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PREPARATION AND EVALUATION OF BIPHASIC BILAYERED
BUCCAL TABLET CONTAINING KETOROLAC IMMEDIATE
RELEASE LAYER AND DOMPERIDONE MALEATE SUSTAINED
RELEASE LAYER
M. Venkataswamy*1, M. Santhoshini
2, J. P. Priyanka
1, K. Prathyusha
1, Jaggareddy
Gari Manasareddy1 and Ramesh Alluri
3
1Department of Pharmaceutics,
3Department of Pharmacology,
Vishnu Institute of Pharmaceutical Education and Research, Vishnupur, Narsapur, Medak,
Telangana, India.
2Department of Pharmaceutics, Sri Indu institute of Pharmacy, Sheriguda Village,
Ibrahimpatnam Mandal, Ibrahimpatnam, Ranga Reddy District.
ABSTRACT
In the present study an attempt was made to design a biphasic Bilayer
buccal Tablet containing Ketorolac immediate release layer and
Domperidone maleate sustained release layer. FT-IR studies reveal that
there were no significant interactions between both the drugs and
between the drugs and their respective excipeints. For achieving
sustained release of Domperidone maleate, bucco adhesive polymers
Carbopol and CMC were used Formulations D6 and D7 gave drug
release 90.12±1.26 and 92.15±1.11 after 8hrs. Therefore D6 and D7
were considered as best formulations among D1 –D 11 for formulation
of bilayer buccal tablets. For achieving immediate result of Ketorolac,
from the results it was concluded that disintegration activity is good
with Crospovidone and SSG, K6 releasing 100.05±1.2, K9 releasing
99.51±1.21% after 14min. The bilayered tablets prepared by taking D6 and D7 of
Domperidone maleate and K6 and K9 formulations of Ketorolac as two layers (K6+D6,
K6+D7, K9+D6, K9+D7) have shown good post compression parameters like hardness,
friability weight variation, drug content etc which were within the limits. Hence they are
considered as optimized formulations.
World Journal of Pharmaceutical Research SJIF Impact Factor 8.074
Volume 7, Issue 11, 905-949. Research Article ISSN 2277–7105
Article Received on
09 April 2018,
Revised on 29 April 2018,
Accepted on 19 May 2018
DOI: 10.20959/wjpr201811-12447
*Corresponding Author
M. Venkataswamy
Department of
Pharmaceutics, Vishnu
Institute of Pharmaceutical
Education and Research,
Vishnupur, Narsapur,
Medak, Telangana, India.
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KEYWORDS: Bilayer buccal Tablet, Domperidone maleate.
INTRODUCTION: The pharmaceutical industry has engendered considerable interest
making it a major participant in the healthcare industry. The advances and progress made by
pharmaceutical industry have greatly contributed in terms of treatment of disease, thereby
enhancing the quality of life.[1]
Over the time, scientists and researchers in the drug
development industries are focusing on alternate routes of administration to add to the
potential of approved drug products, or to overcome the drawbacks of the oral route.
Although oral route is preferred for administration of drugs, it is associated with some
restrictions for example: hepatic first pass metabolism, local GI toxicity and enzymatic
degradation within the GI tract. The Parenteral route having maximum bioavailability suffers
from poor patient compliance and various risks such as anaphylaxis and extravasation
infection these limitations have driven the alternate administration routes via the accessible
mucosal route as they offer many advantages including non invasive administration, rapid
onset of effect, good bio availability, elimination of hepatic first pass metabolism, reduced
amount of administered drug and low dose related side effects. Transmucosal routes of drug
delivery which comprise of the mucosal linings of the nasal, rectal, vaginal, ocular, and oral
cavity offer excellent opportunities and potential advantages over per oral administration for
systemic drug delivery. These advantages include possible bypass of first pass effect,
avoidance of presystemic elimination within the GI tract and depending on the particular
drug, a better enzymatic flora for drug absorption. Amongst the various mucosal routes the
mucosal lining of oral cavity offers distinct advantages like high vascularisation and
accessibility for the administration and removal of a dosage form in addition to high patient
acceptability compared to other non- oral routes of drug administration.[2,3]
The sites of drug
administration in the oral cavity include the floor of the mouth (sublingual), the inside of the
cheeks (buccal) and the gums (gingival). With the advances and progress in biotechnology,
hydrophilic high molecular weight therapeutic agents such as proteins and peptides are
readily available for therapeutic use. However, when administered by the oral route, these
agents suffer from problems such as degradation and poor absorption. To overcome these
obstacles and for successful delivery of proteins and peptides, the buccal route of drug
delivery has acquired significant attention.[4]
LITERATURE REVIEW: Vishnu M. Patel et al., (2007), formulated mucoadhesive
bilayer buccal tablets of propranolol hydrochloride using the bioadhesive polymers sodium
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alginate (Na-alginate) and Carbopol 934P (CP) along with ethyl cellulose as an impermeable
backing layer. The tablets were evaluated for weight variation, thickness, hardness, friability,
surface pH, mucoadhesive strength, swelling index, in vitro drug release, ex vivo drug
permeation, ex vivo mucoadhesion, and in vivo pharmacodynamics in rabbits. Tablets
containing, Na-alginate and CP in the ratio of 5:1 (F2) had the maximum percentage of in
vitro drug release without disintegration in 12 hours. The swelling index was proportional to
Na-alginate content and inversely proportional to CP content. The surface pH of all tablets
was found to be satisfactory (7.0±1.5), close to neutral pH; hence, buccal cavity irritation
should not occur with these tablets. The mechanism of drug release was found to be non-
Fickian diffusion and followed zero-order kinetics.[93]
Luana Perioli et al.,(2007), formulated muco adhesive bilayer tablets for buccal sustained
release of flurbiprofen. The bilayered tablets, using mixtures of mucoadhesive polymers and
an inorganic matrix (hydrotalcite), for the topical administration of flurbiprofen in the oral
cavity. The first layer, responsible for the tablet retention on the mucosa, was prepared by
compression of a cellulose derivative and polyacrylic derivative blend. The second layer,
responsible for buccal drug delivery, was obtained by compression of a mixture of the same
(first layer) mucoadhesive polymers and hydrotalcite containing flurbiprofen. Nonmedicated
tablets were evaluated in terms of swelling, mucosal adhesion, and organoleptic
characteristics; in vitro and in vivo release studies of flurbiprofen-loaded tablets were
performed as well.[94]
Balamurugan et al.,(2008), formulated Mucoadhesive buccal tablet of Domperidone were
fabricated with objective of avoiding first pass metabolism and to improve its bioavailability
with reduction in dosing frequency. The mucoadhesive polymers used in the formulations
were Carbopol 934P, Methocel K4M, MethocelE15LV and Chitosan. Tablets were prepared
by direct compression method using polymer in different ratios. The formulations were
characterized for swelling index, in-vitro bioadhesion strength and in-vitro release studies.
