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World Journal of Pharmaceutical Research
Ramya Sri et al.
World Journal of Pharmaceutical
Research
SJIF Impact Factor 5.045
Volume 3, Issue 10, 1545-1576.
Research Article
ISSN 2277– 7105
FORMULATION AND EVALUATION OF BIOADHESIVE BUCCAL
TABLETS OF MOSAPRIDE CITRATE
Ramya Sri Sura* and S. Pavani
Department of Pharmaceutics, Vaagdevi College of Pharmacy, Ramnagar, Hanamkonda,
Warangal, Telangana, India.
Article Received on
12 October 2014,
ABSTRACT
Revised on 06 Nov 2014,
Accepted on 01 Dec 2014
tablets of Mosapride Citrate so as to avoid it from first pass
The objective of the present study was to develop bioadhesive buccal
metabolism. Different grades of HPMC polymers, Carbopol 934
intended for buccal tablet formulation for selected and studied for their
*Correspondence for
Author
comparative mucoadhesive force, swelling behavior, residence time
Ramya Sri Sura
and surface pH. The preformulation study was performed by FTIR
Department of
spectroscopy and it was revealed the compatibility of drug and
Pharmaceutics, Vaagdevi
polymer. Ex vivo permeation study of Mosapride Citrate pure drug
College of Pharmacy,
Ramnagar, Hanamkonda,
Warangal, Telangana,
solution through the porcine buccal mucosa was performed and the
flux value was found to be 424.735µg.hr -1cm-2 The mucoadhesive
tablets were prepared by direct compression method. The tablets were
India.
evaluated for pre-compression parameters, thickness, hardness, weight
uniformity, content uniformity, surface pH, swelling index, in vitro drug release, ex vivo
residence time, bioadhesion strength, ex vivo permeation. In vitro assembly was used to
measure the bioadhesive strength of tablets with fresh porcine buccal mucosa as model tissue.
The tablets were evaluated for in vitro release in pH 6.8 phosphate buffer for 8 hrs in standard
dissolution apparatus. The pre-compression parameters were in acceptable range of
pharmacopoeial specification. The surface pH of the selected formulations was in the range
of salivary pH and showed ex vivo residence time indicated good adhesive capacity of
selected formulations. Among various selected formulations F11 formulation containing
combination of HPMC K15M and Carbopol 934 in the ratio of 1:1 showed maximum
percentage drug release i.e., 94.9% in 8 hrs with good ex vivo residence time, maximum flux
and permeability coefficient values i.e., 8 hrs 5 min, 418.445 µg.hr -1cm-2 and 0.4122 (cm/hr).
The formulation F11 was followed Korsmeyer peppas mechanism with
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Ramya Sri et al.
Regression value of 0.9829 and n value was found to be 0.6154, it indicates that it follows
non fickian drug release pattern.
KEYWORDS: Buccal tablets, Mosapride Citrate, Bioadhesive polymers, Flux, Permeability
coefficient.
INTRODUCTION
Buccal Delivery involves the administration of drug through buccal mucosal membrane (the
lining in the oral cavity).[1] Oral drug administration many drugs are subjected to presystemic
clearance in liver, which often leads to a lack of correlation between membrane permeability,
absorption and bioavailability.[1-5] Within the oral route, the Buccal cavity is an attractive site
for drug delivery due to ease of administration and avoids possible drug degradation in the
gastrointesinal tract as well as first pass hepatic metabolism.[6] The drug directly reaches to
the systemic circulation through the internal jugular vein and bypasses the drugs from the
hepatic first pass metabolism, which leads to high bioavailability. [7]
Mosapride Citrate is the novel gastro prokinetic agent. Mosapride Citrate during absorption
converted to its active metabolite, Mosapride, which is specific and selective for 5-hydroxy
tryphtophan4 receptor agonist (5-HT4). Mosapride Citrate has got certain characteristics that
a drug should possess to get absorbed through the buccal route viz., high permeability and
low molecular weight. It undergoes first-pass metabolism in the liver which is the reason for
its lower bioavailability, so its bioavailability may be improved when delivered through
buccal route. This molecule is propitiate general considerations for buccal drug delivery.
Hence it is selected as drug candidate for bioadhesive buccal drug delivery. [8-10]
MATERIALS AND METHODS
Materials: Mosapride Citrate was obtained from Sura Labs, Hyderabad. Carbopol 934P,
HPMCK15M, HPMCK100M was procured from Nihar traders pvt Ltd. Remaining materials
was procured from S.D Fine Chem Limited, Mumbai, India. All other reagents used were of
analytical grade.
METHODOLOGY
Formulation development of tablets: Buccal tablets were prepared by a direct compression
method, before going to direct compression all the ingredients were screened through sieve
no.100. HPMCK15M, HPMCK100M and Carbopol934P are the mucoadhesive and
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biodegradable polymers used in this preparation of buccal mucoadhesive drug delivery
systems.
Mosapride citrate was mixed manually with different ratios of HPMCK15M, HPMCK100M
and carbopol 934P and Microcrystalline Cellulose as diluent for 10 min. In every formulation
constant amount of PVPK30 was added as binding agent. The blend was mixed with aerosil
and magnesium stearate for 3-5 min.
Table 1: Composition of Buccal Tablets.
