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Prasad et al. World Journal of Pharmacy and Pharmaceutical Sciences
DESIGN AND EVALUATION OF OSMOTICALLY CONTROLLED
DRUG DELIVERY SYSTEM OF ANTI-HYPERTENSIVE DRUG
LOSARTAN POTASSIUM
Motugatla. Prasad*, E. Bhavya, Vedachalam. Gunasekharan
Department of Pharmaceutics, Rao’s College of Pharmacy, Nellore, A. P, India.
ABSTRACT
The main objective of the present work is to develop a Novel
osmotically controlled drug delivery system of Losartan Potassium. It
was aimed to prepare for prolonged residence in the stomach over
conventional Gastro-retentive approaches. Losartan Potassium tablets
were prepared by direct compression method employing different
polymers like HPMC K4M, HPMC K15M, Carbopol 974P in different
proportions along with sodium bicarbonate as a gas generating agent.
FTIR and DSC studies showed that drug and polymers are compatible.
The prepared granules were evaluated for angle of repose,
compressibility index and hausner’s ratio and results obtained were
satisfactory compressed formulations were further evaluated for weight
variation, hardness, thickness, friability, buoyancy studies, drug
content and in-vitro dissolution studies. All the formulations showed good results which were
compliance with pharmacopoeial standards. Among all formulations HPMC K15M grade
provided better controlled release characteristics with excellent drug release and buoyancy.
Among all formulations it was concluded that the formulations with K15M is optimized for
better release, and FM 8 formulation is optimized among the K15M formulations because of
its equal combination of osmotically controlled polymer and hydrophilic polymer.
KEY WORDS: Osmotically controlled drug delivery, Losartan potassium, HPMC K15M,
Direct compression, Buoyancy studies.
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Article Received on 26 September 2013, Revised on 27 October 2013, Accepted on 30 November 2013
*Correspondence for
Author: *Motugatla. Prasad
Dept. of Pharmaceutics,
Rao’s College of Pharmacy,
SPSR Nellore, A.P, India.
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INTRODUCTION
Osmotically controlled oral drug delivery systems (OCODDS) utilize osmotic pressure as
the energy source for the controlled delivery of drugs. Drug release from these systems is
independent of pH and hydrodynamic conditions of the gastro-intestinal tract (GIT) to a large
extent, and release characteristics can be easily adjusted by optimizing the parameters of the
delivery system.
The challenge in the development of an oral controlled release drug delivery system is not
just to sustain the drug release but also to prolong the presence of the dosage form with in the
gastrointestinal tract (GIT) until all the drug is completely released at the desired period of
time. Gastric emptying is a complex process that is highly variable and alters in vivo
performance of drug delivery systems. Various gastro retentive techniques were used,
including floating, swelling, high density, and bioadhesive system [1,2] have been explored to
increase the gastro retention of dosage forms. Floating systems having low density systems
that have sufficient buoyancy to float over the gastric contents and remain in the stomach
without affecting the gastric emptying rate for a prolonged period. While the system floats
over the gastric contents, the drug is released slowly at the desired rate, which results in
increased gastric retentive time and reduces fluctuation in plasma drug concentration.
Losartan Potassium is an orally active class-I anti-hypertensive agent called as angiotensin-II
receptor antagonists used in the treatment of hypertension. Its short biological half-life (2
hours) necessitates that it be administered in 2 or 3 doses of 2.5 to 10 mg per day. Thus, the
development of controlled-release dosage forms would clearly be advantageous. Moreover,
the site of absorption of Losartan Potassium is in the stomach. Dosage forms that are retained
in the stomach would increase the absorption, improve drug efficiency, and decrease dose
requirements.
MATERIALS AND METHODS
Materials
Losartan Potassium (Lupin pharmaceuticals) HPMC K4M, HPMC K15M (ISP, Hyderabad).
Carbopol 974P, Sodium bicarbonate, microcrystalline cellulose, talc, magnesium stearate was
obtained from S.D fine chemicals Ltd, Mumbai. All the ingredients used were analytical
grade only.
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Methods
Drug and Excipients compatibility studies
IR spectroscopy [3]
The physical properties of the physical mixture were compared with those of plain drug.