The best mucoadhesive performance and in- vitro drug release profile were exhibited by the
tablet containing chitosan and Methocel K4M in ratio of 1:1. It was observed that the
optimized formulation follows Hixson Crowel release kinetics.[95]
Ashwini Madgulkar et al.,(2008), developed trilayered mucoadhesive tablet of itraconazole
with zero-order release. Itraconazole is practically insoluble in water; large interindividual
and intraindividual variations of its oral bioavailability are reported. A mucoadhesive drug
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delivery system is useful to prolong the retention time of a dosage form in the stomach,
thereby improving the oral bioavailability of the drug. Solid dispersion of itraconazole with
Eudragit E100 was prepared by spray-drying method to improve dissolution. Trilayered
mucoadhesive tablet was prepared, with inner core containing solid dispersion of the drug
and with carbopol and HPMC sandwiched between two layers of hydrophilic mucoadhesive
polymer mixture of carbopol and Hydroxypropyl methyl cellulose (HPMC). Amounts of
Carbopol 934P (CP) and Methocel K4M (HPMC) were varied in the outer coat around the
solid dispersion. The drug-release pattern for all the formulation combinations was found to
be nonfickian, approaching zero-order kinetics. Suitable combination of two polymers
provided adequate bioadhesive strength and sustained-release profile with zero-order
kinetics.[96]
JG HIREMATH et al., (2009), prepared the buccoadhesive bilayered tablet of simvastatin
for the treatment of hypercholesterolemia, by using the mucoadhesive polymers such as
carbopol (CP), hydroxy propyl methyl cellulose (HPMC) and polyvinylpyrrolidone (PVP) in
different concentration. Ethyl cellulose is used in backing layer because of its water
impermeable nature. Tablets were prepared by direct compression method. The first layer
which adheres to mucosa was obtained by direct compression of mucoadhesive polymers and
drug. The second layer containing water impermeable agent was compressed on the first
layer. Tablets were subjected for physicochemical characterization tests such as FTIR, DSC,
hardness, weight variation, friability, mucoadhesive strength, in vitro drug release study, in
vitro drug permeation, and stability in human saliva. The FTIR and DSC analysis of drug,
polymers, physicalmixture and formulation indicated that the compatibility of drug with
excipients.[97]
MATERIALS AND METHODS
Table 1: Materials and their Sources.
SNO Name of the ingredient Source
1 Domperidone Gift sample from Aurobindo Pharma ltd, Hyderabad
2 Ketorolac Gift sample from Divis Pharmaceuticals ltd, Hyderabad
3 Mico crystalline cellulose Pioma Chemicals, Mumbai
4 Cross carmellose sodium Shreeji pharma international, vadodara
5 Crosspovidone Kores india ltd
6 Vanillin Wanbury ltd
7 Citric acid Wang Pharmaceuticals,New Delhi
8 Magnesium stearate Panchi chemicals,Hyderabad
9 Mannitol Provizer pharma ltd,Gujarat
10 Carbopol Provizer Pharma ltd,Gujarat
11 Carboxy methyl cellulose Akay organics ltd,India
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Table 2: List of Equipment.
SNO EQUIPMENT MANUFACTURER MODEL
NUMBER
1 Electronic balance Shimadzu AUX 220
2 Sieves United engineering limited ASL00
3 FTIR Shimadzu,Japan model 840
4 Laboratory stirrer Remi RQT-124A
5 Rapid dryer Retsch Th-200
6 Digital PH meter Thermo Orion 2 star
7 Dissolution test apparatus ( U.S.P) Electrolab, india TDT-08L
8 Disintegration tester Thermolab ED-2L
9 Monsento Hardness tester Pharmatest PTB-311E
10 Roche Friabilator Thermolab EF-1N
11 Tablet compression machine 16 station Cadmech machinery co pvt ltd CMD3-16
12 Tap Density Tester (U.S.P.) Electrolab,India ETD-1020
13 Digital Vernier Caliper Mitutoyo Corp, Kawasaki, Japan
14 UV/Visible Spectrophotometer Lab india,Japan UV-3000
DRUG PROFILE
a) DOMPERIDONE MALEATE[110,111]
Name: Domperidone maleate,
Description: A specific blocker of dopamine receptors. It speeds gastrointestinal peristalsis,
causes prolactin release, and is used as antiemetic and tool in the study of dopaminergic
mechanisms.
Structure
Categories: Antiemetics, Dopamine Antagonists
IUPAC NAME: 5-Chloro-1-[1-[3-(2-oxo-1,3-dihydrobenzoimidazol-1-yl)propyl]-4-
piperidyl]-1,3- dihydrobenzoimidazol-2-one maleate.
Chemical name: C22 H24 ClN5O2. C4 H4O4
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Trade names: Motilium, Nauzelin
Routes: Oral, intravenous, rectal
Classes: Benzimidazoles.
Pharmacology: Indication: For management of dyspepsia, heartburn, epigastric pain,
nausea, and vomiting.
Mechanism of action: Antiemetic: The antiemetic properties of domperidone maleate are
related to its dopamine receptor blocking activity at both the chemoreceptor trigger zone and
at the gastric level. It has strong affinities for the D2 and D3 dopamine receptors, which are
found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which -
among others - regulates nausea and vomiting.
Dose and administration
Acute conditions (nausea, vomiting).
Adults: Two tablets (20mg) 3-4times per day, 15-30 min before meals.
Children: 5-12years old, one tablet (10mg) 3-4times per day,15-30min before meals.
Chronic conditions (mainly dyspepsia).
Adults: one tablet (10mg) taken 3times per day, 15-30min before meals.
Children: 5-12years old ½ tablet (5mg) 3-4 times per day, 15-30min before meals.
Pharmacokinetic data
Bio availability: High
Protein binding: 91-93%
Metabolism: Hepatic and Intestinal
Half life: 7hrs
Excretion: Breast milk, renal
Pharmacodynamics: Domperidone maleate is a specific blocker of dopamine receptors. It
speeds gastrointestinal peristalsis, causes prolactin release, and is used as antiemetic and tool
in the study of dopaminergic mechanisms.
b) KETOROLAC[112,113]
Name: Ketorolac
Description: A pyrrolizine carboxylic acid derivative structurally related to indomethacin. It
is an NSAID and is used principally for its analgesic activity.
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Structure
Synonyms: Ketorolac, Ketorolac tromethamine, Ketorolaco(Spanish), Ketorolacum(Latin).
Brand names: Acular, Acular LS, Acular Preservative Free, Toradol.
Categories: Cyclooxygenase Inhibitors.
Chemical Formula: C15H13NO3.
IUPAC Name: 5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-carboxylic acid.
Classes: Pyrrolizines
Pharmacology: Benzoyl Derivatives
Indication: For the short-term (~5 days) management of moderately severe acute pain that
requires analgesia at the opioid level, usually in a postoperative setting.
Mechanism of action: Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID)
chemically related to indomethacin and tolmetin. Ketorolac tromethamine is a racemic
mixture of [-] S- and [+] R-enantiomeric forms, with the S-form having analgesic activity. Its
antiinflammatory effects are believed to be due to inhibition of both cylooxygenase-1 (COX-
1) and cylooxygenase-2 (COX-2) which leads to the inhibition of prostaglandin synthesis
leading to decreased formation of precursors of prostaglandins and thromboxanes from
arachidonic acid. The resultant reduction in prostaglandin synthesis and activity may be at
least partially responsible for many of the adverse, as well as the therapeutic, effects of these
medications. Analgesia is probably produced via a peripheral action in which blockade of
pain impulse generation results from decreased prostaglandin activity. However, inhibition of
the synthesis or actions of other substances that sensitize pain receptors to mechanical or
chemical stimulation may also contribute to the analgesic effect. In terms of the ophthalmic
applications of ketorolac - ocular administration of ketorolac reduces prostaglandin E2 levels
in aqueous humour, secondary to inhibition of prostaglandin biosynthesis.
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Dose and Administration
Oral: 10 mg orally 4 times a day as needed. The maximum daily dose should not exceed 40
mg.
Patients less than 50 kg: The maximum daily dose should not exceed 40 mg.
Parenteral: IM: Patients less than 65 years of age: one dose of 60 mg. Patients who are
renally impaired, and/or less than 50 kg (110 pounds): one dose of 30 mg. IV: Patients less
than 65 years of age: one dose of 30 mg. Patients who are renally impaired, and/or less than
50 kg (110 pounds): One dose of 15 mg.
Absorption: Rapidly and completely absorbed after oral administration.
Protein binding: 99%.
Metabolism: Primarily hepatic. Less than 50% of a dose is metabolized. The major
metabolites are a glucuronide conjugate, which may also be formed in the kidney,
p-hydroxy ketorolac. Neither metabolite has significant analgesic activity.
Route of elimination: The principal route of elimination of ketorolac and its metabolites is
renal. Approximately 6% of a dose is excreted in the feces.
Half life: 2.5 hours for the S-enantiomer compared with 5 hours for the R-enantiomer.
