug conju-gates are tuned in such a way to achieve amphiphilic nature of
the conjugates as a whole. Therefore, by tuning the degree ofsubstitution of pendant drug molecules, the resultant MPDsself-assembled in nanoparticles. We have recently reported a
novel nanoparticulate drug design of aspirin onto a hydrophilicbiopolymer i.e., hydroxypropylmethylcellulose (HPMC) (Huss-ain et al., 2011a,b). Moreover, nano-particulate HPMC-aspirinconjugates have shown delayed release and improved
pharmacokinetics.Our aim was to design pullulan based prodrugs of aspirin
and to study their properties. In addition to the synthesis of
nonionic, acid resistant, neutral, and biocompatible novel bio-conjugates of aspirin, it offers safety to the stomach fromhyperacidity and colon targeted drug delivery. One can exploit
controlled/sustained release of these newly designed MPDs asa future aspect of the present work. We were also focused tostudy self-assembly of pullulan-aspirin conjugates in solutionwithout further structure modification. Self-assembled nano-
particles, thermal degradation and kinetics of the novel poly-meric aspirin conjugates are being reported for the first time.
2. Experimental
2.1. Materials
Aspirin (US Pharmacopoeia standards) used was gifted byAskari Pharmaceuticals, Pakistan. 1,10-Carbonyldiimazole
(CDI) was obtained from Aldrich while pullulan was pur-chased from IL, USA. Analytical grade N,N-dimethylacet-
Please cite this article in press as: Hussain, M.A. et al., Fabricatinovel pullulan-aspirin conjugates. Arabian Journal of Chemistry
amide (DMA), anhydrous lithium chloride and otherchemicals were used as received from Fluka.
2.2. Instrumentation
The FTIR (KBr pellet technique) spectra (m, cm�1) were ac-quired on IR Prestige-21 (Shimadzu, Japan).
The 1H NMR spectra (d, ppm; DMSO-d6, NS 16) of pullu-lan-aspirin conjugates were recorded on Bruker 400 MHz ma-chine while for 13C NMR 5000 Scans were accumulated.
Thermal degradation studies were performed on a SDT Q600 (TA Instruments, USA) thermal analyzer. The thermalspectra were recorded at the onset of significant weight loss un-
der nitrogen at a constant heating rate of 10 �C/min from RTup to 800 �C.
The products were studied by transmission electron micros-copy (TEM) for self-assemblies. TEM used was Philips 420
instrument with an acceleration voltage of 120 kV.
2.3. Dissolution of pullulan
Pullulan was dried under vacuum at 110 �C before dissolutionfor 1 h. Dry pullulan (2 g) was dissolved in DMA (30 mL) bystirring at 90 �C. Polymer was dissolved within 25 min with
optical clarity.
2.4. Synthesis of pullulan-aspirin conjugates 1, a typical example
Aspirin (2.22 g, 12.33 mmol) was dissolved in DMF (40 mL)solvent and CDI (1.99 g, 12.33 mmol) was added in parts un-der nitrogen atmosphere. Reaction mixture was stirred for24 h at RT for the synthesis of reactive imidazolide of aspirin.
This reaction mixture was added slowly to the solution ofpullulan (2 g, 12.33 mmol) in DMA. Reaction mixture wascontinuously stirred at 80 �C for 24 h under nitrogen. Isolation
of the product was carried out by precipitation of reactionmixture into 200 mL ethanol. The precipitates of sample 1
were washed thoroughly with ethanol in order to remove any
of the side products and un-reacted drug contents. Precipitatesof pullulan-aspirin conjugate 1 were dried under vacuum at50 �C. Similar reaction procedures were adopted for the restof pullulan-aspirin conjugates. Yield: 1.95 g (76%);
DS = 0.32 by 1H NMR spectroscopy; FTIR (KBr):m = 3431 (OH), 2926 (aromatic C–H), 1740 (C‚O ester),1462 (CH2) cm�1; 1H NMR (400 MHz, DMSO-d6, d): 1.98(H-7), 3.35–5.70 (AGU-H-1-6), 6.94 (H-9,11), 7.50 (H-10),7.86 (H-8) ppm; 13C NMR (DMSO-d6, d): 170.49 (C-8),168.99 (C-7), 117.75 (C-1), 119.90 (C-3), 130.61 (C-5), 136.16
(C-6), 136.26 (C-4), 160.61 (C-2), 101.84 & 95.99 (C-10),74.45-67.5 (C11–14), 60.56 (C-15), 21.08 (C-9) ppm.