Sample was mixed thoroughly with 100 mg potassium bromide IR powder and compacted
under vacuum at a pressure of about 12 psi for 3 minutes. The resultant disc was mounted in
a suitable holder in Perkin Elmer IR spectrophotometer and the IR spectrum was recorded
from 4000 cm-1 to 625 cm-1 in a scan time of 12 minutes. The resultant spectra were
compared for any spectral changes.
Differential scanning calorimetry
DSC scan of samples were obtained in a Perkin Elmer thermal analyzer equipped with a
monitor and printer. The instrument was calibrated with indium standard. Accurately
weighed 5 mg of sample were placed in an open, flat bottom, Aluminum sample pans.
Thermograms were obtained by heating the sample at a constant rate of 100C/minute. A dry
purge of nitrogen gas (20 ml/min) was used for all runs Samples heated from 350C – 4000C.
Preparation of floating and osmotically controlled tablets of Losartan Potassium
Tablets were prepared by direct compression method. Formulations FM 1 to FM 5 are
composed with HPMC K4M as a hydrophilic polymer and a osmotically controlled polymer
Carbopol 974P, in increasing ratios of Carbopol and decreasing ratios of hydrophilic
polymer. Formulation F1 is composed without osmotically controlled polymer (Table 1).
Formulations FM 6 to FM 10 are composed with HPMC K15M as a hydrophilic polymer and
a osmotically controlled polymer Carbopol 974P, in increasing ratios of Carbopol and
decreasing ratios of hydrophilic polymer. Formulation F2 is composed without osmotically
controlled polymer (Table2). Accurately weighed quantities of hydrophilic polymers,
osmotically controlled polymer, and microcrystalline cellulose were taken in a mortar and
mixed geometrically. To this mixture required quantity of Losartan potassium was added and
mixed slightly with pestle. This mixture was passed through 40# and later collected in a
plastic bag and blended for 5 min. To this required amount of Sodium bicarbonate was added
and again mixed for 5 min. Later sufficient quantity of Magnesium stearate and talc were
added and the final blend was again passed through 40#. Thus obtained blend was mixed
thoroughly for 10 min and compressed into tablets with 8.5 concave Punches and
corresponding dies at a hardness of 6 kg/ cm single station tablet punching machine.
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Table 1: Composition of Losartan Potassium Floating and osmotically controlled tablets
with HPMC K4M
Ingredient FM 1 FM 2 FM 3 FM 4 FM 5 F 1
Losartan potassium 10 10 10 10 10 10
HPMC K4M 70 60 50 40 30 100
HPMC K15M - - - - - -
Carbopol 974P 30 40 50 60 70 -
Sodium bicarbonate 35 35 35 35 35 35
MCC 52 52 52 52 52 52
Magnesium Stearate 2 2 2 2 2 2
Talc 1 1 1 1 1 1
Total weight 200 200 200 200 200 200
Table 2: Composition of Losartan Potassium Floating and osmotically controlled tablets
with HPMC K15M
Ingredients FM 6 FM 7 FM 8 FM 9 FM 10 F 2
Losartan potassium 10 10 10 10 10 10
HPMC K4M - - - - - -
HPMC K15M 70 60 50 40 30 100
Carbopol 974P 30 40 50 60 70 -
Sodium bicarbonate 35 35 35 35 35 35
MCC 52 52 52 52 52 52
Magnesium Stearate 2 2 2 2 2 2
Talc 1 1 1 1 1 1
Total weight 200 200 200 200 200 200
Evaluation Parameters
Pre-compression parameters: [4, 5]
As per standard procedures, the pre-formulation studies including compressibility index,
hausner’s ratio and angle of repose was performed for the powder.
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Post compression parameters
1. Weight Variation Test [6]
To study weight variation, 20 tablets of each formulation were weighed using an electronic
balance and the test was performed according to the official method.
2. Hardness [7]
For each formulation, the hardness of 6 tablets was determined using the Monsanto hardness
tester.
3. Thickness
The thickness of the tablets was determined using a Screw guage.
