Design, Development and In Vitro Evaluation of Directly Compressed Sustained Release Matrix Tablet of Famotidine

Mridanga Raj Ray*, Sekhar Kumar Bose and Koushik Sengupta

Department of Pharmaceutics, Himalayan Pharmacy Institute, Majhitar, East Sikkim- 737136

* Corresponding Author E-mail: mri_royraj@rediffmail.com

ABSTRACT

An attempt has been made in this study to develop sustained release matrix tablet of Famotidine by direct compression

method using two different polymers like- Ethylcellulose (EC) and Eudragit L100 (EL100) in combine form at various ratios. Powders were evaluated for angle of repose, loose bulk density and tapped bulk density whereas the prepared tablets were evaluated for weight variation, thickness and diameter, hardness, friability, drug content and in vitro dissolution study. The drug release kinetic was fitted in three different mathematical models like- Zero order, Higuchi and Korsmeyer-Peppas model. The results indicate that all the formulations predominantly follow Higuchi model and showed Fickian Diffusion controlled drug release

KEY WORDS Famotidine; Ethylcellulose; Eudragit L100. Matrix Tablet .

INTRODUCTION:

The success of a therapy depends on selection of the appropriate delivery system as much as it depends on the drug itself.1 Sustained or time release systems are methods of drug delivery in which one preparation will accomplish the desire medicinal effect with more efficiency and longer duration than multiple dosages of the same drug. The goal of these systems is to supply the optimal concentration of a drug for a longer time than conventional systems allow. Sustained release systems dominate the cyclic nature of multiple tablets dosages form and have many advantages over conventional interval dosages.2 Thus the present drug was chosen as suitable candidate for formulation of sustained release drug delivery system.

Famotidine was selected as it is a potent H2 blocker with low biological half life (2.6 ± 10 hours). It is approximately 20-50 times more potent in inhibiting gastric acid secretion than Cimetidine and 5-8 times more potent than Ranitidine. In low dose it is a drug choice for treatment of duodenal ulcer, Zollinger- Ellison syndrome and Gastro-esophageal reflux disease.3 Direct compression technology was used as it is receiving interest in pharmaceutical sector due to the savings in equipments, materials, labor, time and energy over conventional granulation technique.4

As heat and water are not involved the stability of the product can also be improved which is one of the major advantage of direct compression.5 The objectives of the investigation was to study the utility of using ethylcellulose and Eudragit L100 in the formulation design of sustained release matrix tablet of Famotidine and to observe the in vitro release characteristics and the kinetic of the prepared formulations.

MATERIAL AND METHODS:

Famotidine was received as gift samples from Caplet India Pvt. Limited, Kolkata. EL100 was obtained from Degussa Pharma Polymers, Germany. Ethyl cellulose, Talcum Powder, Magnesium Stearate and Microcrystalline cellulose were purchased from S.D. Fine-chem. Limited, Mumbai. All other reagents used in this study were of analytical grade and obtained from standard sources.

Preparation of tablets

A total number of seven formulations were prepared by direct compression method according to the formula given in Table-1. Preweighed ingredients were passed through Indian Standard Sieve no. 60 separately and collected. Ingredients were mixed in geometrical order and blended to get a uniform mixture. Then the powder mixture was lubricated with talc and compressed using 8 mm round concave face punch to get the tablets having the hardness between 6 to 7 kg/cm2.

Evaluation of Powder characteristics:

Measurement of Angle of Repose-

Angle of repose was determined by funnel method. The

blend was poured through a funnel that can be raised vertically until a maximum cone height (h) was obtained. Radius of the heap (r) was measured and the angle of repose (θ) was calculated by using the formula-

θ = tan-1(h / r) (Table-2)

Bulk density 6

Both loose bulk density and tapped bulk density were determined. Accurately weighed amount of sample was transferred into graduated cylinder. The volume of the packing was recorded. The graduated cylinder was then tapped 100 times and the tapped volume of packing was recorded. Loose bulk density and tapped bulk density were calculated by the following formula:

Loose bulk density = (Weight of the powder sample/ Volume of the packing)

Tapped bulk density = (Weight of the powder sample/Tapped volume of the packing) (Table-2)

Evaluation of the Formulation:

Determination of Weight variation, Thickness and Diameter, Hardness and Friability of the tablets Weight variation was determined by randomly selected individually and calculated their average weight. Then the deviation of individual weight from the average

In vitro drug release studies:

In-vitro drug release studies were carried out using USP Type-II (Paddle type) dissolution test apparatus (Veego, Mumbai) for 12 hours at 50 rpm using 900 ml of pH 1.2 Hydrochloric acid buffer for first 2 hours and pH 6.8 Phosphate buffer for rest of the period as dissolution medium, maintaining the temperature at 37±1°C. Aliquots of 5ml were withdrawn at 1 hour intervals and an equivalent amount of fresh dissolution medium equilibrate at the same temperature was replaced. These aliquots were filtered and the absorbance of the filtrate was measured after making suitable dilution in each case at 267 nm using Shimadzu UV-VIS PharmSpec1700 spectrophotometer. The data for cumulative percentage of drug release was fitted to different models of drug release.

TABLE-1: FORMULATION OF SUSTAINED RELEASE MATRIX TABLET OF FAMOTIDINE

Ingredients

(mg / tablet)

EC : EL 100

F-1 (1:1)

F-2 (1:2)

F-3 (1:3)

F-4 (2:1)

F-5 (2:3)

F-6 (3:1)

F-7 (3:2)

Famotidine

Microcrystall ine cellulose

EL 100

Talc

Magnesium

Stearate

28.5

85.5

45.6

68.4

85.5

28.5

68.4

45.6

FORMULAION F-1 TO F-3 (ZERO ORDER PLOT)

calipers. The hardness of the tablet was calculated with the help of a Monsanto hardness tester. The friability test was done using Roche Friabilator at 25 rpm for 4 minutes after placing twenty preweighed tablets. These tablets were then again weighed and percentage loss in weight was calculated.7 (Table-3)

Determination of drug content:

Three tablets were selected randomly from each batch, powdered separately and then taken into three 100 ml volumetric flasks. In each flask 100 ml of phosphate buffer pH 6.8 was poured and kept for 24 hrs. After filtering the solutions and making suitable dilutions, the absorbance of the filtrate was measured at 267nm using Shimadzu UV-VIS PharmSpec1700 spectrophotometer. From this absorbance, drug content was determined. Drug content was determined according to the following formula-

Drug Content = (Actual drug content /Theoretical drug content) X 100 (Table-3)

FIGURE-2 IN VITRO DISSOLUTION PROFLIE OF FORMULAION F-4 TO F-7 (ZERO ORDER PLOT)

TABLE-2: COMPARATIVE STUDY OF VARIOUS POWDER CHARACTERISTICS FOR FORMULATION F-1 TO F-7

Batch Code	Angel of Repose (θ)	Loose bulk density (g/cm3)	Tapped bulk density (g/cm3)
F-1	24.1586 ±1.1162	0.2269 ± 0.0185	0.4833 ± 0.0214
F-2	22.1817 ± 0.2516	0.2667 ± 0.0241	0.5058 ± 0.0235
F-3	21.8329 ±0.3894	0.2891 ± 0.0322	0.5124 ± 0.0289
F-4	22.1238 ±0.1865	0.3514 ± 0.0256	0.5148 ± 0.0259
F-5	26.3711 ± 0.6531	0.3089 ± 0.0351	0.4923 ± 0.0245
F-6	23.2056 ± 0.5926	0.3214 ± 0.0158	0.5167 ± 0.0251
F-7	21.8382 ± 0.3825	0.2596 ± 0.0182	0.4968 ± 0.0205

Results shown are the mean ± SD. n = 3

TABLE-3: COMPARATIVE STUDY OF VARIOUS PHYSICO-CHEMICAL PARAMETERS OF PREPARED SUSTAINED RELEASE MATRIX TABLETS OF FAMOTIDINE

Results shown are the mean ± SD. n = 3

TABLE-4: MODEL FITTING ANALYSIS OF DRUG RELEASE

Batch Code

Zero order Plot

Higuchi Plot

Korsmeyer – Peppas model

Mechanism

Fickian diffusion Anomalous (non- Fickian) transport Anomalous (non- Fickian) transport Fickian diffusion

