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Journal of Advanced Pharmaceutical Research. 2011, 2(1), 24-30. Research paper A new approach in formulation of oral floating matrix tablets of famotidine
Hindustan Abdul Ahad*,1, Chitta Suresh Kumar1, Kishore Kumar Reddy B1, Anil Kumar B1, Chandra Sekhar A1, Sushma K2, Sairam T2, Sivaji S3
1

Department of Pharmaceutics, College of pharmacy, Sri Krishnadevaraya University, Anantapur- 515003, Andhra Pradesh, INDIA, Tel.: +91 8554 255890;

SVU College of sciences, Sri Venkateshwara University, Tirupati, Andhra Pradesh, India;
3

Data monitor, Vega block, Madhapur, Hyderabad, Andhra Pradesh, India; Corresponding author E.Mail: abdulhindustan@rediffmail.com
Received: Dec 15, 2010; Accepted: Jan 21, 2011

ABSTRACT The main purpose of this work was to prepare floating matrix drug delivery system of Famotidine. Floating matrix tablets of Famotidine were developed to prolong gastric residence time and increase its bioavailability. Rapid gastrointestinal transit could result in incomplete drug release from the drug delivery system above the absorption zone leading to diminished efficacy of the administered dose. Floating matrix tablets containing 100 mg Famotidine were developed using different effervescent salts and polymer combinations. The tablets were prepared by direct compression technique, using polymers such as hydroxyl propyl methyl cellulose (HPMC K4M), Carbopol 934 in combination. Sodium bicarbonate, citric acid, calcium carbonate was incorporated as a gas-generating agent. The effects of sodium bicarbonate on drug release profile and floating properties were investigated. The formulation was optimized on the basis of acceptable tablet properties, floating lag time, total duration of floating and in vitro drug release. The formulated tablets with optimum hardness, uniform thickness, consistent weight uniformity and low friability. The results of dissolution studies, floating lag time indicated that formulations F5 exhibited good and controlled drug release. Applying the linear regression analysis and model fitting showed the selected formulation F4 showed diffusion coupled with erosion drug release mechanism, followed first order kinetics. Optimized floating matrix tablets F5 showed no change in physical appearance, drug content, or in dissolution pattern after storage at accelerated storage conditions. KEYWORDS: Famotidine, floating tablets, buoyancy studies, in vitro release.

INTRODUCTION Oral administration is the most convenient and commonly employed route of drug delivery for systemic action. Indeed, for controlled release system, oral route of administration has received the more attention and success because gastrointestinal

acting locally in the stomach, the challenging task is not only to prolong drug release but the retention of the dosage form in the upper gastrointestinal tract. This results in a higher bioavailability, reduced time intervals for drug administration and thus a better patient compliance (Moes, 1993). Various approaches for gastro retentive dosage forms have been proposed including mucoadhesive systems, swellable and floating systems (Vyas and Khar, 2005). Floating 24

physiology offers more flexibility in dosage form design than other routes. For drugs with a narrow absorption window in the gastrointestinal tract or

Available online at www.pharmresfoundation.com drug delivery systems remain buoyant in the stomach for prolonged period of time without affecting the gastric emptying rate of other contents. Floating matrix systems containing HPMC as the matrix forming excipient begin to swell and form a gel layer with entrapped air around the tablet core after contact with gastric fluid, whereas this gel layer controls the drug release (Whitehead, 1998). Another possibility for the induction of floatation lies in the incorporation of sodium bicarbonate, citric acid and calcium carbonate as gas forming agent dispersed in a HPMC hydrogel matrix as a method. Famotidine is histamine H2 receptor antagonist. It is widely used for duodenal ulcers, gastric ulcers, gastro-esophageal reflux disease and errosive esophagitis. Famotidine is having a short biological half-life of 2.5-3.5 hrs. Famotidine has 40 45% absolute bioavailability on oral administration. In contest of the above principle, a strong need was recognized for the development of a dosage form to deliver sustained release gastro retentive delivery system of famotidine. MATERIALS AND METHODS
Calcium carbonate 10 155 10 120 Carbopol 934 Sodium bicarbonate Citric acid 10 10 5 20 20 10 Famotidine Hydroxy Propyl Methyl Cellulose (K4M) 40 10 40 20