Ingredients
Drug
HPMCK15M
HPMCK100M
CARBOPAL 934
PVPK30
MCC pH 102
Mg. Stearate
Aerosil
Total Weight (mg)
F1
15
15
5
59
2
4
100
F2
15
30
5
44
2
4
100
F3
15
45
5
29
2
4
100
F4
15
15
5
59
2
4
100
F5
15
30
5
44
2
4
100
F6
15
45
5
29
2
4
100
F7
15
15
5
59
2
4
100
F8
15
30
5
44
2
4
100
F9 F10
15
15
7.5
45 7.5
5
5
29
59
2
2
4
4
100 100
F11
15
15
15
5
44
2
4
100
F12 F13
15
15
22.5
7.5
22.5 7.5
5
5
29
59
2
2
4
4
100 100
F14
15
15
15
5
44
2
4
100
Fourier Transform Infrared spectroscopic studies
A Fourier Transform – Infra Red spectrophotometer was used to study the non-thermal
analysis of drug-excipient (binary mixture of drug: excipient 1:1 ratio) compatibility. The
spectrum of each sample was recorded over the 450-4000 cm-1. Pure drug of Mosapride
Citrate, Mosapride Citrate with physical mixture (excipients) compatibility studies were
performed.
[17-18]
EVALUATION OF BUCCAL TABLETS
1. Physicochemical characterization of tablets: [19-20]
The prepared Mosapride citrate buccal tablets were studied for their physicochemical
properties like weight variation, hardness, thickness, friability and drug content.
A. Weight variation
The weight variation test is done by taking 20 tablets randomly and weighed accurately. The
composite weight divided by 20 provides an average weight of tablet. Not more than two of
the individual weight deviates from the average weight by 10 % and none should deviate by
more than twice that percentage. The weight variation test would be a satisfactory method of
determining the drug content uniformity.
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F15
15
22.5
22.5
5
29
2
4
100
Ramya Sri et al.
The percent deviation was calculated using the following formula:
% Deviation = (Individual weight – Average weight / Average weight) X 100
The average weight of tablets in each formulation was calculated and presented with standard
deviation.
Table 2: Pharmacopoeial specifications for tablet weight variation.
Average weight of tablets (mg)
80 or less
More than 80 but less than 250
250 or more
Maximum % of difference allowed
10
7.5
5
B. Tablet Thickness
The Thickness and diameter of the tablets from production run is carefully controlled.
Thickness can vary with no change in weight due to difference in the density of granulation
and the pressure applied to the tablets, as well as the speed of the tablet compression
machine. Hence this parameter is essential for consumer acceptance, tablet uniformity and
packaging. The thickness and diameter of the tablets was determined using a Digital Vernier
caliper. Ten tablets from each formulation were used and average values were calculated. The
average thickness for tablets is calculated and presented with standard deviation.
C. Tablet Hardness
Tablet hardness is defined as the force required to breaking a tablet in a diametric
compression test. Tablets require a certain amount of strength, or hardness and resistance to
friability, to withstand the mechanical shocks during handling, manufacturing, packaging and
shipping. The resistance of the tablet to chipping, abrasion or breakage under condition of
storage transformation and handling before usage depends on its hardness. Six tablets were
taken from each formulation and hardness was determined using Monsanto hardness tester
and the average was calculated. It is expressed in Kg/cm2.
D. Friability
Tablet hardness is not an absolute indicator of the strength because some formulations when
compressed into very hard tablets lose their crown positions. Therefore another measure of
the tablet strength, its friability, is often measured. Tablet strength is measured by using
Roche friabilator. Test subjects to number of tablets to the combined effect of shock, abrasion
by utilizing a plastic chamber which revolves at a speed of 25 rpm for 4 minutes, dropping
the tablets to a distance of 6 inches in each revolution. A sample of preweighed tablets was
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placed in Roche friabilator which was then operated for 100 revolutions. The tablets were
then dedusted and reweighed. Percent friability (% F) was calculated as
Friability (%) = Initial weight of 10 tablets – final weight of 10 tabletsX 100
Initial weight of 10 tablets
F (%) = [Wo-W/WO] Х100
Where, W0 is the initial weight of the tablets before the test and
W is the final weight of the tablets after test.
E. Assay
Six tablets of each formulation were taken and amount of drug present in each tablet was
determined. Powder equivalent to one tablet was taken and added in 100ml of pH 6.8
phosphate buffer followed by stirring for 10 minutes. The solution was filtered through a
0.45μ membrane filter, diluted suitably and the absorbance of resultant solution was
measured by using UV-Visible spectrophotometer at 272 nm using pH6.8 phosphate buffer.
2. In vitro release studies
The drug release rate from buccal tablets was studied using the USP type II dissolution test
apparatus. Tablets were supposed to release the drug from one side only; therefore an
impermeable backing membrane was placed on the other side of the tablet. The tablet was
further fixed to a 2x2 cm glass slide with a solution of cyanoacrylate adhesive. Then it was
placed in the dissolution apparatus. The dissolution medium was 500 ml of pH 6.8 phosphate
buffer at 50 rpm at a temperature of 37 ± 0.5 °C. Samples of 5 ml were collected at different
time intervals up to 8 hrs and analyzed after appropriate dilution by using UV
Spectrophotometer at 272nm.
3. Swelling Studies
Buccal tablets were weighed individually (designated as W1) and placed separately in Petri
dishes containing 15 mL of phosphate buffer (pH 6.8) solution. At regular intervals (0.5,1, 2,
3, 4, 5 and 6hr), the buccal tablets were removed from the Petri dishes and excess surface
water was removed carefully using the filter paper. The swollen tablets were then reweighed
(W2) (Ritthidej et al., 2002). This experiment was performed in triplicate. The swelling index
(water uptake) calculated according to the following Eq.
Swelling index = (W2-W1) X 100
W1
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4. In vitro bioadhesion strength
Bioadhesion strength of tablets were evaluated using a microprocessor based on advanced
force gauge equipped with a motorized test stand (Ultra Test Tensile strength tester,
Mecmesin, West Sussex, UK) according to method describe as it is fitted with 25kg load cell,
in this test porcine membrane was secured tightly to a circular stainless steel adaptor and the
buccal tablet to be tested was adhered to another cylindrical stainless steel adaptor similar in
diameter using a cyanoacrylate bioadhesive. Mucin 100 µl of 1 %w/v solution was spread
over the surface of the buccal mucosa and the tablet immediately brought in contact with the
mucosa. At the end of the contact time, upper support was withdrawn at 0.5mm/sec until the
tablet was completely detached from the mucosa. The work of adhesion was determined from
the area under the force distance curve.
