Experiment No.

09

Date:

FORMULATION AND EVALUATION OF MATRIX TABLETS OF FAMOTIDINE USING HYDROPHILIC POLYMER

AIM: To formulate and evaluate matrix tablets of Famotidine using hydrophilic polymer. REFERENCE: 1. Vyas S P, Khar R K; Controlled Drug Delivery: Concepts and Advances; 1st edition; Vallabh Prakashan, 2002, p. 156-189. 2. Shargel L, Yu A B C; Modified release drug products. In: Applied Biopharmaceutics and Pharmacokinetics; 4th edition; McGraw Hill. 1999, p. 169-171. REQUREMENTS: Chemicals Required: Famotidine, HPMC K100, PVP, Isopropyl alcohol, Talc, Magnesium stearate, Ethyl cellulose, Lactose monohydrate. Apparatus required: Tablet press, Tray drier, UV Spectrophotometer, Sieve . THEORY: Matrix tablets are the type of tablet which is designed such that it releases its contents regarding first order kinetics or zero order kinetics due to special arrangement and combination of hydrophobic and hydrophilic polymers as an excipient to form a matrix. Example of such a matrix tablets are, controlled release tablet, sustained release tablet. These all come under the category of modified release tablet. These are the type of controlled drug delivery systems, which release the drug in continuous manner. These release the drug by both dissolution controlled as well as diffusion controlled mechanisms. To control the release of the drugs, which are having different solubility properties, the drug is dispersed in swell able hydrophilic

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substances, an insoluble matrix of rigid non swellable hydrophobic materials or plastic materials.

Drug Release from Matrix systems Drug in the outside layer exposed to the bathing solution is dissolved first and then diffuses out of the matrix. This process continues with the interface between the bathing solution and the solid drug moving toward the interior. It follows that for this system to be diffusion controlled, the rate of dissolution of drug particles within the matrix must be much faster than the diffusion rate of dissolved drug leaving the matrix. Table I: Composition of matrix tablet formulations of Famotidine Ingredients Amount(mg)

Famotidine Ethyl cellulose Hydroxypropyl Methylcellulose K 100M Polyvinyl pyrrolidone (PVP K30) Lactose Monohydrate Talc Magnesium Stearate Isopropyl Alcohol

40 20 40 3 87 6 4 q.s.

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PROCEDURE: Preparation of Famotidine CR tablets: The formulations of controlled release tablets of famotidine using HPMC K100M were prepared by wet granulation method. 1. At first Famotidine and HPMC K100M were mixed, Lactose and ethyl cellulose were added to the drug polymer mixture and blended thoroughly for 5 minutes. 2. Polyvinyl Pyrollidone (PVP) was dissolved in sufficient quantity of isopropyl alcohol (IPA) until it forms a solution and this was added to the drug mixture and mixed thoroughly to form a coherent mass. 3. Then the coherent mass was passed through Sieve No: 16 to form granules and the collected granules were dried at 40C 2C for 2 hours. 4. The dried granules were passed through sieve No: 22. The granules retained on sieve No: 22 were evaluated for bulk density, tapped density; bulkiness, angle of repose, compressibility index and Hausners ratio. 5. Then the granules were mixed with magnesium stearate, talc and finally compressed into tablets.

Evaluation of tablets 1. Hardness The tablets to be tested are held between a fixed and a moving jaw of hardness test apparatus (Monsanto) and reading of the indicator is adjusted to zero. The screw knob was moved forward until the tablet breaks and the force required to break the tablet was noted .

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2. Friability Friability test was performed using Roche friabilator. Ten tablets were weighed and placed in the friabilator, which was then operated for 25 revolutions per minute. After 100 revolutions the tablets were dusted and reweighed . The percentage friability was determined using the formula, Percentage friability = Initial weight - Final weight 100 Initial weight 3. Weight Variation For weight variation test, twenty tablets were selected at random and weighed individually. The individual weights were compared with average weight for determination of weight variation . 4. Drug Content Ten tablets were weighed and powdered. Powder equivalent to 100mg of famotidine was dissolved in 10ml of 0.1M HCl, then make upto 100ml with phosphate buffer pH7.4 in 100ml standard flask. From this 10g/ml, equivalent solution was prepared and analyzed at 265 nm using UV double beam spectrophotometer. After that the drug content was measured from the standard curve. 5. Dissolution Studies In vitro release study was performed using USP apparatus type II at 50 rpm. The dissolution medium was 900ml of phosphate buffer PH 7.4. It was maintained at a temperature of 370.5o C. The drug release was evaluated by taking 10ml sample (which was replaced with fresh medium) every one-hour interval upto 10 hours and suitably diluted with phosphate buffer pH7.4 and absorbance was measured at 265 nm using UV spectrophotometer .