METHODOLOGY
The bilayer tablets of Ketorolac and Domperidone maleate were developed in two stages.
Blends of immediate release layer of Ketorolac and sustained release layer of Domperidone
maleate were prepared separately by direct compression technique. The individual layers
were optimized based on the in vitro drug release data and bilayer tablets were prepared by
using the optimized formulae.
Analytical Method Development
Determination of Absorption Maxima
A solution of Ketorolac and Domperidone maleate containing the concentration 10 µg/ml
was prepared in 6.8 pH phosphate buffer, U.V Spectrum was taken using (Lab India UV-
3000, Japan). The solution was scanned in the range of 200-400 nm, the results were shown
in.
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Calibration Curve for Ketorolac
Ketorolac equivalent to 10 mg was weighed accurately and added to 10 ml volumetric flask.
It was dissolved in little amount of water and diluted with phosphate buffer pH 6.8 to get a
stock solution A. From the stock solution A, 1 ml was pipetted out and transferred to another
10 ml volumetric flask and the volume was made up with phosphate buffer pH 6.8 to get a
stock solution B. From the stock solution B, 0.2, 0.4, 0.6, 0.8, 1, 1.2ml was pipetted out and
diluted to 10 ml with phosphate buffer to get 2, 4, 6, 8, 10 and 12 µg/ml solutions.
Absorbance of each of these solutions is recorded spectrophotometrically at 322 nm (Lab
India UV-3000, Japan). The data was presented in (Table 15) and calibration curve was
shown in (Fig 10).
Calibration Curve for Domperidone maleate
Domperidone equivalent to 10 mg was weighed accurately and added to 10 ml volumetric
flask. It was diluted with phosphate buffer pH 6.8 to get a stock solution A. From the stock
solution A, 1 ml was pipetted out and transferred to another 10 ml volumetric flask and the
volume was made up with phosphate buffer pH 6.8 to get a stock solution B. From the stock
solution B, 0.2, 0.4, 0.6, 0.8, 1,1.2 ml was pipetted out and diluted to 10 ml with phosphate
buffer to get 2, 4, 6, 8,10 and 12 µg/ml solutions. Absorbance of each of these solutions is
recorded spectrophotometrically at 283 nm (Lab India UV-3000, Japan). The data was
presented in (Table 16) and calibration curve was shown in (Fig 11).
PRE FORMULATION STUDIES
Organoleptic Properties
a) Colour: A small quantity of Ketorolac and Domperidone maleate powders were taken in
butter paper and viewed in well- illuminated place.
b) Taste and odour: Very less quantity of Ketorolac and Domperidone maleate was used to
get taste with the help of tongue as well as smelled to get odour.
Solution Properties
a) Solubility: The solubility’s of substances is determined by shake flask method, according
to this method the drug is added in surplus to the solvents and shaken at a predetermined
time, the saturation is confirmed by observing the presence of undissolved drug, Solvents
such as methanol, alcohol, water, isopropyl alcohol are used for solubility studies.
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Flow Properties[125]
: These studies were conducted for the two drugs separately. The data
was presented in the table 21,22.
a) ANGLE OF REPOSE
The angle of repose of was determined by the funnel-method. The accurately weighed
powder was taken in a funnel. The height of the funnel was adjusted in such a manner that the
tip of the funnel just touched the apex of the heap of the granules. The powder was allowed to
flow through the funnel freely onto the surface. The diameter of the powder cone measured
and angle of repose was calculated using the following equation.
Angle of Repose (θ) = tan-1
(h/r)
Where h and r are the height and radius of the powder cone, θ is the angle of repose.
b) Determination of Bulk Density and Tapped Density
An accurately weighed quantity of the powder (W) was carefully poured into the graduated
cylinder and volume (V0) was measured. Then the graduated cylinder was closed with lid and
set into the tap density tester (USP). The density apparatus was set for 100 tabs and after that
the volume (Vf) was measured and continued operation till the two consecutive readings were
equal.
The bulk density and the tapped density were calculated using the following formulae.
Bulk density = W/V0, Tapped density =W/Vf
Where, W = Weight of the powder, V0 = Initial volume, Vf = final volume.
Measurement of Powder Compressibility
a) Compressibility Index (Carr’s Index)
Carr’s index (CI) is an important measure that can be obtained from the bulk and tapped
densities. In theory, the less compressible a material the more flowable it is.
Carr’s Index = Tapped density – Bulk density / Tapped Density
Where, TD is the tapped density and BD is the bulk density.
b) Hausner’s Ratio
It is the ratio of tapped density and bulk density. Hausner found that this ratio was related to
inter particle friction and, as such, could be used to predict powder flow properties. Generally
a value less than 1.25 indicates good flow properties, which is equivalent to 20% of Carr’s
index.
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Hausner’s ratio = Tapped density / Bulk density
DRUG - POLYMER COMPATIBILITY STUDIES
Fourier Transform Infrared Radiation (FTIR)
The Fourier Transform Infrared Radiation measurement (FTIR) spectral measurements were
taken at ambient temperature using IR spectrophotometer (Shimadzu, model 840, Japan).
Spectra of drug and polymer were taken and analyzed for any major interaction. The pure
drug, physical mixtures and optimized formulations were subjected for FTIR analysis. The
samples were prepared in 1:1 ratio for drug and excipients on KBr-press. The samples were
scanned over a range of 4000-400 cm-1 using Fourier transformer infrared
spectrophotometer. Spectra were analysed for drug polymer interactions. These were done
qualitatively in order to assess the pattern of peaks and for comparison purpose. The graphs
were shown in the(Fig 12,13,14).
FORMULATION OF KETOROLAC IMMEDIATE RELEASE LAYER TABLETS
Ketorolac immediate release layer tablets were prepared by Direct Compression method.
Ketorolac and other excipients like microcrystalline cellulose, sodium starch glycolate, CCS
and CP were sifted through sieve no 40 #. The sifted powders were thoroughly mixed for
approximately 5 min and again passed through sieve no 40 # for maintaining uniformity in
particle size. Vanillin and Citric acid were added. Above mixture was lubricated for 2 min
with magnesium stearate which was already passed through sieve 60 then the tablets were
compressed by using CADMACH multistation compression machine by using 8mm punch.
In batches F1 to F3 CCS was used, F4 to F6 CP was used and in F7 to F9 SSG was used. The
formulation was shown in.
Table 3: Composition of Ketorolac immediate release layer by direct compression.
Ingredients K1 K2 K3 K4 K5 K6 K7 K8 K9
Ketorolac 10 10 10 10 10 10 10 10 10
MCC 156 151.5 147 156 151.5 147 156 151.5 147
CCS 9 13.5 18 - - - - - -
CP - - - 9 13.5 18 - - -
SSG - - - - - - 9 13.5 18
Vanillin 2 2 2 2 2 2 2 2 2
Citric acid 1 1 1 1 1 1 1 1 1
Magnesium
stearate 2 2 2 2 2 2 2 2 2
Total Weight – 180mg
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FORMULATION OF DOMPERIDONE MALEATE SUSTAINED RELEASE LAYER
The dose of Domperidone for sustained release was taken as 20mg. Tablets were prepared by
direct compression method. Appropriate quantities of Domperidone, and excipeints like
Mannitol, Micro crystalline cellulose, Carbopol, CMC, Vanillin were measured accurately as
per formula and all the measured powders were sifted through Sieve no # 40. The sifted
powders were thoroughly mixed for approximately 5 min and again passed through sieve no
40 # for maintaining uniformity in particle size. Above mixture was lubricated for 2 min with
magnesium stearate which was already passed through sieve 60.
The above powder was compressed into tablets by CADMACH multi station tablet
compression machine by using 8 mm punch. In Batch F1 to F4, Carbopol was used as the
sustained release polymer and in Batch F5 to F8 CMC was used and in F9 to F11 both
Carbopol and CMC were used.