2.5. Transmission electron microscopy
Nanoparticles of pullulan-aspirin conjugates 3 were preparedusing dialysis process. Sample 3 (20 mg) was taken in a typicalbatch, dissolved in purified DMSO (5 mL). Dialysis process
was continued for 4 days against water along with constantstirring. The nanoparticle suspension was concentrated. TheTEM samples were prepared using drop casting on carbon
on, characterization, thermal stability and nanoassemblies of(2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.001
Table 1 Reaction conditions and results of the esterification of pullulan (2 g) using in situ activated aspirin with CDI at 80 �C for 24 h.
Sample Mole ratioa Yield (g/%) DSb Solubility
1 1:1:1 1.95/76 0.32 Acetone, DMF, DMSO, DMA
2 1:2:2 2.10/79 0.36 Acetone, DMF, DMSO, DMA
3 1:3:3 2.25/81 0.38 Acetone, DMF, DMSO, DMA
4 1:6:6 2.29/81 0.40 Acetone, DMF, DMA
a AGU:aspirin:CDI.b DS (degree of substitution) calculated by 1H NMR spectroscopy.
N
N
N
NC
O
+C OH
O
O CH3
O DMF, 24 h, RTC
O
O CH3
O
N
N
-CO2
-Imidazole
+80oC, 24 h
CDI
Imidazolide
R = H,
O
O CH3
O
-Imidazole
O
OH
HOHO
O
O O
HOOH
O
OH
O
OHHO
Pullulan
OH
O
OR
RORO
O
O O
ROOR
O
OR
O
ORRO
OR
Where;
Pullulan-Aspirin conjugates
ImidazolideAspirin
Scheme 1 Synthesis of MPDs of aspirin with pullulan applying in situ activation of aspirin with CDI.
Figure 1 FTIR (KBr) spectrum of pullulan-aspirin conjugate 2.
Fabrication, characterization, thermal stability and nanoassemblies of novel pullulan-aspirin conjugates 3
coated copper grids. The TEM grids were dried under air be-fore studying by TEM.
2.6. Thermal degradation kinetic analysis
The kinetics of thermal decomposition of pullulan-aspirin con-jugates were examined by Friedman, Broido and Chang meth-
ods. Friedman kinetic model (Friedman, 1964) uses thefollowing equation;
Please cite this article in press as: Hussain, M.A. et al., Fabricatinovel pullulan-aspirin conjugates. Arabian Journal of Chemistry
lndadt
� �¼ lnZþ n lnð1� aÞ � Ea
RT
where, da/dt is the rate of weight loss directly taken from the
DTG curve; Z is the frequency factor of decomposition reac-tion; n is the reaction order; 1�a is the weight of sample leftat a certain temperature that is also taken from the TG curve;
Ea is the activation energy; R is the gas constant and T is theabsolute temperature recorded.The order of the reaction wascalculated from the Changmodel as given below (Chang, 1994).
on, characterization, thermal stability and nanoassemblies of(2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.001
4 M.A. Hussain et al.
lnd/dt
ð1� /Þn� �
¼ lnZ� Ea
RT
A straight line was obtained when ln [(da/dt)/(1�a)n] was plot-ted versus 1/T in case if the assumed n value is found correct.The slope and intercept of the straight line were used to calcu-late the Ea and Z values.
The Broido method (Broido, 1969) was also used to calcu-late kinetic parameters, i.e., Ea and Z as per followingequation.
ln ln1
y
� �¼ � Ea
RTþ Constant
where, y = (wt�w1)/(w0�w1), wt = weight at a given time t,
w0 = initial weight and w1 is final weight.