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The ingredients were weighed accurately and mixed thoroughly. Granulation was done with a solution of HPMC K4M in sufficient isopropyl alcohol. The damp mass was passed through # 40 mesh and the granules obtained were dried in conventional hot air oven at 450C for 15 m. The dried granules were sized through 40/60 mesh, lubricated with magnesium stearate and purified talc and then compressed on a single punch tablet machine ((M/s Remek, Ahmedabad, India). Five formulations were prepared and named them as F1, F2, F3, F4 and F5 respectively. The detailed composition of each formulation was showed in Table 1.
Table 1: Composition of various formulations Ingredients (mg) F1 F2 F3 40 30 F4 40 40 F5 40 50

30 30 15 10 85

40 40 20 10 50

50 50 25 10 15

Materials Famotidine was obtained as a gift sample from Waksman Selman Pvt. Ltd, Anantapur, India. Sodium bicarbonate, citric acid, calcium carbonate was procured from S.D. Fine chemicals Mumbai. All the reagents used were of AR grade. The drug samples were characterized by means of UV EVALUATION Pre-compression parameters (Indian
Micro crystalline cellulose Magnesium stearate Talc

5 5

5 5

5 5

5 5

5 5

spectrophotometric method along with determination of solubility and pH for their authentication. Preparation of floating tablets of famotidine

Pharmacopoeia, 1996, Banker, 1987) Angle of repose Angle of repose was determined by using funnel method. Powder was poured from a funnel that 25

Available online at www.pharmresfoundation.com can be raised vertically until a maximum cone height (h), was obtained. Diameter of heap, (D), was measured. The angle of repose (), was calculated by eq.1 and 2. IC = Dt - Db / Dt . (5) tan = h / r.. (1) Where, = tan (h / r) .... (2)
-1

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Carrs index (IC) It is expressed in percentage and is expressed by eq.5.

Dt is the tapped density of the powder and Db Where, is the angle of repose, h is the height in cm and r is the radius. It is expressed in percentage and is expressed Bulk density Apparent bulk density was determined by pouring presieved drug excipient blend into a graduated cylinder and measuring the volume and weight as it is. It is expressed in g/ml and is given by eq.3. Db = M / V0 . (3) Where, M is the mass of powder and V0 is the Bulk volume of the powder Tapped density It was determined by placing a graduated cylinder, containing a known mass of drug- excipient blend, on mechanical tapping apparatus. The tapped volume was measured by tapping the powder to constant volume. It is expressed in g/ml and is given by eq.4. Dt = M / Vt (4) Where, M is the mass of powder and Vt is the tapped volume of the powder. SI = Weight of tablet at time (t) -Initial weight of tablet /Initial weight of tablet x 100.. (7) Post compression parameters (Ichikawa 1991; Yang et al. 1999) The prepared floating tablets were evaluated for uniformity of weight using 20 tablets, hardness (Monsanto tester) and friability using 10 tablets. The results are expressed as mean S.D. (n=5). 26 Where, Dt is the tapped density of the powder and Db is the bulk density of the powder. EVALUATION OF TABLETS Determination of swelling index The swelling index of tablets was determined in 0.1N HCl (pH 1.2) at room temperature. The weights of swelled tablets were determined at regular time intervals over a period of 24 h. The swelling index (SI), expressed as a percentage, and was calculated from the following eq.7. by eq.6. HR= Dt / Db (6) is the bulk density of the powder. Hausners ratio (HR)