Table 4: Composition of Domperidone maleate sustained release layer.
s.no Ingredients D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11
1 Domperidone maleate 20 20 20 20 20 20 20 20 20 20 20
2 Mannitol 40 40 40 40 40 40 40 40 40 40 40
3 MCC 96 76 56 36 96 76 56 36 56 56 56
4 Carbopol 40 60 80 100 - - - - 40 26.6 20
5 CMC - - - - 40 60 80 100 40 53.4 60
6 Vanillin 2 2 2 2 2 2 2 2 2 2 2
7 Magnesium stearate 2 2 2 2 2 2 2 2 2 2 2
Total weight -200mg
PRE-COMPRESSION PARAMETERS OF BLENDS
The Domperidone maleate sustained release layer and Ketorolac directly compressible blends
were evaluated for various pre compression parameters like Angle of repose, Bulk density,
Tapped density, Carr’s index, Hausner’s ratio etc, by following the standard methods
described earlier, The data was presented in.(Table22,23).
EVALUATION OF THE COMPRESSED TABLETS[125]
Both Ketorolac and Domperidone maleate tablets were evaluated for post compression
parameters like hardness, weight variation, friability, drug content uniformity etc. The
Domperidone maleate SR tablets were evaluated for muco adhesive strength and in vitro
dissolution study. Ketorolac IR tablets were evaluated for in vitro disintegration study and in
vitro dissolution study. From the in vitro dissolution study best formulations were selected.
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Determination of Drug Content for Ketorolac
The drug content was carried out by weighing 10 tablets from each batch and calculated the
average weight. Then the tablets were triturated to get a fine powder. From the resulting
triturate, powder was weighed accurately which was equivalent to 10 mg of Ketorolac and
dissolved in a 100 ml volumetric flask containing 50 ml of phosphate buffer 6.8 pH and
volume was made up to 100 ml with same solvent. The volumetric flask shaken using
sonicator for 1hr and after suitable dilution with phosphate buffer 6.8 pH, the drug content is
determined using UV-Visible Spectrophotometer at 322 nm.
Determination of Drug Content for Domperidone[126]
The drug content was carried out by weighing 10 tablets from each batch and calculated the
average weight. Then the tablets were triturated to get a fine powder. From the resulting
triturate, powder was weighed accurately which was equivalent to 20 mg of Ketorolac and
dissolved in a 100 ml volumetric flask containing 50 ml of phosphate buffer 6.8 pH and
volume was made up to 100 ml with same solvent. The volumetric flask shaken using
sonicator for 1hr and after suitable dilution with phosphate buffer 6.8 pH, the drug content is
determined using UV-Visible Spectrophotometer at 283 nm.
Invitro Disintegration time
The disintegration time for all immediate release formulations was carried out using tablet
disintegration test apparatus. Six tablets were placed individually in each tube of
disintegration test apparatus and discs were placed. The medium, water was maintained at a
temperature of 37°±2°C and time taken for the entire tablet to disintegrate completely was
noted. Average of three determinations was taken. The data was presented in the table.
In-Vitro Bioadhesive strength measurement Test[126]
(Methods Based on Measurement of Adhesion Strength)
For In-vitro study, an apparatus designed for determination of mucoadhesive bond strength
was used. Bioadhesive strength expressed in Newton, required for detachment of the tablet
from the mucosa was determined using the fresh sheep buccal mucosa as mucosal
substrate.
In Vitro DRUG RELEASE STUDIES[126]
In vitro dissolution studies of buccal tablets of Modeldrug were carried out in USP
typeII (paddle) Dissolution Testing Apparatus (Electrolab), employing a paddle stirrer at 50
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rpm using 900ml of pH 6.8 Phosphate buffer at 37±0.5oC as dissolution medium. One tablet
was used in each test. The tablets were supposed to release drug from one side only; therefore
an impermeable backing membrane side of tablet was fixed to a 2×2 cm glass slide with a
solution of ethyl cellulose coating. Then it was placed in dissolution apparatus.
At predetermined time intervals 5ml of the samples were withdrawn by means of a
syringe fitted with a pre filter. The volume withdrawn at each interval was replaced with
same quantity of fresh dissolution medium maintained at 37±0.5°C. The samples were
analyzed for drug release by measuring the absorbance at 265 nm using UV-Visible
spectrophotometer after suitable dilutions.
FORMULATION OF BI LAYER BUCCAL TABLETS
Bilayer tablets were prepared by taking best formulations from both the individual layers.
Domperidone maleate blend was first introduced into the die cavity, a slight compression was
made and then Ketorolac blend was introduced into the die cavity followed by final
compression with optimum hardness to form the bi layer tablets. Here compression was made
by using tablet compression machine (Cadmach, India) with 12mm punches. Bilayer tablets
were prepared and evaluated for various post compression parameters and in vitro
dissolution. The composition of bilayer buccal tablets were shown in table.
Table 5: Composition of Bilayer Buccal Tablets.
Ingredients K6+D6(mg) K6+D7(mg) K9+D6(mg) K9+D7(mg)
Immediate release layer
Ketorolac 10 10 10 10
MCC 147 147 147 147
CCS - - - -
CP 18 18 - -
SSG - - 18 18
Vanillin 2 2 2 2
Citric acid 1 1 1 1
Magnesium stearate 2 2 2 2
Sustained release layer
Domperidone 20 20 20 20
Mannitol 40 40 40 40
MCC 76 56 76 56
Carbopol - - - -
CMC 60 80 60 80
Vanillin 2 2 2 2
Citric acid 2 2 2 2
Total weight 380 380 380 380
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EVALUATION OF BILAYER BUCCAL TABLETS
All the post compression parameters like thickness, hardness, weight variation, friability,
content uniformity of both the drugs were measured. The data was presented in the (table 28).
RESULTS AND DISCUSSIONS
Absorption maxima of Ketorolac and Domperidone
Absorption Maximum of Ketorolac was found to be 322nm and for Domperidone maleate the
absorption maximum was found to be 283nm.
Development of Calibration curve
Calibration curve of Ketorolac in 6.8 pH buffer
The wavelength of Ketorolac in 322nm was scanned from the concentration range of
2,4,6,8,10,12 µg/ml.Standard calibration graph of Ketorolac in water at pH6.8 was plotted by
taking concentration vs absorbance and good correlation was obtained with R2
value of 0.998
which obey Beer – Lambert’s law.
Table 16: Data for Calibration Curve of Ketorolac.
S. no Concentration(µg/ml) Absorbance at 322nm
1 0 0
2 2 0.090
3 4 0.185
4 6 0.249
5 8 0.332
6 10 0.406
7 12 0.482
8 14 0.565
Figure 10: Calibration Curve of Ketorolac in pH6.8 Phosphate buffer.
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Calibration Curve of Domperidone maleate: The wavelength of Domperidone maleate in
283nm was scanned from the concentration range of 0, 2, 4,6,8,10,12, 14 µg/ml. standard
calibration graph of Domperidone maleate in water was plotted by taking concentration vs.
absorbance and a good correlation was obtained with R2 value of 0.998 which obey Beer –
Lambert’s law.
Table 17: Data for Calibration Curve of Domperidone maleate.
S.no Concentration (µg/ml) Absorbance at 283nm
1 2 0.075
2 4 0.118
3 6 0.184
4 8 0.230
5 10 0.298
6 12 0.358
7 14 0.408
Figure 11: Calibration Curve of Domperidone maleate in pH6.8 Phosphate buffer
PREFORMULATION STUDIES
Organoleptic Properties
Table 18: Organoleptic Properties of Ketorolac.
Test Specification/ Limits Observations
Colour White to off white White Powder
Taste Abnormal taste Abnormal taste
Odour Slight characteristic odour Characteristic odour
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Table 19: Organoleptic Properties of Domperidone maleate
Test Specification/ Limits Observations
Colour White to slightly beige
coloured powder White powder
Taste Sour/bitter taste Bitter taste
Odour Odourless Odourless
Solution Properties
a) Solubility: The following (Table 20,21) illustrates the results
Table 20: Solubility of Ketorolac.