The peak detachment force was maximum force to detach the tablet from the mucosa.
Force of adhesion = Bioadhesion strengthx 9.8
1000
Bond strength = Force of adhesion
surface area
5. Surface pH
Weighed tablets were placed in boiling tubes and allowed to swell in contact with pH 6.8
phosphate buffer (12mL). Thereafter, surface pH measurements at predetermined intervals of
0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, and 8 h were recorded with the aid of a digital pH meter. These
measurements were conducted by bringing a pH electrode near the surface of the tablets and
allowing it to equilibrate for 1 min prior to recording the readings. Experiments were
performed in triplicate (n=3).
6. Moisture absorption
Agar (5% m/V) was dissolved in hot water. It was transferred into Petri dishes and allowed to
solidify. Six buccal tablets from each formulation were placed in a vacuum oven overnight
prior to the study to remove moisture, if any, and laminated on one side with a water
impermeable backing membrane. They were then placed on the surface of the agar and
incubated at 37°C for one hour. Then the tablets were removed and weighed and the
percentage of moisture absorption was calculated by using following formula:
% Moisture Absorption =
Final weight – Initial weight x 100
Initial weight
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7. Ex vivo residence time
The Ex vivo residence time is one of the important physical parameter of buccal
mucoadhesive tablet. The adhesive tablet was pressed over excised pig mucosa for 30 sec
after previously being secured on glass slab and was immersed in a basket of the dissolution
apparatus containing around 500 ml of phosphate buffer, pH 6.8, at 37 0C. The paddle of the
dissolution apparatus as adjusted at a distance of 5 cm from the tablet and rotated at 25 rpm
(figure 2). The time for complete erosion or detachment from the mucosa was recorded.
Fig. 1 Schematic representation of Ex vivo residence time study.
8. Ex vivo permeation studies through porcine buccal mucosa [1]
The aim of this study was to investigate the permeability of buccal mucosa to Mosapride
Citrate. It is based on the generally accepted hypothesis that the epithelium is the ratelimiting barrier in the buccal absorption.
Tissue permeation
Buccal tissue was taken from Pigs slaughter-house. It was collected within 10 minutes after
slaughter of pig and tissue was kept in Krebs buffer solution. It was transported immediately
to the laboratory and was mounted within 2hrs of isolation of buccal tissue. The tissue was
rinsed thoroughly using phosphate buffer saline to remove the adherent material. The buccal
membrane from the tissue was isolated using surgical procedure. Buccal membrane was
isolated and buccal epithelium was carefully separated from underlying connective tissue.
Sufficient care was taken to prevent any damage to the epithelium.
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Procedure
Ex vivo permeation study of candesartan through the porcine buccal mucosa was performed
using Franz diffusion cell and membrane assembly, at 37°C ± 0.2°C and 50 rpm. This
temperature and rpm was maintained by magnetic stirrer. Porcine buccal mucosa was
obtained from a local slaughter house and used within 2 hr of slaughter. The tissue was stored
in Krebs buffer at 4°C upon collection. After the buccal membrane was equilibrated for 30
min with the buffer solution between both the chambers, the receiver chamber was filled with
fresh buffer solution (pH 6.8), and the donor chamber was charged with 5 mL (1mg/mL) of
drug solution. Aliquots (5mL) were collected at predetermined time inter wells up to 8 hr and
the amount of drug permeated through the buccal mucosa was then determined by measuring
the absorbance at 272 nm using a UV spectrophotometer. The medium of the same volume (5
mL), which was pre-warmed at 37°C, was then replaced into the receiver chamber.
The experiments were performed in triplicate (n = 3) and mean values were used to calculate
flux (J) and permeability coefficient (P).
J = (dQ/dt)
A
P = (dQ/dt)
ΔCA
Where, J is Flux (mg.hrs-1cm-2)
P is permeability coefficient (cm/h)
dQ/dt is the slope obtained from the steady state portion of the curve
ΔC
is the concentration difference across the mucosa and
A
the area of diffusion (cm2)
Kinetic Analysis of Dissolution Data: [21-23]
To analyze the in vitro release data various kinetic models were used to describe the release
kinetics.
1. Zero – order kinetic model – Cumulative % drug released versus time.
2. First – order kinetic model – Log cumulative percent drug remaining versus time.
3. Higuchi‟s model – Cumulative percent drug released versus square root of time.
4. Korsmeyer equation / Peppa‟s model – Log cumulative % drug released versus log time.
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1. Zero order kinetics: Zero order release would be predicted by the following equation:At = A0 – K0t
Where, At = Drug release at time„t‟.
A0 = Initial drug concentration
K0 = Zero – order rate constant (hr-1).
When the data is plotted as cumulative percent drug release versus time, if the plot is linear
then the data obeys Zero – order release kinetics, with a slope equal to K0.
2. First Order Kinetics: First – order release would be predicted by the following equation:Log C = log C0 – Kt / 2.303
Where, C = Amount of drug remained at time„t‟.
C0 = Initial amount of drug.
K = First – order rate constant (hr-1).
When the data is plotted as log cumulative percent drug remaining versus time yields a
straight line, indicating that the release follow first order kinetics. The constant „K‟ can be
obtained by multiplying 2.303 with the slope values.
3. Higuchi’s model: Drug release from the matrix devices by diffusion has been described by
following Higuchi‟s classical diffusion equation.
Q = [D /  (2 A - Cs) Cst]1/2
Where, Q = Amount of drug released at time„t‟.
D = Diffusion coefficient of the drug in the matrix.