4. Friability
A sample of 6 tablets was taken and was carefully dedusted prior to testing. The tablets were
accurately weighed and placed in the drum of the Roche Friabilator. The drum was rotated
for 100 times at 25 rpm and the tablets were removed, dedusted and accurately weighed.
Friability of tablets was calculated by using following equation.
f = (1- W0 / W) × 100
Wo = initial weight, W = final weight.
5. Drug content
Ten tablets were powdered in a mortar. An accurately weighed quantity of powdered tablets
(100 mg) was extracted with 0.1N HCl (pH 1.2 buffer) and the solution was filtered through
0.45 µ membranes. Each extract was suitably diluted and analyzed spectrophotometrically at
275 nm.
6. Buoyancy studies
The In-vitro floating behaviour (buoyancy) of the tablets was determined by floating lag
time.[8] The tablets were placed in 100 ml beaker containing 0.1 N HCl (pH 1.2). The floating
lag time (time taken by the tablet to reach the surface) and total floating time (floating
duration of the tablet) were determined.
7. In-vitro drug release studies
The release rate of drug from floating and osmotically controlled tablets was determined
using USP type II apparatus. The dissolution test was performed in triplicate, using 900ml of
0.1N HCl, at 37± 0.5˚C at 50 rpm for 24 hrs. A 5ml sample was withdrawn from the
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dissolution apparatus at specified time points and the samples were replaced with fresh
dissolution medium.The samples were filtered through a 0.45-µm membrane filter and
diluted if necessary. Absorbances of these solutions were measured at 275nm using U.V-
Visible Spectrophotometer. Cumulative drug release was calculated using the equation (y =
0.0238x + 0.000246) generated from Beer Lambert’s calibration curve in the linearity range
of 5-50µg/ml.
Curve fitting analysis
To study the drug release kinetics, the data obtained from in vitro drug release studies were
plotted in various kinetic models such as a zero-order, first order, Higuchi and peppas
equations.
Stability studies
The optimized formulation was subjected to stability studies at 40±20C and 75±5% RH for a
period of three months. After each month, tablet was analyzed for drug content and In-vitro
drug release along with other physical parameters.
RESULTS AND DISCUSSION
The IR and DSC studies revealed that there is no interaction between drug and excipients
shown in Fig 1, 2, 3. DSC was performed and thermograms were compared. The melting
point of Losartan that was recorded using this technique was 215.60C. The same melting
point was obtained in the DSC of the selected formulation (FM 8). This result indicates there
was no interaction of drug with excipients Fig 4, 5.
Fig 1: IR spectrum of Losartan Potassium
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Fig 2: IR spectrum of pure drug with HPMC K4M and Carbopol 974P
Fig 3: IR spectrum of pure drug with HPMC K15M and Carbopol 974P
Fig 4: DSC of Losartan Potassium
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Fig 5: DSC of selected formulation FM 8
Precompression parameters: The properties like compressibility index, angle of repose, and
Hausner ratio were calculated and all estimated parameters found within the limits (Table 3).
Table 3: Precompression properties of all formulations
Precompression parameters: All formulations were tested for Physical parameters like
hardness, thickness, weight variation, friability and found to be within the pharmacopoeial
limits. The results of the tests were tabulated in Table 4. The drug content of all the
formulations was determined and was found to be within the permissible limit. This study
indicated that all the prepared formulations were good.