3. Results and discussion
3.1. Synthesis and characterization
The MPDs of aspirin with a hydrophilic polysaccharide, i.e.,pullulan, were synthesized using one pot and homogeneousreaction conditions (Samples 1–4). Pre-dissolved pullulan
5.06.07.08.09.0
O
OH
HOHO
O
OO
HOOH
O
OH
O
OHHO
O O
O
H3CO
12
3
4 56
7
8
9
11 01
AGU-
H-9,11H-10
H-8
Figure 2 The 1H NMR (400 MHz) spec
100125150175
O
OH
HOHO
O
OO
HOOH
O
OH
O
OHHO
O O
O
H3CO
12
3 4
5
67
89
1011
12
13
14
15
C-1C-3
C-2C-5
C-4,6C-8
C-7C-10
Figure 3 The 13C NMR (400 MHz, DMSO-d
Please cite this article in press as: Hussain, M.A. et al., Fabricatinovel pullulan-aspirin conjugates. Arabian Journal of Chemistry
was reacted with imidazolide of aspirin drug prepared afteractivation of its carboxylic acid functional group with 1,10-car-bonyldiimidazole (CDI). Reaction methodology is generalized
in Scheme 1.Aspirin was first activated with a fascinating RCOOH acti-
vating reagent CDI. CDI reacts with RCOOH of aspirin to
make its imidazolide. Imidazolide was then reacted with the–OH functional groups of the anhydroglucose units (AGU)of pullulan to generate ester linkage. In this way, ester conju-
gates as MPDs of aspirin were successfully synthesized. A baseimidazole was generated in situ that neutralizes the unreacteddrug therefore no extra base is needed during the reaction.Pullulan-aspirin conjugates 1–4 were fabricated by using dif-
ferent mole ratios of the reactants (AGU:CDI:aspirin). The re-sults of esterification reactions are given in Table 1 for allnewly fabricated MPDs of aspirin onto pullulan.
Aspirin has been previously attached with another cellulosederivative i.e., hydroxypropylmethylcellulose (HPMC).Although, it was pioneering work for the attachment of aspirin
onto any ether derivative of cellulose the reaction resulted inlow DS of aspirin onto HPMC (Hussain et al., 2011a,b). TheDS of aspirin in HPMC-aspirin conjugates was obtained in
the range of 0.04–0.14. However, considerably high drug load-
1.02.03.04.0
H-1-6 H-7
DMSO-d6
ppm
trum of pullulan-aspirin conjugate 1.
255075
C-9C-11-14
C-15
ppm
6) spectrum of pullulan-aspirin conjugate 1.
on, characterization, thermal stability and nanoassemblies of(2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.001
Table 2 The results of thermal analysis and kinetics of aspirin, pullulan and pullulan-aspirin conjugate 3.
Sample Step Tdi, Tdm, Tdf Method R2 n M (Slope) Ea (kJ/mol) lnZ Z (s�1)
Pullulan-aspirin conjugate I 135, 213, 289 Friedman 0.991 – �4189 34.83 6.905 9.9 · 102
Broido 0.999 – �5545 46.10 11.07 6.4 · 104
Chang 0.997 1 �3998 33.24 6.605 7.4 · 102
II 316, 365, 411 Friedman 0.979 – 33,638 279.68 �51.93 3.6 · 1022
Broido 0.999 – �32,961 274.05 51.48 2.3 · 1022
Chang 0.999 1 �30,604 254.46 49.44 3.0 · 1021
III 529, 623, 643 Friedman 0.995 – �23,415 194.68 25.34 1.0 · 1011
Broido 0.999 – �27,357 227.45 31.00 2.9 · 1013
Chang 0.986 1 �23,982 199.39 26.32 2.7 · 1011
Pullulan I 278, 320, 371 Friedman 0.988 – 32,497 270.19 53.72 2.1 · 1023
Broido 0.999 – �19,683 163.65 33.13 2.4 · 1014
Chang 0.999 1 �18,537 154.13 32.63 1.5 · 1014
Aspirin I 134, 152, 189 Friedman 0.999 – 16,634 138.30 38.53 5.4 · 1016
Broido 0.991 – �19,598 162.95 45.46 5.5 · 1019
Chang 0.997 1 �19,176 159.43 46.49 1.6 · 1020
Friedman 0.998 – �10,579 87.96 17.99 6.5 · 107
II 250, 327, 356 Broido 0.999 – �15,787 131.26 26.45 3.1 · 1011
Chang 0.999 1 �12,568 104.5 21.71 2.7 · 109
Fabrication, characterization, thermal stability and nanoassemblies of novel pullulan-aspirin conjugates 5
ing was achieved in the present study. Ds. was found in therange of 0.32–0.40 for pullulan-aspirin conjugates with same
mole ratios of drug to polymer. This increased drug loadingcan potentially reduce the size of dose.