Available online at www.pharmresfoundation.com In vitro buoyancy studies (Rosa et al., 1994) The formulated tablets from each formulation were kept in a 100ml beaker containing simulated gastric fluid of pH 1.2. The time taken for the tablet to rise to the surface and float was taken as floating lag time. The duration of time the dosage form constantly remained on the surface of medium was determined as the total floating time. Drug Content Estimation The drug content in each formulation was determined by triturating 20 tablets and powder equivalent to average weight was added in 100ml of 0.1N hydrochloric acid, followed by stirring for 30 m. The solution was filtered through a 0.45 membrane filter, diluted suitably and the absorbance of resultant solution was measured spectrophotometrically at 265nm using 0.1 N HCl as blank. In-vitro drug release studies The release rate of famotidine from floating tablets was determined using USP Dissolution Testing Apparatus 2 (paddle method; Systronics, Mumbai, India). The dissolution test was performed using 900 ml of 0.1N hydrochloric acid, at 37 0.5C and 50 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus hourly and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45 membrane filter and diluted to a suitable concentration with 0.1N hydrochloric acid. Absorbance of these solutions was measured at 265 nm using Elico SL-210 UV/VIS double beam spectrophotometer. Cumulative

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In vitro drug release kinetic studies (Higuchi et al., 1963, Peppas et al., 1989) The exact mechanism by which famotidine releasing from dosage form was determined by analyzing the data to various kinetic models viz., zero order, first order, Korsmeyer- Peppas, Higuchi and square root models. The data were processed for regression analysis using MS EXCEL-2010 statistical function. Accelerated stability studies The promising formulation was tested for a period of 3 months at different temperature of 400C with 75% RH, for their drug content (Remunan, 1992). RESULTS AND DISCUSSION The angle of repose of formulated tablets were ranged from 24.190.02 to 29.100.21, indicates good flow property. The values of loose bulk density and tapped bulk densities were required to calculate Compressibility Index and Hausners ratio. The carrs Index was ranged from 18.44 to 28.33 and Hausners ratio was ranged from 0.010 to 0.139 which indicates the good flow ability of the powder formulation. The results of the flow properties were shown in Table 2. The weight of the tablet varied between 250.204.10 to 252.313.29 mg. The variation in weight was within the range and complying with pharmacopoeial specifications. The hardness for different formulations was found to be between 5.020.28 to 7.010.49 kg/cm2. The friability was ranged from 0.280.02 to 0.680.04 %, indicates the formulated tablets have good mechanical strength. The drug content was ranged from

percentage drug release was calculated using an equation obtained from a standard curve.

99.955.62 to 100.510.95%. The buoyancy floating 27

Available online at www.pharmresfoundation.com time was ranged from 41 to 68 s and total floating time was ranged from 8 to 16 h for various formulations. All these values were represented in Table 3. The drug release from floating tablets was shown in Fig.1.
Table2: Flow properties of granules Form ula tion F1 Angle of repose (0) Bulk Density (g/cm3) 0.5420.0 4 0.5620.0 5 0.4200.0 1 0.4570.0 4 0.4380.0 2 Tapped Density (g/cm3) 0.6410. 01 0.6300. 02 0.6220. 04 0.5830. 08 0.6250. 04 Carrs Index (IC) 18.44 Hausners ratio (HR)

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The optimized formulation was subjected to accelerated stability studies as per ICH guidelines. The formulated tablets did not show any changes in all the characters before and after stability studies and these values were represented in table 5.

26.150.1 9 25.440.2 5 29.100.2 1 26.120.1 1 24.190.0 2

0.010

F2

21.75

0.139

F3

28.33

0.060

F4

26.05

0.081

F5

28.03

0.119

Fig 1: In-vitro drug release profile of formulated tablets Table 4: Kinetic release data of different model for optimized formulation (F5) Kinetic model Slope 6.7537 -0.0795 0.47982 25.597 0.1807 R2 0.9204 0.9819 0.9869 0.9938 0.9859

Table 3: Post compression parameters of formulated floating tablets Formulatio n F1 F2 Weigh t (mg) Hardness (Kg/cm2) Friabi -lity (%) Drug content (%) 250.20 4.10 251.22 5.69 251.21 4.29 252.31 3.29 250.90 2.74 5.020.28 6.150.60 0.280 .04 0.520 .04 0.280 .02 0.550 .09 0.680 .04 100.234 .64 100.296 .51 99.955. 62 99.972. 45 100.510 .95 Buoya -ncy lag time (s) 68 59 Total floatin -g time (h) >8 >10

Zero order First order Korsmeyer-Peppas Higuchi Hixson Crowells

All the tablets were prepared by effervescent approach. The combination of sodium bicarbonate and