Formulation code Compressibility Index (%)
Angle of repose
Hausner Ratio
FM 1 12.5 28º. 7' 1.15 FM 2 15.9 29º.3' 1.19 FM 3 12.8 27º.5' 1.13 FM 4 15.7 28º.1' 1.17 FM 5 12.4 28º.4' 1.10 FM 6 11.2 27º.9' 1.13 FM 7 12.2 26º.7' 1.16 FM 8 12.3 28º.7' 1.15 FM 9 15.9 29º.3' 1.19
FM 10 12.8 27º.6' 1.13 F 1 12.4 28º.4' 1.14 F 2 11.2 27º.9' 1.13
Temp Cel400.0350.0300.0250.0200.0150.0100.050.0
Heat Flow (J/g)
10.00
8.00 6.00 4.00 2.00 0.00
-2.00
-4.00
-6.00
-8.00
-10.00
53.4Cel-0.11(J/g)
215.4Cel-3.26(J/g) 285.5Cel
-3.87(J/g)
3 3 . 4 J / g
3 5 . 7 J / g
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Table 4: Post-compression parameters
Formulation
code Hardness
(kgs) Weight
variation (mg) Thickness
(mm) Friability
(%) Drug
content (%)
FM 1 6.1±0.1 200.8±0.2 3.21±0.1 0.65 ± 0.1% 99.01%
FM 2 5.8±0.1 200.61±0.2 3.11±0.2 0.71 ± 0.2% 101.02%
FM 3 5.6±0.2 201.01±0.3 3.24±0.1 0.81 ± 0.2% 98.2%
FM 4 5.4±0.3 200.0±0.1 3.22±0.2 0.89 ± 0.1% 97.28%
FM 5 5.1±0.1 200.7±0.2 3.19±0.1 0.91 ± 0.2% 99.12%
FM 6 6.1±0.2 200.1±0.1 3.21±0.2 0.47 ±0.11% 102.06%
FM 7 5.9±0.2 199.8±0.2 3.11±0.1 054±0.2% 100.07%
FM 8 5.8±0.3 199.7±0.3 3.17±0.2 0.63±0.2% 100.01%
FM 9 5.5±0.1 200.9±0.3 3.23±0.1 0.69±0.1% 99.01%
FM 10 5.4±0.2 200.3±0.1 3.10±0.2 0.72±0.1 101.2%
F1 6.4±0.3 200.7±0.1 3.15±0.1 0.23±0.2 99.6%
F2 6.8±0.1 201.1±0.2 3.13±0.2 0.22±0.1% 99.98% Floating properties: The results of the tests were tabulated in Table 5 .Tablets of all batches
had floating lag time below 2 minutes regardless of viscosity and content of HPMC because
of evolution of CO2 resulting from the interaction between sodium bicarbonate and
dissolution medium, entrapment of gas inside the hydrated polymeric matrices enables the
dosage form to float by lowering the density of the matrices. It was clearly observed that the
reduction in concentration of HPMC in each batch the floating lag time increased as well as
floating duration decreased. And also increase in viscosity of HPMC polymers delayed the
floating lag time and prolonged the drug release.
Table 5: Floating properties
Formulation Floating Lag Time (sec) Floating Time (hrs)
FM 1 19 18
FM 2 18 16
FM 3 16 16
FM 4 14 15
FM 5 13 15
FM 6 39 >24
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FM 7 30 >24
FM 8 24 23
FM 9 20 23
FM 10 19 22
F1 32 >24
F2 41 >24
In-vitro drug release data and profiles: Formulations FM 1 to FM 5 are composed with
HPMC K4M as a hydrophilic polymer and a osmotically controlled polymer Carbopol 974P,
in increasing ratios of Carbopol and decreasing ratios of hydrophilic polymer. Formulation
F1 is composed without osmotically controlled polymer, which is designed to find out the
difference in drug release rate compared to floating and osmotically controlled tablets. Here
the effect of concentration of hydrophilic polymer to carbopol is observed (Table 6).
The graph (Fig 6) shows that, the decrease in concentration of HPMC retards the drug release
from formulation. This may be expected due to the increase in concentration of carbopol
974P which is having high molecular weight as well as more drug release retarding property
compared to that of HPMC K4M. There is no much difference in drug release was observed
with formulations of FM 1 – FM 5 to that of F 1 which has no osmotically controlled polymer
in its formulation.