Quantity of Ketorolac Quantity of Solvents Inference
100mg 100ml of water Freely soluble
100mg 100ml of 95% ethanol Slightly soluble
100mg 100ml methanol Freely soluble
Table 21: Solubility of Domperidone maleate.
Quantity of
Domperidone maleate Quantity of Solvents Inference
100 mg 100 ml of water Very slightly soluble in
water
100 mg 100 ml of 95%ethanol Very Slightly soluble
100 mg 100 ml of methanol slightly soluble
Table 22: Precompression Parameters Of Ketorolac.
Formulati
on Code
Bulk density
(g/cc)
±SD
Tapped
density
(g/cc)±SD
Carrs
index(%)
±S.D
Hausners
ratio
±S.D
Angle of
Repose(θ)
±S.D
Powder
flow
properties
K1 0.46±0.006 0.55±0.022 16.36±0.12 1.19±0.09 16.36±0.12 Excellent
K2 0.45±0.006 0.54±0.009 16.6±0.10 1.2±0.08 16.66±0.25 Excellent
K3 0.46±0.005 0.55±0.034 16.36±0.11 1.19±0.08 16.52±0.23 Excellent
K4 0.32±0.006 0.38±0.019 15.7±0.25 1.18±0.72 14.73±0.19 Excellent
K5 0.45±0.004 0.52±0.011 13.46±0.15 1.15±0.06 18.75±0.18 Excellent
K6 0.48±0.004 0.57±0.013 15.78±0.17 1.18±0.065 15.32±0.16 Excellent
K7 0.47±0.005 0.56±0.015 16.07±0.10 1.19±0.072 17.42±0.16 Excellent
K8 0.47±0.002 0.54±0.020 12.9±0.12 1.14±0.058 16.14±0.13 Excellent
K9 0.45±0.003 0.56±0.027 19.6±0.22 1.24±0.075 19.08±0.13 Excellent
K1-K9(Ketorolac Formulations)(n=3,±S.D) (S.D= Standard deviation)
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Table 23: Precompression Parameters Of Domperidone Maleate.
Formulat
ion code
Bulk
density(g/cc)
±S.D
Tapped
density(g/cc)±S
D
Carrs
index
(%)±S.D
Hausners
ratio±S.D
Angle of repose
Degrees±S.D
Powder flow
properties
D1 0.214±0.02 0.251±0.026 14.74±0.18 1.17±0.23 25.49±0.18 Good
D2 0.308±0.01 0.364±0.025 15±0.12 1.18±0.24 26.24±0.12 Good
D3 0.276±0.03 0.322±0.022 14±0.14 1.16±0.19 29.05±0.14 Good
D4 0.521±0.03 0.629±0.026 17±0.12 1.2±0.16 33.65±0.12 Fair
D5 0.324±0.01 0.376±0.0212 13±0.13 1.16±0.19 29.25±0.13 Good
D6 0.320±0.01 0.397±0.02 19±0.13 1.24±0.18 32.27±0.13 Fair
D7 0.341±0.02 0.388±0.02 12±0.16 1.13±0.18 26.97±0.16 Free flowing
D8 0.518±0.012 0.627±0.023 17±0.15 1.21±0.18 33.21±0.15 Fair
D9 0.422±0.011 0.506±0.025 19±0.13 1.19±0.23 26.56±0.13 Fair
D10 0.481±0.011 0.572±0.026 15±0.14 1.18±0.24 28.75±0.13 Good
D11 0.475±0.013 0.566±0.027 16±0.17 1.19±0.19 27.33±0.17 Fair
D1 – D11 (Domperidonemaleate formulations) n=3,±S.D) (S.D= Standard deviation)
DRUG - POLYMER COMPATIBILITY STUDY
Fourier Transform Infrared Radiation (FTIR)
All the above bands associated with the Ketorolac and Domperidone maleate are present in
the FTIR spectra of drug(fig12,fig13). This shows there is no chemical interaction between
drug and excipients(fig 14).
Figure 12: FTIR spectra of Pure Ketorolac.
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S.no Functional
Group
Characteristic Peak
cm-1
Observed Peaks
cm-1
1 0-H 3200-3600 3422.48
2 C=0 1670-1820 1628.09
3 C-N 1080-1360 1277.28
4 C=C 1400-1600 1474.69
Figure 13: Ftir Spectra of Pure Domperidone.
S.no Functional
Group
Characteristic Peak
cm-1
Observed Peaks
cm-1
1 C-N 1080-1360 1285.62
2 N-H 3300-3500 3350.97
3 C-H 2850-3000 2938.30
4 C=C 1400-1600 1600.95
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Figure 14: FTIR Spectra of Bilayered Buccal tablets (ketorolac IR layer+Domperidone
maleate SR layer).
S.no Functional
Group
Characteristic Peak
cm-1
Observed Peaks
cm-1
1 0-H 3500-3700 3505.03
2 C-H 2850-3000 2918.67
3 C=0 1670-1820 1728.04
4 N-H 3300-3500 3400.28
EVALUATION OF COMPRESSED TABLETS
Table 24 Results of post compression parameters of Ketorolac trimethamine.
Formulation
code
Average
Weight (mg)
(n=20)
Thickness
(mm)
(n=3)
Hardness
(Kg/cm2 )
(n=3)
Friability
(n=20)
Disintegration
time(sec)
Drug
content%
K1 178.67±0.42 2.22±0.01 2.40 0.56 1min 10sec 99.03±0.53
K2 180.48±0.53 2.30±0.02 2.35 0.47 43 sec 99.86±0.51
K3 178.72±0.85 2.34±0.04 2.30 0.51 32 sec 99.27±0.42
K4 180.81±0.63 2.42±0.02 2.30 0.64 57sec 100.61±0.47
K5 179.76±1.30 2.35±0.03 2.25 0.45 36sec 98.83±0.23
K6 180.60±0.76 2.40±0.02 2.22 0.40 20sec 100.83±0.21
K7 179.26±0.72 2.32±0.01 2.45 0.51 47sec 97.56±0.13
K8 178.35±1.30 2.25±0.02 2.35 0.44 30sec 99.63±0.22
K9 181.02±0.03 2.22±0.02 2.25 0.39 18sec 99.27±0.12
*(±S.D)(S.D= Standard deviation)
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Data of Ketorolac
The prepared tablets containing CP,CCS, sodium starch glycolate ( as super disintegrant
were evaluated for parameters such as Weight variation, Hardness, Friability, Thickness,
drug content, in vitro disintegration time and in vitro dissolution profile was shown in
(Table 24,26).
From the results reported in (Table 24) weight variation was found to be less than±7.5%,
which is the pharmacopoeial limits.
Hardness of formulation was in the range of 2.25 to 2.45 kg/cm2.
The friability value of the formulation was 0.40% to 0.64% the results of friability
indicate that the tablets were mechanically stable, complies with pharmacopoeial limit of
F less than 1%.
Thickness of the formulation was between 2.22±0.01 to 2.42±0.02 mm showing fairly
uniform tablets. Drug content was uniform ranging from 97.56±0.13 to 100.83±0.21, the
in vitro disintegration time was found to be in the range of 18 sec to 1min 10sec.