Aspirin prodrugs synthesized by the CDI method were
found soluble in different organic solvents, i.e., DMSO,DMF, acetone and DMA. The products were thoroughly char-acterized by using different spectroscopic techniques. Thermo-
gravimetric (TG) analyses were used to determine the stabilityof the fabricated MPDs. Transmission election microscopy(TEM) was used to study nanoassemblies in solution. The de-tailed structure characterization is given below.
Aspirin conjugates 1–4 have shown ester peaks in FTIRspectra. The FTIR (KBr) spectrum of pullulan-aspirin conju-gate 2 (Fig. 1) has shown ester absorptions at 1744, aromatic
C–H absorption at 2926 and unreacted –OH absorption at3437 cm�1. Nevertheless, pullulan-aspirin conjugates 1–4 havedisplayed aromatic C–H absorptions, hydroxyl group absorp-
tion and CH2 (polymer) absorption signals as well in the FTIRspectra that indicate the success of esterification reactions.
The 1H NMR (400 MHz) spectra of pullulan-aspirin conju-gates were recorded in DMSO-d6. The typical spectrum of
sample 1 (Fig. 2) showed the presence of the aromatic ring cou-pled with pullulan polymer backbone as aromatic protonswere detectable at d 6.94–7.86 ppm. The aromatic H-9 and
H-11 overlapped and absorbed at d 6.94 ppm while H-8 andH-10 absorbed at 7.86 and 7.50 ppm, respectively.
Figure 4 The TG (LHS) and DTG (RHS) curves of aspirin
Please cite this article in press as: Hussain, M.A. et al., Fabricatinovel pullulan-aspirin conjugates. Arabian Journal of Chemistry
These results have demonstrated that the unsaturated sys-tem is not destroyed during the entire course of the reaction.
Broad signals of aromatic protons also suggest the covalentattachment of aromatic system onto different positions of hy-droxyl groups in the pullulan polymer chains. Protons of
pullulan polymer backbone/anhydroglucose unit (AGU) weredetectable at 3.35–5.70 (AGU-H-1-6) ppm. The 1H NMRspectrum has proved that samples fabricated by using the
CDI method are highly pure as no sign of any impurity is de-tected in spectrum. The DS was also possible to be calculatedby the comparison of signal intensities of the aromatic ringabsorption with AGU-Hs. The DS of the samples 1–4 was
found in the range of 0.32–0.40 (see Table 1).A typical 13C NMR spectrum of sample 1 recorded in
DMSO-d6 shows the characteristic signals at d 170.49 and
168.99 for the carbonyl absorptions of acetyl moiety onto aspi-rin and ester (CO) linkage with the polymer, respectively indi-cating success of the reaction (Fig. 3). It is common to observe
two or three signals of C-10 of three sugars of maltotriosyl unitof the pullulan because of geometrically diverse environment.Nevertheless, C-10 absorbed at 101.84 and 95.99 ppm forpullulan-aspirin conjugate 1. The C-11-14 of pullulan maltotri-
ose unit appears in the range of 67.5–80.03 ppm. The 13CNMR spectrum of pullulan-aspirin conjugate 1 is found com-parable for maltotriose region with the NMR spectra of pullu-
lan nonaacetate (Tezuka, 1998), and pullulan abietates(Hussain and Heinze, 2008).
(- - -), pullulan (....) and pullulan-aspirin (__) conjugate 3.
on, characterization, thermal stability and nanoassemblies of(2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.001
Figure 5 TEM images of the pullulan-aspirin conjugate 3 showing nanoparticle formations in the range of 500–680 nm for majority of
the population.