Anomalous (non- Fickian) transport

Fickian diffusion

F - 1

F - 2

F - 3

F - 4

F - 5

F – 6

F - 7

0.8682

0.8929

0.8658

0.8313

0.9047

0.9019

0.8198

0.9889

0.9895

0.9803

0.9706

0.9849

0.9950

0.9672

0.4837

0.5212

0.5183

0.5000

0.5384

0.5000

0.4918

Kinetic analysis of dissolution data:

Kinetic models had described drug dissolution from solid dosage forms where the dissolved amount of drug is a function of the test time.8 The drug release profile was subjected to different models of drug release (Zero order, Higuchi model and Korsmeyer – Peppas model) and best-fit model was selected on the basis of Correlation coefficient (R2) and the values “n” is determined for Korsmeyer – Peppas model. The “n” value in Korsmeyer – Peppas model is used to indicate different release mechanisms. When the value of n =0.5 indicate Fickian diffusion-controlled drug release, when it in between 0.5 to 1 indicate Anomalous transport, n = 1 show Case II transport and n > 1 indicate Super case II transport.8, 9

RESULTS:

Evaluation of Powder characteristic indicates good flowability with an angle of repose value ranging from 21-260. The loose bulk density and tapped bulk density of all the formulation showed acceptable range (Table- 2). Physico-chemical evaluation such as weight variation, hardness and friability revealed that the tablets compressed were stable and having good physical characteristics (Table-3). Thickness and diameter of all the formulations were found in the range of 4.03 ± 0.12 mm to 4.18 ± 0.14 mm and 8.11 ±0.04 mm to 8.16 ±0.16 mm respectively. The percentage drug content for different tablets formulation varied from 98.38 ± 0.26 to 99.35 ± 0.04 was found to be within limits which indicate uniform drug distribution in all the formulations. After in-vitro drug release study in pH 6.8 Phosphate buffer, it was found that 97.15%, 98.08%, 99.39%, 97.05%, 98.72%, 98.23%, 97.09% were release from the formulation F-1 to F-7 respectively.

DISCUSSION:

In order to describe the kinetics of the release process of the drug from the formulations three kinetic models such as Zero order, Higuchi model and Korsmeyer – Peppas model were used (Table-4). The dissolution data for all formulations were plotted in accordance with the Zero order equation, i.e., percent dissolved as a function of time (Fig-1).

FORMULAION F-1 TO F-3 (HIGUCHI PLOT)

Therefore above investigation showed combination of EC and can be use as matrix carriers in the formulation design of sustained release matrix delivery system for Famotidine. investigation, it can concluded that slow, controlled and complete release of Famotidine over a period of 12 hours was obtained from the formulation F-6 employing EC : EL100 ratio of 3 : 1. It is also evident from the results that F-Famotidine as it showed R2 value of Higuchi model more near to one compared to the other formulations and followed Fickian Diffusion controlled drug release.

It is evident from the figure that the plots are curvilinear, suggesting that the release process is not Zero order in nature. This indicates that the dissolution rate of the drug is independent of the amount of drug available for dissolution and diffusion from the matrix. On plotting the dissolution data in accordance with the Higuchi equation, i.e., percent dissolved as a function of the square root of time (Fig-2), showed Correlation coefficient (R2) values are near to unity compared to Zero order model. Therefore it indicates that the release process of all the formulations is diffusion controlled and predominantly follow Higuchi model. Among these formulations F-6 having EC : EL100 ratio 3 : 1 showed R2 value of Higuchi model more near to one i.e. 0.9926 (Table-4). Considering the “n” value obtained from the Korsmeyer-Peppas model, indicating Fickian Diffusion controlled drug release for the formulations F-1, F-4, F-6, F-7 whereas F-2, F-3 and F-5 showed Anomalous (non- Fickian) transport. (Table-4)

Authors wish to thank Caplet India Pvt. Limited, Kolkata; for providing gift sample of Famotidine and Himalayan Pharmacy Institute, E-Sikkim; for providing necessary laboratory facilities.

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Received on 21.05.2008 Modified on 10.07.2008

Research J. Pharm. and Tech. 1(3): July-Sept. 2008; Page 175-178