A = Total amount of drug in unit volume of matrix.
Cs = the solubility of the drug in the matrix.

= Porosity of the matrix.

= Tortuosity.
t
= Time (hrs) at which „q‟ amount of drug is released.
Above equation may be simplified if one assumes that „D‟, „Cs‟, and „A‟, are constant. Then
equation becomes:
Q = Kt1/2
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When the data is plotted according to equation i.e. cumulative drug release versus square root
of time yields a straight line, indicating that the drug was released by diffusion mechanism.
The slope is equal to „K‟.
4. Korsmeyer equation / Peppa’s model
To study the mechanism of drug release from the buccal tablets of mosapride citrate, the
release data were also fitted to the well – known exponential equation (Korsmeyer equation /
Peppa‟s law equation), which is often used to describe the drug release behavior from
polymeric systems.
Mt / Ma = Ktn
Where, Mt / Ma = the fraction of drug released at time„t‟.
K = Constant incorporating the structural and geometrical characteristics of the drug /
polymer system.
n = Diffusion exponent related to the mechanism of the release.
Above equation can be simplified by applying log on both sides, And we get:
Log Mt / Ma = LogK + n Logt
When the data is plotted as log of drug released versus log time, yields a straight line with a
slope equal to „n‟ and the „K‟ can be obtained from y – intercept. For Fickian release „n‟ =
0.5 while for anomalous (non – Fickian) transport „n‟ ranges between 0.5 and 1.0.
Table.3. Mechanism of Drug Release as per Korsmeyer Equation / Peppa’s Model.
S. No
1.
2.
3.
n value
n <0.5
0.5<n<1
n>1
Drug Release
Fickian release
Non-Fickian release
Case II transport
RESULTS AND DISCUSSION
Preformulation studies
Drug – excipient compatibility studies by physical observation
Mosapride Citrate was mixed with various proportions of excipients showed no colour
change at the end of two months, proving no drug-excipient interactions. The hydrophilic
matrix of HPMC alone provided sustained release of the Mosapride citrate for 24 hours. The
FTIR study was carried out to know the compatibility of the excipients with mosapride citrate
dihydrate, the active constituent of the formulation. The FTIR spectrum of pure mosapride
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citrate dihydrate, mixture of mosapride citrate dihydrate with HPMC K100M,HPMC K4M
polymers and mixture of mosapride citrate dihydrate, HPMC K100M,HPMC K4M with.
Lactose, talc, magnesium stearate, aerosil were analyzed for compatibility study. The study of
FTIR spectrum confirms that the mosapride citrate dihydrate and excipients used in the
formulation are compatible with each other.
FTIR spectra of the drug and the optimized formulation were recorded. The FTIR spectra of
pure Mosapride Citrate drug, drug with polymers (1:1) shown in the below figures
respectively. The major peaks C=O at 1719.61cm-1, C-F peak at 1221.68cm-1, aromatic C=C
at 1544.17cm-1, amide N-H stretch at 3673.46 cm-1 which are present in pure drug Mosapride
are also present in the physical mixture, which indicates that there is no interaction between
drug and the polymers, which confirms the stability of the drug.
There was no disappearance of any characteristics peak in the FTIR spectrum of drug and the
polymers used. This shows that there is no chemical interaction between the drug and the
polymers used. The presence of peaks at the expected range confirms that the materials taken
for the study are genuine and there were no possible interactions.
Fig 2: FTIR studies of pure drug Mosapride Citrate.
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Fig 3: FTIR studies of Mosapride Citrate+HPMC K15.
Fig 4: FTIR studies of Mosapride Citrate+HPMC K100.
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Fig 5: FTIR studies of pure drug Mosapride Citrate+CP.
Fig 6: FTIR studies of Mosapride Citrate+HPMC K15+CP.
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Fig 7: FTIR studies of pure drug Mosapride Citrate+HPMC K100+CP.
Fig 8: FTIR studies of optimized formulation.
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Table 4: FTIR Results.
Peak of functional groups {wave length(cm-1)}
C=O
C-F
C=C
N-H
Drug
1719.61
1221.68
1544.17
3673.46
Drug+HPMCK15
1719.41
1045.72
1544.32
3678.07
Drug+HPMCK100
1718.91
1221.67
1544.26
3657.23
Drug+CP
1716.88
1220.36
1542.32
3691.15
Drug+HPMCK15+CP
1720.77
1220.89
1546.27
3660.31
Drug+HPMCK100+CP 1717.28
1220.84
1541.81
3569.02
Optimized formulation
1717.23
1220.87
1541.21
3670.38
IR Spectra
Solubility Studies
Table 5: Solubility studies.
S. No
1
2
Medium
Phosphate pH6.8 buffer
Phosphate pH 7.4 buffer
Amount present (µg/mL)
86
94
Saturation solubility of Mosapride Citrate in various buffers were studied and shown in the
Table 16. The results revealed that the solubility of the Mosapride was increased from pH 6.8
to 7.4. The solubility of the Mosapride Citrate in phosphate buffer pH 6.8 is 86 µg/mL and it
was selected as the suitable media for the release studies because the pH of the phosphate
buffer pH 6.8 is nearer to that of buccal mucosa pH.
Standard graph in phosphate buffer pH 6.8 (λ
max 272
nm)
Standard graph of Mosapride Citrate was plotted as per the procedure in experimental method
and its linearity is shown in Table 17 and Fig 9. The standard graph of Mosapride Citrate
showed good linearity with R2 of 0.999, which indicates that it obeys “Beer- Lamberts” law.
Table 6: Calibration graph values of Mosapride Citrate in pH 6.8 phosphate buffer.
S. No
1
2
3
4
5
6
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Concentration (µg/mL)
0
10
20
30
40
50
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Absorbance
0
0.198
0.396
0.601
0.804
0.998
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Fig 9: Calibration graph of Mosapride Citrate in pH 6.8 phosphate buffer.