6 M.A. Hussain et al.
3.2. Thermal stability analysis of pullulan-aspirin conjugates
The initial decomposition (Tdi), maximum decomposition tem-perature (Tdm) and final decomposition (Tdf) of the pullulan-aspirin conjugate 3 were assessed by thermogravimetry (TG)
and differential thermogravimetry (DTG) curves. The thermaldecomposition data of pullulan-aspirin conjugate 3 are shownin Table 2 while the TG Curves and DTG thermograms of
sample 3 are shown in Fig. 4.The thermograms of pullulan-aspirin conjugate 3 have
shown three-step degradation. The conjugate 3 was found
thermally stable up to 135 �C (Tdi) with 14.2% weight lossin overall first step degradation. However Tdm and Tdf werefound at 213 and 289 �C, respectively which are considerably
higher than pure aspirin (152, 189 �C) indicating the extra sta-bility imparted in pullulan-aspirin conjugate 3. The pullulan-aspirin conjugate 3 has shown major degradation in step-II.An overall weight loss of 67.68% was observed in this step.
A Tdm 365 �C was observed for the conjugate 3 which is higherthan Tdm of step-II for pure aspirin (327 �C). This result hasindicated that aspirin becomes 38 �C more stable in conju-
gates. In step III, a slow degradation proceeds to completionleaving behind 0.85% char yield at 643 �C. It is concludedfrom above mentioned results that pullulan-aspirin conjugates
are thermally more stable than pure aspirin and pullulan.From thermogravimetric analysis, some kinetic parameters
like activation energy (Ea), order of reaction (n) and frequency
factor (Z) were determined. . To study the kinetic parameters(Ea and Z) of thermal degradation, Friedmann and Broidomodels were employed. The order of reaction n was calculatedby using the Chang model. The details on the kinetics and
comparison of the results are summarized in Table 2. The re-sults have indicated comparable Ea values of the step-I degra-dation of conjugate 3, i.e., 34.83, 46.10 and 33.24 kJ/mol as
calculated by Friedmann, Broido and Chang models, respec-tively. Applying same models, aspirin has shown Ea values138, 163 and 159 kJ/mol, for the relevant first step. The n
was calculated through the Kissinger model which indicatedthe first order kinetic of the said degradation steps. The conju-gate 3 has shown Ea values of 280, 274 and 254 kJ/mol, respec-tively for step-II degradation, while pure aspirin showed Ea
values 88, 131 and 104 kJ/mol, respectively for step-II. As allthe Ea values are not very high therefore it is roughly estimatedthat degradation generally follows first order kinetics. It is
noted from Table 2 that the application of different kineticmodels on the TG curves gives almost comparable results.
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3.3. Transmission electron microscopy (TEM)
The TEM analyses were carried out to study the behavior ofpullulan-aspirin conjugates in solution by the solvent diffusionmethod. The TEM images of the molecular self-assembly have
revealed the formation of nanoparticles in case of sample 3
(Fig. 5) in the range of 500–680 nm for the major populationof nanoparticles. Nanoparticle formation is indicative of the
fact that there lies a very good balance of hydrophobicityand hydrophilicity in sample 3 that favored the formation ofnanoparticles of the water soluble biopolymer pullulan. Such
nanoparticulate drug design for aspirin MPDs onto pullulanmay lead to improved pharmacokinetic profile of aspirin.
4. Conclusion
A water soluble and biocompatible polysaccharide, i.e., pullu-lan was successfully evaluated to be used as a valuable covalent
drug carrier for NSAIDs, i.e., aspirin. The newly synthesizedMPDs of aspirin appeared thermally highly stable and org-ano-soluble. All of the products were highly pure and thor-oughly characterized. Pullulan-aspirin conjugates self-
assemble in nanoparticles in useful size regimen, therefore, saidnovel MPDs of aspirin could be highly potent for its betterpharmacokinetic profile and controlled release of aspirin.
Acknowledgement
K. Abbas gratefully acknowledges the financial support pro-vided by the Higher Education Commission (HEC) of Paki-stan under ‘‘HEC Indigenous 5000 fellowships Scheme’’.
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