Article wjpps 1388664456

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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.

[email protected]

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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

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2. Lehr CM (1994). Bioadhesion technologies for the delivery of peptide and protein drugs

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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

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8. Rosa M, Zia H, Rhodes T. Dosing and testing in-vitro of a bioadhesive and floating drug

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Article wjpps 1388664456