Calibration graph in phosphate buffer pH 7.4 (λ max 272 nm)
Standard graph of Mosapride Citrate was plotted as per the procedure in experimental method
and its linearity is shown in Table 18 and Fig 11. The standard graph of Mosapride Citrate
showed good linearity with R2 of 0.997, which indicates that it obeys “Beer- Lamberts” law.
Table 7: Calibration graph values of Mosapride Citrate in pH 7.4 phosphate buffer.
S. No
1
2
3
4
5
6
0
10
20
30
40
50
Absorbance
0
0.185
0.358
0.598
0.784
0.989
Fig 10: Calibration graph of Mosapride Citrate in pH 7.4 phosphate buffer.
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Ex vivo permeation of drug solution through the porcine buccal mucosa
Ex vivo permeation study of Mosapride Citrate drug solution through the porcine buccal
mucosa was performed using franz diffusion cell. The membrane assembly was kept at
37±0.2◦C and 450 rpm. This rpm was maintained by magnetic stirrer. Phenol red was used as
marker compound and not to permeate through porcine membrane. Absences of phenol red in
the receiver compartment indicate the intactnes of the buccal membrane.
Table 8: Calibration values of Phenol red.
S. No
1
2
3
4
5
6
7
8
9
0
1
5
7
10
20
25
30
35
Absorbance
0
0.09
0.143
0.198
0.264
0.542
0.654
0.792
0.881
Fig 11: Calibration of Phenol red.
Table 9: Ex vivo permeation of Mosapride Citrate drug solution through the porcine
buccal mucosa.
Time (hrs)
0
0.5
1
2
3
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Cumulative amount of mosapride
citrate permeated (%)
0
9.87±1.05
13.34±0.85
17.24±1.12
26.38±1.33
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4
5
6
7
8
Flux
31.91±1.54
43.55±0.98
70.38±1.15
91.39±0.74
93.23±0.75
424.735 µg.hr-1cm-2
Fig 12: Ex vivo permeation of drug solution through the porcine buccal mucosa.
The tissue could be isolated successfully because no detectable level of phenol red (Marker
compound) was observed in the receiver compartment. Hence it did not show any penetration
and shows the intactness of the porcine buccal mucosa. The flux, permeability coefficient
were found to be 424.735 µg.hr-1cm-2, 0.418 cm/hr respectively.
Evaluation
Characterization of pre-compression blend: The pre-compression blend of Mosapride
Citrate buccal tablets were characterized with respect to angle of repose, bulk density, tapped
density, carr‟s index and hausner‟s ratio. Angle of repose was less than 28o, carr‟s index
values were less than 11 for the pre-compression blend of all the batches indicating good to
fair flowability and compressibility. Hausner‟s ratio was less than 1.25 for all the batches
indicating good flow properties.
Table 10: Physical properties of pre-compression blend.
Formulation
Code
F1
F2
F3
F4
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Angle of
repose (Ө)
25.10◦
25.43◦
25.41◦
26.40◦
Bulk density
(gm/cm3)
0.53±0.01
0.54±0.03
0.54±0.02
0.51±0.01
Tapped density
(gm/cm3)
0.59±0.01
0.60±0.02
0.58±0.03
0.61±0.06
Vol 3, Issue 10, 2014.
Carr's
Index (%)
9.43±0.12
9.40±0.13
10.01±0.19
10.11±0.02
Hausner's
ratio
1.09±0.02
1.10±0.01
1.13±0.06
1.16±0.01
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F5
27.12◦
0.58±0.03
0.63±0.03
◦
F6
25.31
0.59±0.03
0.64±0.04
F7
26.11◦
0.56±0.01
0.63±0.01
◦
F8
26.15
0.53±0.03
0.58±0.03
◦
F9
26.10
0.54±0.01
0.61±0.03
F10
25.95◦
0.53±0.03
0.60±0.01
◦
F11
25.43
0.56±0.04
0.58±0.05
F12
25.41◦
0.53±0.06
0.56±0.03
◦
F13
25.13
0.54±0.07
0.57±0.04
F14
25.01◦
0.53±0.09
0.61±0.03
◦
F15
26.40
0.51±0.03
0.58±0.03
All the values represent mean ± Standard deviation (SD), n=3
10.34±0.13
10.12±0.34
9.93±0.11
10.13±0.02
10.20±0.13
9.50±0.11
9.61±0.13
9.89±0.18
10.12±0.13
9.83±0.13
9.34±0.02
1.17±0.03
1.11±0.06
1.13±0.03
1.12±0.01
1.13±0.03
1.01±0.02
1.03±0.03
1.04±0.04
1.07±0.06
1.09±0.01
1.09±0.03
Evaluation of buccal tablets
Physical evaluation of Mosapride Citrate buccal tablets: The results of the weight
variation, hardness, thickness, friability, and drug content of the tablets are given in Table 22.
All the tablets of different batches complied with the official requirement of weight variation
as their weight variation passes the limits. The hardness of the tablets ranged from 3.6 to 5
kg/cm2 and the friability values were less than 0.561% indicating that the buccal tablets were
compact and hard. The thickness of the tablets ranged from 2.71 - 2.91 mm. All the
formulations satisfied the content of the drug as they contained 98-100% of Mosapride
Citrate. Thus all the physical attributes of the prepared tablets were found to be practically
within control limits.
Table 11: Physical evaluation of Mosapride Citrate buccal tablets.