Table 25 Results of Post compression parameters of Domperidone maleate
Formulation
code
Average
Weight (gms)
(n=20)
Thickness
(mm)
(n=3)
Hardness(k
g/cm2)
(n=3)
Friability
(n=20)
Muco adhesive
strength
(gms)
Drug
content%
D1 199.51±0.87 2.41±0.06 5.7±0.2 0.56 19 99.83±0.2
D2 199.24±0.82 2.45±0.06 5.8±0.3 0.49 23 98.94±0.3
D3 200.09±1.04 2.49±0.02 6.1±0.2 0.63 30 98.12±0.42
D4 199.95±0.94 2.49±0.02 6.2±0.2 0.54 36 99.63±0.25
D5 199.61±0.86 2.42±0.02 5.7±0.3 0.56 13 99.52±0.23
D6 199.40±0.73 2.51±0.04 5.6±0.3 0.38 18 100.83±0.2
D7 199.86±0.57 2.60±0.04 5.5±0.4 0.54 23 99.12±0.26
D8 199.27±0.83 2.62±0.02 6.0±0.2 0.69 26 100.02±0.1
D9 198.58±0.51 2.56±0.02 5.8±0.3 0.54 25 98.7±0.35
D10 199.90±0.93 2.54±0.02 6.0±0.2 0.46 27 99.6±0.29
D11 200.09±1.04 2.52±0.02 5.8±0.3 0.41 28 99.21±0.19
*(±S.D)(S.D= Standard deviation)
Data of Domperidone maleate: It was observed from (Table. 24) that the prepared tablets
were evaluated for Weight variation, Hardness, Friability, Thickness, muco adhesive
strength, drug content.
Thickness was found to be in the range of 2.42 to 2.62 mm.
Hardness of the tablets was in the range of 5.5±0.2 to 6.2±0.2 kg/cm2 which was
sufficient for the handling of tablets throughout the shelf life.
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Percentage % friability was between 0.38 – 0.69 % and complies with pharmacopoeial
limit of less than 1%.
Weight variation was found to be than±7.5% which is a pharmacopoeial limit.
Drug content of Domperidone maleate was found to be in the range of 98.12±0.42 to
100.83±0.78%, was within the limits as per I.P and ICH guidelines.
Muco adhesive strength was found to be in the range of 13 -36 gms.
Invitro drug release of ketorolac tablets
Table 26: Cumulative % Drug Release of ketorolac tablets*(n=3,±S.D)( S.D = Standard
deviation).
Time
(min) K1 K2 K3 K4 K5 K6 K7 K8 K9
2 14.23
±1.3
16.2
±1.2
25.3
±1.22
18.32
±1.14
23.11
±1.3
39.02
±1.2
12.04
±1.2
18.04
±1.22
23.04
±1.20
4 25.02
±1.2
30.12
±1.22
38.04
±1.23
33.33
±1.12
40.21
±1.2
56.17
±1.3
28.17
±1.21
32.05
±1.3
39.04
±1.21
6 37.05
±1.2
45.42
±1.1
56.12
±1.32
46.19
±1.21
59.31
±1.24
72.19
±1.21
39.23
±1.27
44.12
±1.26
50.13
±1.14
8 58.13
±1.1
60.21
±1.20
68.14
±1.34
58.42
±1.26
67.52
±1.1
86.25
±1.25
50.22
±1.24
59.16
±1.23
68.14
±1.18
10 69.24
±1.2
72.02
±1.32
79.25
±1.21
71.45
±1.22
80.12
±1.4
95.24
±1.27
63.17
±1.3
74.27
±1.16
77.24
±1.28
12 80.22
±1.3
85.14
±1.25
90.26
±1.20
89.52
±1.18
95.12
±1.32
99.32
±1.31
78.16
±1.32
83.28
±1.12
96.28
±1.17
14 91.17
±1.4
93.17
±1.3
96.28
±1.25
95.23
±1.3
97.04
±1.22
100.0
5±1.2
90.23
±1.1
97.32
±1.22
99.51
±1.21
*(n=3,±S.D)(S.D = Standard deviation)
From the table it can be noted that the drug release of formulations K1,K2,K3 at the end of
14sec was found to be 91.17±1.4, 93.17±1.3 and 96.28±1.25.
The drug release of K4,K5, K6 was found to be 95.23±1.3, 97.04±1.22, 100.05±1.2 at the end
of 14 min.
The drug release of K7, K8, K9 was found to be 90.23±1.1, 97.32±1.22 and 99.51±1.21 at the
end of 14 min.
In formulations K1, K2, K3, CCS was used as super disintegrant with increasing
concentrations of 9mg in K1,13.5 mg in K2 and 18mg in K3.
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In formulations from K4 to K6,CP was used as super disintegrant with increasing
concentrations of 9mg in K4, 13.5mg in K5 and 18mg in K6. In formulations from K7 to
K9,SSG was used as super disintegrant with increasing concentrations of 9mg in K7,13.5mg
in K8 and 18 mg in K9.
Invitro drug release of Domperidone maleate tablets
Table 27: Cumulative % drug release of Domperidone maleate tablets.
Time
(hrs) D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11
1 27.02
±1.1
13.12
±1.2
9.12
±1.22
3.12
±1.12
22.12
±1.24
12.04
±1.23
8.03
±1.21
3.12
±1.1
10.23
±1.16
8.12
±1.1
16.02
±1.36
2 38.12
±1.21
20.20
±1.3
17.12
±1.2
7.13
±1.21
35.16
±1.3
25.21
±1.12
16.04
±1.3
12.23
±1.2
18.11
±1.2
14.02
±1.12
24.13
±1.34
3
43.14
±1.23
31.31
±1.32
26.02
±1.20
14.03
±1.14
46.25
±1.29
32.04
±1.21
24.12
±1.26
18.16
±1.34
27.12
±1.17
20.13
±1.31
32.12
±1.27
4 56.24
±1.16
43.32
±1.24
30.32
±1.23
26.04
±1.23
59.27
±1.26
44.17
±1.21
36.13
±1.11
24.09
±1.22
39.05
±1.14
26.12
±1.26
40.14
±1.26
5 73.26
±1.24
52.21
±1.21
39.12
±1.14
32.52
±1.23
76.21
±1.31
51.31
±1.31
48.21
±1.24
35.91
±1.26
46.54
±1.22
37.34
±1.16
47.02
±1.21
6 82.32
±1.31
67.23
±1.23
45.47
±1.16
39.53
±1.28
80.31
±1.13
66.29
±1.32
63.14
±1.31
39.54
±1.14
57.36
±1.22
41.37
±1.23
53.21
±1.12
7 87.51
±1.29
70.06
±1.26
56.81
±1.11
43.24
±1.29
83.32
±1.20
79.10
±1.21
79.12
±1.22
47.23
±1.22
60.12
±1.28
52.12±
1.42
67.21
±1.23
8 89.53
±1.30
79.12
±1.18
58.23
±1.2
46.36
±1.10
87.13
±1.12
90.12
±1.26
92.05
±1.11
68.12
±1.32
72.23
±1.30
69.44
±1.16
78.22
±1.21
*(n=3,±S.D)(S.D = Standard deviation)
The drug release of Domperidone formulations D1, D2, D3 was found to be 89.53±1.30,
79.12±1.18, 58.23±1.2 at the end of 8hrs.The drug release of D4, D5, D6 was found to be
46.36±1.10, 87.13±1.12 and 90.12±1.26 at the end of 8th
hr. The drug release of D7, D8, D9
at the end of 8 hrs was found to be 92.05±1.11, 68.12±1.32 and 72.23±1.30. The drug release
of D10 and D11 was found to be 69.44±1.16 and 78.22±1.21 at the end of 8th
hr. Carbopol
was used in the formulations from D1 to D4 in increasing concentrations from 40 to 100mg.
CMC was used in the formulations from D5 to D8 in increasing concentrations from 40 to
100mg.
In formulations from D9 to D11 both Carbopol and CMC were used, with equal
concentrations of Carbopol and CMC in D9(40mg of Carbopol and 40mg of CMC)and
uneual quantities of Carbopol and CMC in D10 and (26.6mg of Carbopol and 53.4 mg of
CMC) and 20mg of Carbopol and 60mg of CMC in D11.
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Table 28: Evaluation of Bilayer Buccal Tablets.