F3 F4 F5

7.010.49 5.940.56 6.230.25

48 45 41

>12 >12 >16

citric acid provided desired floating ability but, additionally calcium carbonate was included to increase the effervescent and it act as antacid. So, this combination was selected for the formulation of the floating tablets. It was observed that the gas generated is trapped and protected within the gel, formed by hydration of polymer (Hydroxy Propyl Methyl Cellulose and Carbopol 934), thus decreasing the density of the tablet below 1 and tablet becomes buoyant. The tablet swelled radially and axially during 28

This dissolution was treated with kinetic modeling viz., First order, Korsmeyer-Peppas, Higuchi and Hixson Crowells modeling. The data was represented in table 4.

Available online at www.pharmresfoundation.com in-vitro buoyancy studies. All the batches of tablets were found to exhibit short floating lag times due to presence of sodium bicarbonate and citric acid. Decrease in the citric acid level increased the floating lag time and tablets were found to float for longer duration. The pH of the stomach is elevated under fed condition (~3.5), therefore citric acid was incorporated in the formulation to provide an acidic medium for sodium bicarbonate; more over citric acid has an stabilizing effect on famotidine formulation. It is evident from the in-vitro dissolution data that increase in citric acid concentration increased the release rate but reduced the floating time, probably due to of excess carbon dioxide, disturbing the monolithic tablet.
Table 5: Accelerated stability studies data of Optimized Formulation (F 5) Month Parameter Physical appearance 0 Brownish white, smooth, flat 6.23 0.68 100.51 1st Brownish white, smooth, flat 6.22 0.69 100.51 2nd Brownish white, smooth, flat 6.22 0.69 100.51 3rd Brownish white, smooth, flat 6.23 0.70 100.50

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The prepared formulations sustained the drug release for a period up to 16 h. CONCLUSION The effervescent-based floating drug delivery was a promising approach to achieve in-vitro buoyancy. The addition of gel-forming polymer Hydroxy Propyl Methyl Cellulose (K4M) and gasgenerating agent sodium bicarbonate along with citric acid was essential to achieve in-vitro buoyancy. Incorporation of calcium carbonate results in increase in effervescent efficacy additionally it has antacid property. The drug release from the tablets was sufficiently controlled. ACKNOWLEDGEMENTS The authors are very grateful to Waksman Selman Pvt. Ltd, Anantapur, India for providing famotidine as gift sample. REFERENCES 1. Banker GS, Anderson NR. In The Theory and Practice of Industrial Pharmacy, Lachmann L, Liberman HA, Kaing JL. Eds. Varghese Publishing House: Bombay, 1987, 297-299. 2. Higuchi T. Mechanism of rate of sustainedaction medication. J Pharm Sci. 1963, 52, 1145-1149. 3. Ichikawa M, Watanabe S, Miyake Y. A new multiple-unit oral floating dosage form I: Preparation and in vitro evaluation of floating and sustained release characteristics. J Pharm Sci. 1991, 80, 1062-1066. 4. Indian Pharmacopoeia. The Controller Publications: Delhi, 1996, Vol. II, pp.734-736. of

Hardness (kg/cm2) Friability (%) Drug content (%) Buoyancy Lag Time (s) Total Floating Time (h) In vitro release (%)

41

41

41

40

>16

>16

>16

>16

5. Moes AJ. Gastroretentive dosage forms. Crit. Rev. Ther. Drug. 1993, 10, 143-195. 6. Peppas NA, Sahlin JJ. A simple equation for the description of solute release III. Coupling of diffusion and relaxation. Int J Pharm. 1989, 57, 169172. 29

96.08

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96.06

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demonstrating prolonged gastric retention. J Control Release. 1998, 55, 3-12. 10. Vyas SP and Khar RK. Gastroretentive systems. In: Controlled drug delivery concepts & Advances, Vallabh Prakashan. 2005, 96-199.

11. Yang L, Esharghi J, Fassihi R. A new intra gastric

delivery system for the treatment of helicobacter pylori associated gastric ulcers: in vitro evaluation, J Control Release. 1997, 57, 215-222.

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