Formulation
Weight
Thickness Hardness Friability
code
variation (mg)
(mm)
(Kg/cm2)
(%)
F1
103±1
2.76±0.01
4.5±0.7
0.420
F2
104±2
2.74±0.04
4.2±0.5
0.341
F3
101±1
2.71±0.01
3.6±0.6
0.363
F4
101±2
2.80±0.06
4.8±0.5
0.561
F5
105±3
2.81±0.04
3.8±0.4
0.482
F6
97±3
2.74±0.05
4.4±0.6
0.513
F7
99±1
2.76±0.03
5.0±0.1
0.412
F8
100±2
2.71±0.04
4.6±0.2
0.432
F9
98±3
2.73±0.03
4.0±0.3
0.512
F10
103±2
2.95±0.02
4.2±0.6
0.523
F11
99±1
2.74±0.04
3.8±0.5
0.531
F12
100±2
2.78±0.01
4.5±0.4
0.432
F13
99±1
2.80±0.01
4.6±0.3
0.390
F14
98±2
2.81±0.06
4.2±0.6
0.382
F15
99±1
2.79±0.04
4.0±0.3
0.463
All the values represent mean ± Standard deviation (SD), n=3
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Vol 3, Issue 10, 2014.
Content
uniformity (%)
99±0.12
99±0.30
100±0.10
100±0.30
99±0.60
99±0.40
98±0.90
99±0.10
100±0.10
99±0.30
99±0.10
99±0.20
99±0.10
100±0.60
99±0.80
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In vitro release studies
In vitro drug release studies were conducted in phosphate buffer pH 6.8 and the studies
revealed that the release of Mosapride Citrate from different formulations varies with
characteristics and composition of matrix forming polymers as shown in graphs 16 to 20.
Table 12: In vitro dissolution data for formulations F1 - F3 by using HPMC K15M
Polymer.
Time
(hrs)
0
0.5
1
2
3
4
5
6
7
8
% Cumulative drug release
F1
F2
F3
0
0
0
26.73±0.87 16.73±0.25
9.42±0.43
31.04±0.93
20.42±0.69
13.23±0.51
44.92±0.76
25.90±0.46
20.40±1.09
57.06±1.05
35.56±0.87
29.91±0.92
75.57±1.17
44.93±1.13
33.23±0.67
81.08±0.95
54.40±1.19
38.73±0.81
94.90±0.59
66.58±0.99
46.56±0.74
99.56±1.25
79.92±1.57
49.94±0.61
87.73±0.77
59.56±0.98
Fig 13: In vitro dissolution data for formulations F1 - F3 by using HPMC K15M
polymer.
From the above graphs it was evident that HPMC K15M in the concentration of 1:2 (F2)
drug with other two ratios 1:1, 1:3 drug polymer ratios. In case of F1 formulation the polymer
quantity was in sufficient to produce the required retarding nature upto 8 hrs, maximum drug
release was occured in 6 hrs only, where as in F3 formulation the quantity of polymer was
because high hence it showed more drug retardation with less drug release that is 59.56% in 8
hrs.
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Ramya Sri et al.
polymer.
Time(hrs)
0
0.5
1
2
3
4
5
6
7
8
F4
F5
F6
0
0
0
14.23±0.34 12.56±0.39
7.73±0.51
20.91±0.49 16.57±0.29 11.56±0.44
32.73±0.57 18.94±0.93 16.59±0.67
42.93±0.48 27.73±0.58 18.94±0.39
50.42±0.93 42.41±0.72 22.72±0.71
57.75±0.84 47.93±0.53 28.23±0.83
68.56±0.91 54.43±0.48 36.06±0.98
83.73±0.56 66.56±0.86 48.43±0.57
90.90±0.75 72.73±0.79 60.40±0.84
Fig 14: In vitro dissolution data for formulations F4 - F6 by using HPMC K100M
polymer.
From the above graphs it was evident that HPMC K100M in the concentration of 1:1
(F4), drug to polymer ratio, is showing better result 90.90% drug release when compared
with other two ratios 1:2, 1:3 drug polymer ratios. As the concentration of polymer increases
the retarding of drug release also increased. Hence they were not considered.
Table 14: In vitro dissolution data for formulations F7 - F9 by using Carbopol 934
polymer.
Time(hrs)
0
0.5
1
2
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F7
F8
F9
0
0
0
24.40±0.23 16.56±0.39 11.06±0.28
35.56±0.46 26.23±0.45 16.73±0.37
49.91±0.37 35.59±0.57 21.07±0.62
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3
4
5
6
7
8
61.06±0.64
70.73±0.75
81.72±0.86
94.91±0.91
98.23±0.58
-
44.25±0.32
50.55±0.25
66.58±0.66
78.23±0.79
89.42±0.91
92.06±0.89
34.45±0.55
41.09±0.49
46.56±0.97
52.43±0.84
60.73±0.68
70.40±0.75
Fig 15: In vitro dissolution data for formulations F7- F9 by using Carbopol 934 polymer.
From the above graphs it was evident that Carbopol 934
in the concentration of 1:2 (F8),
drug to polymer ratio, is showing better result 92.06% drug release when compared with
other two ratios 1:1, 1:3 drug polymer ratios. In case of F7 formulation the polymer was
insufficient to produce required bioadhesion strength and the maximum drug was released in
6 hrs only where as in F9 formulation the concentration become high and the drug release
was retarded more than 8 hrs, hence it was not taken in to consideration.
and Carbopol 934 polymers.
Time(hrs)
0
0.5
1
2
3
4
5
6
7
8
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F10
F11
F12
0
0
0
20.47±0.23 15.06±0.25 5.73±0.39
35.73±0.47 24.45±0.38 11.06±0.48
41.06±0.55 33.23±0.19 18.93±0.27
52.23±0.67 41.06±0.45 29.44±0.57
64.72±0.89 46.57±0.59 35.56±0.64
72.08±0.38 51.41±0.33 46.57±0.93
98.45±0.76 64.56±0.72 52.23±0.81
98.91±0.95 85.56±0.84 57.56±0.44
94.90±0.67 70.40±0.79
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Fig 16: In vitro dissolution data for formulations F10 - F12 by using HPMC K15M and
Carbopol 934 polymers.