Formulation
Code
Average
weight±S.D(n=20)
Hardness (kg/cm2)
(±S.D)(n=3)
Thickness
(mm)(±S.D)(n=3)
Friability
(%) (n=20)
Drug Content (%)
Ketorolac Domperidone
K6+D6 379.23±0.87 5.7±0.2 4.41±0.06 0.45 100.12±0.2 99.12±0.13
K6+D7 380.12±0.42 5.7±0.3 4.5±0.05 0.51 100.83±0.3 99.95±0.17
K9+D6 378.21±0.12 5.6±0.2 4.23±0.03 0.52 99.42±0.2 99.82±0.21
K9+D7 378.12±0.23 5.5±0.2 4.32±0.04 0.58 99.27±0.4 98.12±0.32
*(±S.D)(S.D= Standard deviation)
In Vitro DRUG RELEASE OF BILAYER BUCCAL TABLETS
Table 29 Cumulative % Drug Release of Bilayer Buccal Tablets.
Time
Intervals K6+D6 (%) K6+D7(%) K9+D6(%) K9+D7(%)
Ketorolac Domperidone Ketorolac Domperidone Ketorolac Domperidone Ketorolac Domperidone
0min 0 0 0 0 0 0 0 0
2min 38.12±1.24 - 38.16±1.3 - 24.09±1.14 - 25.12±1.12 -
4 min 56.21±1.2 - 55.15±1.13 - 38.91±1.21 - 39.12±1.2 -
6min 71.39±1.3 - 72.13±1.22 - 50.86±1.12 - 50.12±1.4 -
8 min 86.18±1.12 - 86.23±1.21 - 67.87±1.23 - 68.21±1.3 -
10 min 94.25±1.33 - 93.12±1.24 - 75.78±1.24 - 77.12±1.23 -
12 min 99.09±1.24 - 98.12±1.12 - 96.96±1.13 - 95.03±1.27 -
14 min 99.51±1.21 - 100.12±1.16 - 99.5±1.12 - 99.73±1.1 -
1 hrs - 12.09±1.21 - 8.13±1.2 - 13.43±1.13 - 9.12±1.23
2 hrs - 27.63±1.22 - 16.23±1.3 - 26.86±1.22 - 17.12±1.23
3 hrs - 32.89±1.3 - 25.43±1.2 - 31.86±1.23 - 25.09±1.13
4 hrs - 45.36±1.33 - 37.31±1.11 - 44.96±1.24 - 34.12±1. 24
5 hrs - 52.63±1.34 - 49.23±1.23 - 50.47±1.12 - 49.13±1.25
6 hrs - 66.23±1.24 - 64.56±1.21 - 66.37±1.11 - 65.23±1.31
7hrs - 79.02±1.3 - 78.12±1.23 - 80.12±1.21 - 80.02±1.25
8hrs - 90.02±1.14 - 92.57±1.23 - 89.12±1.21 - 91.25±1.13
*(n=3,±S.D)(S.D = Standard deviation)
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The bilayer tablets prepared by combining K6,K9 of Ketorolac immediate release layer and
D6, D7 of Domperidone sustained release layer were evaluated for weight variation,
hardness, friability, thickness, drug content, in vitro drug release etc. The properties were
shown in the (table 27,28).
Data of Bilayer buccal tablets
The thickness of the tablets was found to be 4.41±0.06, 4.5±0.05, 4.23±0.03, 4.32±0.04
mm.
The hardness of the tablets was found to be 5.7±0.2, 5.7±0.3, 5.6±0.2, 5.5±0.2 kg/cm2 and
was sufficient for the handling throughout the shelf life.
Percentage weight loss (or) % Friability was measured and found to be in the range of
0.45, 0.51, 0.52, 0.58 % and was within the pharmacopoeial limit that is less than 1%.
The tablets passed the weight variation test as per USP limits as they have shown less
than 5% of deviation from their weight.
Drug contents of Ketorolac and Domperidone maleate in the bilayered tablet were found
to 100.12±0.2 and 99.12±0.13, 100.83±0.3 and 99.95±0.17, 99.42±0.2 and 99.82±0.21,
99.27±0.4 and 98.12±0.32 respectively.
For both drugs their drug contents were within the limit as per I.P and ICH guidelines and
have shown good content uniformity.
In vitro dissolution studies
Dissolution profile of bilayer buccal tablets was reported in (Table 28). Dissolution was
performed in pH 6.8 Phosphate buffer for 12 hrs and % drug release was calculated by UV–
spectroscopic method, Ketorolac release occurred initially for 14 min by giving %
99.51±1.21, 100.12±1.16, 99.5±1.12, 99.73±1.1 drug release.
Here, drug release was calculated by measuring absorbance by keeping Domperidone maleate
formulation as blank. Domperidone maleate drug release was measured up to 8 hrs from first
hour by keeping Ketorolac formulation as a blank. Domperidone maleate gave 90.02±1.14,
92.57±1.23, 89.12±1.21, 91.251.13 drug release at the end of 8 hrs.
Out of the four optimised formulations K6+D6,K6+D7,K9+D6,K9+D7, the drug release was
more in case of K6+D7,hence it is considered as the best formulation.
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Figure 15: Comparison of in vitro dissolution characteristics of Ketorolac K1,K2,K3(×)
(n = 3).
Figure 16: Comparison of in vitro dissolution characteristics of Ketorolac K4,K5,K6(×)
(n = 3).
Figure 17: Comparison of in vitro dissolution characteristics of Ketorolac K7,K8,K9(×)
(n = 3).
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Figure 18: Comparison of in vitro dissolution characteristics of Domperidone maleate
D1,D2,D3(×) (n = 3).
Figure 19: Comparison of in vitro dissolution characteristics of Domperidone maleate
D4,D5,D6(×) (n = 3).
Figure 20 Comparison of in vitro dissolution characteristics of Domperidone maleate
D7,D8,D9(×) (n = 3).
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Figure 21: Comparison of in vitro dissolution characteristics of Domperidone
D10,D11(×) (n = 3).
Table 30 In vitro Kinetic Release Characteristics of Formulation (K6+D6).
Time(hours) SQRT
Time Log Time
%
Cumulative
Drug release
%
Cumulative
Drug
remained
Log %
Cumulative
Drug release
Log %
Cumulative
Drug
remained
0 0 0 0 0 0 0
1 1 0 12.09 87.91 1.082 1.944
2 1.414 0.301 27.63 72.37 1.44 1.859
3 1.732 0.477 32.89 67.11 1.517 1.826
4 2 0.602 45.36 54.64 1.656 1.737
5 2.236 0.699 52.63 47.37 1.721 1.675
6 2.44 0.778 66.23 33.77 1.821 1.528
7 2.64 0.845 79.02 20.98 1.897 1.321
8 2.82 0.903 90.02 9.98 1.954 0.999
Figure 22: Zero Order Graph of Optimized Formulation K6+D6.
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Figure 23: First Order Graph of Optimized Formulation K6+D6.
Figure 24: Higuchi Graph of Optimized Formulation K6+D6.
Figure 25: Korsmeyer - Peppas Graph of Optimized Formulation K6+D6.
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Table 31: In vitro Kinetic Release Characteristics of Formulation (K6+D7).
Time(hours) SQRT
Time
Log
Time
%
Cumulative
Drug
release
%
Cumulative
Drug
remained
Log %
Cumulative
Drug release
Log %
Cumulative
Drug
remained
0 0 0 0 0 0 0
1 1 0 8.13 91.87 0.91 1.963
2 1.414 0.301 16.23 83.77 1.21 1.923
3 1.732 0.477 25.43 74.57 1.405 1.872
4 2 0.602 37.31 62.69 1.571 1.797
5 2.236 0.699 49.23 50.77 1.692 1.705
6 2.44 0.778 64.56 35.44 1.809 1.549
7 2.64 0.85 78.12 21.88 1.892 1.340
8 2.82 0.903 92.57 7.43 1.966 0.87
Figure 26: Zero Order Graph of Optimized Formulation K6+D7.
Figure 27: First Order Graph of Optimized Formulation K6+D7.
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Figure 28: Higuchi Plot of Optimized Formulation K6+D7.
Figure 29: Korsmeyer - Peppas Graph of Optimized Formulation K6+D7.
Table 32: In vitro Kinetic Release Characteristics of Formulation (K9+D6).