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6.Kinetic Analysis To analyze the mechanism of drug release rate kinetics of all the formulations, the results of in vitro release profiles were fitted into Higuchi model, zero order kinetic model and Korsmeyer model. The results of invitro release profiles were plotted in models of data treatment as follows: 1. Cumulative percent drug released versus time (zero order kinetic model) . 2. Cumulative percent drug release versus square root of time (Higuchi model) . 3. Log cumulative percent drug released versus log time (korsmeyers model)

Table-II Evaluation of Famotidine Granules: Parameters Bulk density(gm/cm3) Tapped density(gm/ cm3) Angle of repose Compressibility index(%) Hausners ratio Value 0.64 0.69 26.5 7.2 1.07

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Table-III Evaluation of Famotidine Tablets: Parameters Hardness (kg/cm2) Friability(%) Weight variation(mg) % Drug content Value 3.5 0.19 199 5.2 97.44

1. Preparation of standard curve of Famotidine: i) 25 mg of standard Famotidine was weighed accurately and was dissolved in 250 ml of phosphate buffer (pH 7.4) in a volumetric flask. ii) A series of diluted solutions of Famotidine (i.e. 2, 4, 6, 8 & 10 g/ml) were prepared by diluting 0.2, 0.4, 0.6, 0.8 and 1.0 ml of the solution prepared in step (i) up to 10 ml with phosphate buffer (pH 7.4). iii) Absorbance of each diluted solution was measured in a UV spectrophotometer at a max of 265 nm using phosphate buffer (pH 7.4) as blank. iv) A concentration Vs absorbance graph was prepared taking concentration at Xaxis and absorbance at Y-axis. A straight line was obtained.

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Data for standard curve of Famotidine in Phosphate buffer ph 7.4 Conc(g/ml) 0 2 4 6 8 10 Absorbance 0 0.0594 0.1284 0.1821 0.2498 0.3149

Standard curve of Famotidine in Phosphate buffer P H 7.4 0.35 0.3 Absorbance 0.25 0.2 0.15 0.1 0.05 0 0 2 4 6 Concentration 8 10 12 Absorbance

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Table IV Evaluation of drug release: Matrix tablet with HPMC Time (min) 0 30 60 90 120 180 240 300 360 Drug Absorbance Concentration(gm/ml) released(mg) 0 0.0743 0.1674 0.2147 0.2894 0.3496 0.4232 0.4654 0.6224 0 2.43 5.43 6.96 9.36 11.30 13.68 15.04 20.10 0 2.187 4.887 6.264 8.424 10.17 12.31 13.536 18.09 % drug release 0 5.46 12.21 15.66 21.06 25.42 30.77 33.84 45.22

Drug release profile of Famotidine from matrix tablet

50 %Drug release 40 30 20 10 0 0 100 200 Time(min) 300 400 %Drug release

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Kinetic Study: 1. Zero order kinetic model: Time (min) 0 30 60 90 120 180 240 300 360 %Drug release 0 5.46 12.21 15.66 21.06 25.42 30.77 33.84 45.22

Zero order release model

50 40 %Drug release R = 0.9675 30 20 10 0 0 100 200 Time(min) 300 400 Linear (%Drug release) %Drug release

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2.Higuchi model: Square root of time(min) 0 5.47 7.74 9.48 10.95 13.41 15.49 17.32 18.97 %Drug release

0 5.46 12.21 15.66 21.06 25.42 30.77 33.84 45.22

Higuchi model
50 40 %Drug release 30 20 10 0 0 -10 5 10 15 20 Square root of time(min) R = 0.9574 %Drug release Linear (%Drug release)

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3.Korsmeyers model: Log time(min) 0 1.47 1.77 1.95 2.08 2.25 2.38 2.48 2.55 Log %Drug release 0 0.737 1.08 1.19 1.32 1.40 1.48 1.53 1.65

Korsmeyers model
1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 -0.2 0 R = 0.9845 Log %Drug release Linear (Log %Drug release)

Log % Drug release

1 2 Log time(min)

TableV: Curve fitting analysis for Famotidine formulations: Regression Coefficient (R2) Zero order Plot 0.963 Higuchis Plot 0.957 Korsmeyers plot 0.984

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Conclusion: The results of experimental studies of famotidine matrix tablets proved that the granules of famotidine showed good flow properties, tablet evaluation tests are within the acceptable limits, the kinetic studies revealed that all the formulations followed Korsmeyers model drug release. The drawbacks of the conventional dosage forms of famotidine can be minimized by Famotidine CR tablets. Thus the results of the above study clearly indicated that famotidine may be formulated as controlled release tablets using HPMC K 100M as polymer by wet granulation method, which will provide continuous release of drug at a predetermined rate and for a predetermined time.