From the above graphs it was evident that Carbopol 934 and HPMC K15M in the
concentration of 1:1 (F11) was showing better result 94.9% drug release when compared with
other ratios. In F10 formulation the combination of 2 polymers concentration was insufficient
to produce desired strength and retardation action, where as in case of F12 formulation the
concentration of HPMC K15 and Carbopol 934 were increased due to increased amount of
polymers the retardation of drug release was increased hence they were not considered.
Time(hrs)
0
0.5
1
2
3
4
5
6
7
8
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F13
F14
F15
0
0
0
11.06±0.39 7.23±0.28 5.73±0.43
15.08±0.51 11.56±0.56 8.06±0.58
22.72±0.26 18.93±0.49 14.23±0.74
35.57±0.47 24.41±0.35 17.22±0.41
46.07±0.61 28.07±0.69 22.57±0.63
57.22±0.89 34.25±0.87 29.44±0.85
72.74±0.75 46.58±0.33 35.06±0.77
88.23±0.96 53.72±0.61 39.23±0.59
91.06±0.56 64.40±0.46 49.90±0.82
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Fig 17: In vitro dissolution data for formulations F13 - F15 by using HPMC
K100M
From the above graphs it was evident that Carbopol 934 and HPMC K100M in the
concentration of 1:1 (F13) was showing better result 91.06% drug release when compared
with other ratios. F14 and F15 formulation showed more retardation nature due to increased
quantities of polymers. They were not considered because of less drug release in 8 hrs.
Table 17: Ex vivo residence time, moisture absorption, surface pH, bioadhesion strength
values of selected formulations.
Ex vivo
Moisture
residence
absorption
time (hrs)
F2
6hr 33min
44±0.25
F4
7hr 51min
51±0.12
F8
7hr 34min
46±0.25
F11
8hr 5min
66±0.33
F13
6hr 10min
58±0.35
Each value represents the mean±SD (n=3)
Formulation
Code
Surface
pH
6.81±0.25
6.71±0.10
6.74±0.25
6.84±0.04
6.73±0.14
Bioadhesion strength
Peak detachment
Work of
force (N)
adhesion (mJ)
3.8±0.41
17.42±6.10
4.2±0.32
14.23±6.31
3.6±0.22
12.42±6.16
4.8±0.12
23.41±6.18
4.2±0.22
18.32±6.12
Ex vivo residence time is one of the important physical parameter of buccal bioadhesive
tablets. The ex vivo residence time was determined by specially designed apparatus. Among
the selected formulations F11 formulation has shown more residence time when compared
with other formulations. F11 formulation contains combination of HPMC K15M and
Carbopol 934. F2 formulation showed only 6 hrs 33 mins residence time, as it contains only
HPMC K15M polymer where as F4 formulation showed residence time almost equal to the
F11 formulations as in contains high viscous polymer that is HPMC K100M. The F8
formulation which contains Carbopol 934 7 hrs 34 min residence time. F13 formulation
which contains combination of HPMC K100 and Carbopol 934 showed less residence time.
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The moisture absorption: studies give important information of the relative moisture
absorption capacities of polymers and it also give information regarding whether the
formulations maintain the integrity or not. Among the selected formulations F11 formulation
shown good moisture absorption. The moisture absorption value for F2 was very less when
compared to F11 because as it contains low viscous HPMC polymer where as in case of F4
an F8 they were unable to show good moisture absorption values when used individually. But
in combination both F11 and F13 formulations showed good moisture absorption values.
The surface pH of the buccal tablets was determined in order to investigate the possibility of
any side effects. As an acidic or alkaline pH may cause irritation to the buccal mucosa, it was
determined to keep the surface pH as close to neutral as possible. The surface pH of the
selected formulations was found to be 6.71±0.10 to 6.84±0.04 and the pH was near to the
neutral. These results suggested that the polymeric blend identified was suitable for oral
application and formulations were not irritant to the buccal mucosa.
Bioadhesion strength: was measured for the selected formulations. From this two
parameters such as peak detachment force (N) and work of adhesion were calculated and they
were found to be good for the formulation F11. The peak detachment force and work of
adhesion values were found to be less when the polymers were used individually in case of
F2, F4, F8 formulations but when the polymers were taken in combination they showed
desired values, in turn F11 that is combination of HPMC K15 and Carbopol 934 showed high
value than the combination of HPMC K100M and Carbopol 934.
Swelling studies
Table 18: Swelling index of selected formulations.
Time (hrs)
0
0.5
1
2
3
4
5
6
7
8
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F2
0
11.1
18.3
24.3
25.3
31.1
42.2
51.3
63.4
68.5
Swelling Index (%)
F4
F8 F11
0
0
0
12.5 11.3 13.4
23.4 17.4 21.5
23.6 20.1 26.3
29.5 23.1 30.1
34.6 30.3 34.3
48.7 38.1 43.2
54.4 44.3 56.3
63.3 53.3 69.4
67.4 58.2 81.3
Vol 3, Issue 10, 2014.
F13
0
13.6
22.1
23.3
28.3
33.2
39.4
46.4
51.3
61.4
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Fig18: Swelling studies of Mosapride Citrate selected buccal tablets.
The swelling studies were performed for the formulations which were shown desired drug
release. Swelling behavior of a buccal system was essential for uniform and prolonged
release of drug and proper bioadhesion. The combination of polymers containing HPMC
K15M and Carbopol 934 was shown good swelling index when compared the formulations
containing HPMC K15M, HPMC K100M alone and combination of HPMC K100M and
Carbopol 934. The swelling index values for the formulations F2, F4, F8, F11 & F13 were
reported.