Table 6: Drug release profile of Losartan Potassium floating osmotically controlled
tablets prepared with HPMC K4M
Time(hrs) FM1 FM2 FM3 FM4 FM5 F 1
0.5 22.1% 20.3% 19.4% 16.8% 10.7% 20.6%
1 36.8% 29.4% 29.7% 25.8% 22.1% 38.8%
2 54.8% 50.4% 48.7% 36.5% 28.2% 62.8%
3 75.4% 59.6% 55.6% 49.8% 56.1% 71.4%
4 81.3% 74.8% 72.% 67.7% 64.1% 89.3%
5 89.2% 81.1% 82.1% 72.2% 69.1% 91.0%
6 97.1% 92.0% 96.1% 85.1% 75.1% 98%
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Fig 6: Graphical representation of cumulative percent drug release of Losartan floating
and osmotically controlled tablets prepared with HPMC K4M
Formulations FM 6 to FM 10 are composed with HPMC K15M as a hydrophilic polymer and
a osmotically controlled polymer Carbopol 974P, in increasing ratios of Carbopol and
decreasing ratios of hydrophilic polymer. Formulation F2 is composed without osmotically
controlled polymer, which is designed to find out the difference in drug release rate compared
to floating and osmotically controlled tablets (Table7). Here the effect of concentration of
hydrophilic polymer to Carbopol is observed. The graph (Fig 7) shows that, the decrease in
concentration of HPMC retards the drug release from formulation. This may be expected due
to the increase in concentration of Carbopol 974P which is having high molecular weight as
well as more drug release retarding property compared to that of HPMC K15M. There is no
much difference in drug release was observed with formulations of FM 6 – FM 10 to that of
F2 which has no osmotically controlled polymer in its formulation. And it has been clearly
revealed that the increase in viscosity of HPMC polymers retards the drug release from the
formulations.
Table 7: Drug release profile of Losartan Potassium floating osmotically controlled
tablets prepared with HPMC K15M
Time(hrs) FM 6 FM 7 FM 8 FM 9 FM 10 F 2
0.5 14.8% 12.9% 15.4% 10.3% 8.1% 18.8%
1 22.7% 20.8% 23.3% 18.8% 16.2% 26.7%
2 29.6% 33.7% 28.7% 26.7% 22.5% 35.8%
3 35.9% 41.6% 31.6% 32.6% 36.8% 59.7%
4 49.5% 53.2% 39.5% 51.0% 48.1% 65.5%
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5 54.7% 58.0% 45.3% 63.9% 60.8% 79.7%
8 63.4% 62.7% 54.1% 72.1% 68.4% 94.4%
10 72.1% 75.8% 59.6% 79.2% 75.8% 94..6%
12 89..4% 79.4% 65.9% 86.6% 79.9% 96.9%
Fig 7: Graphical representation of cumulative percent drug release of Losartan
Potassium floating and osmotically controlled tablets prepared with HPMC K15M
Curve fitting analysis: It was found out that the optimized formulation was best explained
by the Higuchi’s equation, as the plots showed highest linearity (R2 = 0.992) (Fig 8) followed
by Zero order (R2 = 0.932) (Fig 9) and first order (R2 = 0.882) (Fig 10). This explains why
the drug diffuses at a comparatively slower rate as the distance for diffusion increases, which
is referred to as square root kinetics (or Higuchi’s Kinetics).
To know the mechanism of drug release the dissolution data was fitted into Korsmeyer -
Peppas equation. It also indicated a linearity (R2 = 0.525) (Fig 11) and the release exponent
(n) value was found to be 0.57, which appears to indicate a coupling of the diffusion and
erosion mechanism-so called anomalous diffusion-and may indicate that drug release is
controlled by more than one process. The results of curve fitting analysis were shown in
Table 8.
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Table 8: Regression coefficient (R2) values for different kinetic models for optimized all
tablets.
Formula code Zero order First order Higuchi Korsmeyer Peppas
R2 R2 R2 R2 n
FM1 0.933 0.817 0.986 0.988 0.603
FM2 0.970 0.872 0.995 0.995 0.621
FM3 0.962 0.860 0.991 0.993 0.606
FM4 0.985 0.919 0.979 0.989 0.655
FM5 0.900 0.825 0.955 0.965 0.802
FM6 0.943 0.815 0.987 0.986 0.625
FM7 0.928 0.778 0.981 0.984 0.637
FM8 0.932 0.882 0.992 0.525 0.571
FM9 0.936 0.771 0.990 0.985 0.671
FM10 0.929 0.762 0.984 0.981 0.729
F1 0.926 0.773 0.978 0.972 0.634
F2 0.927 0.817 0.981 0.981 0.585
Fig 8: Higuchi drug release kinetics for FM8
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Fig 9: Zero order release kinetics for FM8
Fig 10: First order release kinetics for FM 8
Fig 11: Korsmeyer-Peppas drug release kinetics for FM 8
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Stability studies: The optimized tablets from batch FM 8 were charged for stability studies.