Time(hours) SQRT Time Log Time
%
Cumulative
Drug release
%
Cumulative
Drug
remained
Log %
Cumulative
Drug release
Log %
Cumulative
Drug
remained
0 0 0 0 0 0 0
1 1 0 13.43 86.57 1.128 1.937
2 1.414 0.3010 26.86 73.14 1.429 1.864
3 1.732 0.4771 31.86 68.14 1.503 1.833
4 2 0.602 44.96 55.04 1.652 1.74
5 2.236 0.6990 50.47 49.53 1.703 1.694
6 2.44 0.778 66.37 33.63 1.821 1.526
7 2.64 0.85 80.12 19.88 1.903 1.298
8 2.82 0.903 89.12 10.88 1.949 1.036
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Figure 30: Zero Order Graph of Optimized Formulation K9+D6.
Figure 31: First Order Graph of Optimized Formulation K9+D6.
Figure 32: Higuchi plot of Optimized Formulation K9+D6.
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Figure 33: Korsmeyer - Peppas Graph of Optimized Formulation K9+D6.
Table 33: In vitro Kinetic Release Characteristics of Formulation (K9+D7)
Time(hours) SQRT Time Log Time
%
Cumulative
Drug release
%
Cumulative
Drug
remained
Log %
Cumulative
Drug release
Log %
Cumulative
Drug
remained
0 0 0 0 0 0 0
1 1 0 9.12 90.88 0.959 1.958
2 1.414 0.301 17.12 82.88 1.233 1.918
3 1.732 0.477 25.09 74.91 1.399 1.874
4 2 0.602 34.12 65.88 1.533 1.818
5 2.236 0.699 49.13 50.87 1.691 1.706
6 2.44 0.778 65.23 34.77 1.814 1.541
7 2.64 0.85 80.02 19.98 1.903 1.300
8 2.82 0.903 91.25 8.75 1.960 0.942
Figure 34: Zero order graph of optimised formulation K9+D7.
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Figure 35: First order graph of optimised formulation K9+D7.
Figure 36: Higuchi graph of optimised formulation K9+D7.
`
Figure 37: Korsmeyer - Peppas graph of optimised formulation K9+D7
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Table 34: Results of Kinetic Studies for Optimized Bilayer Buccal Tablets
S.no Formulation Zero
Order R2
First
Order R2
Higuchi
R2
Koresmeye
r Peppas R2
N Mechanism of Drug
Release
1 K6+D6 0.994 0.712 0.914 0.694 0.865 Zero order release,
Non fickian diffusion
2 K6+D7 0.987 0.818 0.847 0.626 0.955 Zero order release,
Erosion
3 K9+D6 0.992 0.707 0.908 0.696 0.848 Zero order release,non
fickian diffusion
4 K9+D7 0.981 0.811 0.841 0.646 0.932 Zero order release,
erosion *
R2 = Correlation coefficient; n= Diffusional exponent
KINETIC STUDY FOR DOMPERIDONE BUCCAL SR LAYER OF BILAYER
TABLET
The release rate kinetic data for K6+D6, K6+D7, K9+D6, K9+D7 is shown in (Table
29,30,31,32). As shown in (Figures 22-37), drug release data was best explained by zero
order equation, as the plots showed the highest linearity (R2 = 0.994), (R
2 = 0.987), (R
2 =
0.992), (R2 = 0.981) followed by and Higuchi’s equation (R
2 = 0.914), (R
2 = 0.847), (R
2 =
0.908), (R2 = 0.841). As the drug release was best fitted in zero order kinetics, indicating that
the rate of drug release is concentration independent. Higuchi’s kinetics explains why the
drug diffuses at a comparatively slower rate as the distance for diffusion increases.
Mechanism of drug release
In order to understand the complex mechanism of drug release from the K6+D6,
K6+D7,K9+D6, K9+D7, the % in vitro drug release was fitted into Korsmeyer - peppas
model and the diffusional exponent value (n) was interpreted for mechanism of drug release.
The release exponent value (n) thus obtained was 0.865, 0.955, 0.848, 0.932 therefore, we
can conclude that K6+D6,K9+D6 follows non- Fickian Transport, with Zero order, Higuchi
mechanism and K6+D7,K9+D7 follows Zero order, Higuchi mechanism with erosion release.
STABILITY STUDIES
The formulations (K6+D6), (K6+ D7), (K9+D6),(K9+D7) were evaluated for stability by
conducting accelerated stability studies. The formulation were stored at 40o C at 75% RH for
2 months and analyzed for their physical parameters and drug content and in vitro drug
release studies at every one month interval. The data was shown in the (Table 34,35).
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Table 35: Characteristics of Bilayer Buccal Tablets during Stability Studies.
Time
Drug content(%) Hardness (kg/cm
2)
Ketorolac Domperidone
K6+
D6 K6+D7 K9+D6 K9+D7 K6+D6 K6+D7 K9+D6
K9+
D7 K6+D6
K6+
D7 K9+D6
K9+
D7
Zeromonth 100.9±0.12 100.77±0.65 99.39±0.56 99.24±0.12 99.07±0.31 99.91±0.46 99.76±0.42 98.1±0.31 5.7±0.1 5.7±0.2 5.6±0.2 5.5±0.2
First month 99.77±0.53 99.81±0.38 98.25±0.24 98.16±0.35 98.42±0.27 98.91±0.28 98.57±0.35 97.42±0.28 5.65±0.1 5.67±0.2 5.55±0.2 5±0.1
Twomonth 99.29±0.26 99.46±0.19 98.16±0.32 98.05±0.15 98.12±0.13 98.57±0.17 98.12±0.13 97.11±0.17 5.6±0.3 5.61±0.1 5.5±0.3 4.9±0.3
*(n=3,±S.D)(S.D = Standard deviation)
Table 36: Characteristics of Bilayer buccal Tablets during Stability Studies.
Time Friability (%) In Vitro Drug Release at the end of 8 hrs
K6+D6 K6+D7 K9+D6 K9+D7 K6+D6 K6+D7 K9+D6 K9+D7
Zero month 0.41 0.48 0.51 0.56 90±0.58 92.35±0.34 89.1±0.54 91.12±0.12
First month 0.35 0.46 0.48 0.51 89.56± 0.61 92.15±0.32 88.89±0.52 90.99±0.21
Two month 0.31 0.41 0.45 0.48 89.12±0.45 92.07±0.12 88.65±0.65 90.85±0.35
*(n=3,±S.D)(S.D = Standard deviation)
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CONCLUSION
In the present study an attempt was made to design a biphasic Bilayer buccal Tablet
containing Ketorolac immediate release layer and Domperidone maleate sustained release
layer. FT-IR studies reveal that there were no significant interactions between both the drugs
and between the drugs and their respective excipeints. For achieving sustained release of
Domperidone maleate, bucco adhesive polymers Carbopol and CMC were used Formulations
D6 and D7 gave drug release 90.12±1.26 and 92.15±1.11 after 8hrs. Therefore D6 and D7
were considered as best formulations among D1 –D 11 for formulation of bilayer buccal
tablets.
For achieving immediate result of Ketorolac, from the results it was concluded that
disintegration activity is good with Crosspovidone and SSG, K6 releasing 100. 05±1.2 and
K9 releasing 99.51±1.21 % after 14min. The bilayered tablets prepared by taking D6 and D7
of Domperidone maleate and K6 and K9 formulations of Ketorolac as 2layers
(K6+D6,K6+D7,K9+D6,K9+D7) have shown good post compression parameters like
hardness, friability weight variation, drug content etc which were within the limits. Hence
they are considered as optimized formulations.
Out of the four optimized formulations, K6+D7 showed good % drug release, hence it is
considered as the best formulation. The stability study indicates that the formulations were
stable. From this study by preparing bilayer buccal tablets by direct compression technique, it
was concluded that we could reduce the total dose, dosage frequency, dose related side
effects, and improve the bioavailability of Domperidone maleate which in turn improves the
patient compliance. Future scope for this study is the scaling up for industrial applications.
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