Ex vivo permeation studies through porcine buccal mucosa
The aim of this study was to investigate the permeability of buccal mucosa to Mosapride
Citrate. It is based on the generally accepted hypothesis that the epithelium is the ratelimiting barrier in the buccal absorption was shown in table 30 & fig 20.
Table 19: Ex vivo permeation studies of selected formulations through porcine buccal
mucosa.
Time (hrs)
0
0.5
1
2
3
4
5
6
7
8
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F2
0
11.86±0.12
19.01±0.22
26.16±0.28
28.22±0.33
36.99±0.38
58.81±0.44
73.55±0.78
75.17±0.42
76.64±0.52
F4
F8
0
0
8.18±0.13
9.21±0.45
11.86±0.41 12.60±0.33
16.06±0.12 16.43±0.40
21.44±0.32 24.83±0.38
29.62±0.20 31.32±0.84
59.77±0.12 37.95±0.20
65.59±0.28 40.90±0.39
82.17±0.34 62.64±0.48
87.70±0.32 85.862±0.78
Vol 3, Issue 10, 2014.
F11
0
10.68±0.52
13.34±0.32
17.24±0.33
26.82±0.40
33.38±0.32
40.60±0.45
67.80±0.65
91.39±0.33
93.23±0.20
F13
0
7.51±0.33
10.90±0.45
15.55±0.36
23.80±0.26
30.29±0.85
31.98±0.10
37.58±0.42
49.38±0.11
72.96±0.52
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Flux
(µg.hrs-1cm-2)
Permeability
coefficient
(cm/hr)
389.42
409.128
323.46
418.445
270.168
0.111
0.2218
0.1525
0.4122
0.0666
Fig 19: Ex vivo permeation studies graph of selected formulations through porcine
buccal mucosa.
From the Table it was evident that selected formulations were showing good flux and
permeability coefficient values. Among the selected formulations F11 formulation was
showing maximum flux value of 418.445 (µg.hrs -1cm-2) and permeability coefficient value
was 0.412 (cm/hrs).
6. Release kinetics
Data of in vitro release studies of formulations which were showing better drug release were
fit into different equations to explain the release kinetics of Mosapride Citrate release from
buccal tablets. The data was fitted into various kinetic models such as zero, first order
kinetics, higuchi and korsmeyer peppas mechanisms and the results were shown in below
table.
Table 20: Release kinetics and correlation coefficients (R2).
Formulation
code
F2
F4
F8
F11
F13
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Mathematical models (Release kinetics)
Zero order First order
Higuchi
Korsmeyer-Peppas
R2
R2
R2
R2
n value
0.986
0.9119
0.9348
0.9427
0.6177
0.9856
0.9082
0.9623
0.9820
0.6636
0.977
0.9317
0.9236
0.9812
0.6178
0.9317
0.9662
0.6154
0.9654
0.9829
0.992
0.9012
0.920
0.9742
0.6073
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Fig 20: Zero order plot of optimized formulation.
Fig 21: First order plot of optimized formulation.
Fig 22 : Higuchi plot of optimized formulation.
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Fig 23: Koresmeyer-peppas plot of optimized formulation.
CONCLUSION
Mosapride Citrate was formulated as buccal tablets to improve its bioavailability by avoiding
first pass metabolism. HPMC K15M, HPMC K100M and Carbopol 934 were selected as
polymers. Various formulations were prepared by using these polymers alone and in
combinations. Ex vivo permeation study of Mosapride Citrate drug solution through the
porcine buccal mucosa was performed using franz diffusion cell and the flux value was found
to be 424.735 µg.hr-1cm-2. The pre-compression blend of Mosapride Citrate buccal tablets
were characterized with respect to angle of repose, bulk density, tapped density, carr‟s index
and hausner‟s ratio and all the results indicated that the blend was having good flow nature
and better compression properties. The swelling studies were performed for the formulations
which were shown desired drug release. Peak detachment force (N) and work of adhesion
were calculated and they were found to be good. F11 formulation was showing 94.9% drug
release in 8 hrs and following Korsmeyer peppas mechanism with regression value of 0.9829
and n value was found to be 0.6154 which indicates it follows non fickian drug release
pattern. F11 formulation was showing maximum flux value and permeability coefficient
value i.e., 418.44 (µg.hrs-1cm-2) and 0.4122 (cm/hrs). So based on the results F11 was found
to be an optimized formula and concluded that Mosapride Citrate can used as buccal
mucoadhesive tablets.
Based on the all studies F11 formulation was found to be better when compared with all other
formulations. This formulation contains Carbopol 934 and HPMC K15M in the concentration
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of 1:1 (15 mg: 15 mg) (F11). It showed 94.9% drug release in 8 hrs. F11 formulation has
shown more residence time when compared with other formulations i.e., 8 hrs 5 min. F11
formulation shown good moisture absorption. The surface pH of the F11 formulations was
found to be 6.84±0.04 and the pH was near to the neutral. These results suggested that the
polymeric blend identified was suitable for oral application and formulations were not irritant
to the buccal mucosa. Peak detachment force (N) and work of adhesion were calculated and
they were found to be good for the formulation F11. Swelling index value was also found to
be good for this formualion. F11 formulation was showing maximum flux value, permeability
coefficient value i.e., 418.445 (µg.hrs-1cm-2),
0.4122 (cm/hrs) respectively. This formulation was following Korsmeyer peppas mechanism
with regression value of 0.9829 and n value was found to be 0.6154 which indicates it
follows non fickian drug release pattern.
ACKNOWLEDGEMENTS
The authors would like to thank Sura Labs, Hyderabad, for providing the gift samples of
Mosapride Citrate for the project work. The authors are thankful to principal & Chairman of
Vaagdevi College of Pharmacy,Warangal, Telangana for their kind help and providing all
necessary facilities.
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