There was no change in physical appearance, colour. Formulations were analyzed at the end
of 3 months for the assay and dissolution studies. Average drug content of the tablets were
found to be 98.5±0.6% of the labeled claim. In vitro dissolution profile showed that there was
no significant change in the release rate of the drug from optimized tablets at the end of 3
months.
CONCLUSION
Systematic studies were conducted using different polymers in different concentrations to
prepare Losartan potassium floating and osmotically controlled tablets. All the prepared
systems were evaluated for the different properties.
Formulated tablets gave satisfactory results for various evaluation parameters like tablet,
hardness, friability, weight variation, Thickness, floating lag time, floating duration,
content uniformity, ex vivo osmotically controlled strength and in-vitro drug release.
In all formulations Carbopol 974P is used to add osmotically controlled strength but the
concentration of this polymer has significantly influenced the drug release due to its
retarding property. Comparing the two different grades of Hydroxypropyl methyl
cellulose (K4M, K15M), it was found that low-viscosity grades of HPMC K4M
formulations released drug rapidly compared to K15M. Among all formulations K15M
grade provided better controlled release characteristics with excellent drug release and in
vitro buoyancy. From the above results, it was also evident that at higher viscosity grades
of polymer concentrations, the rate of drug release was retarded greatly.
All the formulated tablets from FM1 to FM10 shown the excellent osmotically controlled
property compared to formulations with no osmotically controlled property i.e., F1, F2.
Moreover, there is no much difference is observed in drug release compared to F1, F2.
And the rate of drug release is somewhat controlled due to osmotically controlled
polymer.
Drug release profiles are fitted to kinetic modelings like zero order, first order, Higuchi
model and korsmeyer peppas models. And it was found that the formulations were best
fitted to Higuchi model.
Stability studies were conducted for optimized formulation at different conditions. And
the formulation is found stable in all the conditions.
Floating and osmotically controlled tablets of Anti-Hypertensive drug Losartan potassium
can be formulated as an approach to increase gastric residence time thereby improve its
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bioavailability and to overcome the limitations of conventional approaches of gastric
retention.
All the Formulations gave better-controlled drug release. Here the polymers used to
improve the gastric residence are cellulose polymers HPMC K4M, HPMC K15M.
It was concluded that the formulations with K15M is optimized for better release. And
FM 8 formulation is optimized among the K15M Formulations because of its equal
combination of osmotically controlled polymer and hydrophilic polymer.
REFERNCES
1. Wei, Z.L. Huang, et al. Preparation of the 5-Fu floating sustained release tablet for gastric
retention. Beijing da xue xue bao. Yi xue ban Journal of Peking University. Health
sciences 2004; 36(4): 439-442.
2. Lehr CM (1994). Bioadhesion technologies for the delivery of peptide and protein drugs
to the gastrointestinal tract. Crit. Rev. Ther. Drug Carrier Syst.11:119-160.
3. Gilbert S, Banker, Anderson. The Theory and Practice of Industrial Pharmacy. Leon
Lachman. In: 3rd edition. pp.318-319.
4. Cooper J, Gun C., Powder Flow and Compaction. Inc Carter SJ, Eds. Tutorial Pharmacy.
New Delhi, CBS Publishers and Distributors; 1986, 211- 233.
5. Aulton M.E, Wells T.I., Pharmaceutics: The Science of Dosage Form Design. London,
England, Churchill Livingston; 1998,247.
6. Lachman L, Lieberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy.
3rd ed. Bombay: Varghese publishing house; 1991. p. 300.
7. Lachman L, Liberman HA, Kang JL. The theory and practice of industrial pharmacy, 3
Ed, Varghese Publishing House, Mumbai, 1987, 297-299.
8. Rosa M, Zia H, Rhodes T. Dosing and testing in-vitro of a bioadhesive and floating drug
delivery system for oral application. Int J Pharm 1994; 105: 65‐7.