Development and Evaluation of Optimized Gastroretentive Mucoadhesive Tablets of Famotidine for Gastro-Esophageal Reflux Disease

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1 Thulluru et al: Formulation and Evaluation of Gastro-Retentive Floating Extended Release Metoprolol Tablets International Journal of Pharmaceutical Sciences and Nanotechnology Research Paper Development and Evaluation of Optimized Gastroretentive Mucoadhesive Tablets of Famotidine for Gastro-Esophageal Reflux Disease Suryavanshi Vishal*, Sayyed Nazim and Khan Imran Department of Pharmaceutics, Ali Allana College of Pharmacy Akkalkuwa, District Nandurbar, Maharashtra, India. Received December 12, 2014; accepted May 17, 2015 Volume 8 Issue 3 July September 2015 MS ID: IJPSN SURYAVANSHI ABSTRACT The aim of the present investigation was to increase the gastric residence time of Famotidine by designing and optimization of gastroretentive mucoadhesive tablet, thereby improving bioavailability of Famotidine. Famotidine conventional tablets have been reported by many Scientists to exhibit poor oral bioavailability and fluctuations in plasma drug concentration. This results, either in precipitation of side effects or reduction in drug concentration at the target site. Famotidine is a histamine H2-receptor antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome and gastro esophageal reflux disease. The effective treatment requires administration of 20 mg of Famotidine 4 times a day. A conventional dose of 20 mg can inhibit gastric acid secretion up to 6 hours but not up to 12 hours. An alternative dose of 40 mg leads to plasma fluctuations; thus a sustained release dosage form of famotidine is desirable. The short biological half-life of drug (2.5-4 hours) also favors development of a sustained release formulation. Thus objective of present study to reduce the dosing frequency by developing, optimizing and evaluating gastroretentive mucoadhesive tablet for sustain release. A 3 2 full factorial design is employed to study the effect of independent variables like Carbopol-940 and HPMC K100M, which significantly influence characteristics like ex-vivo mucoadhesive strength and in-vitro drug release. Tablets were prepared by direct compression technique. No significant change was observed in physical appearance, drug content, hardness, mucoadhesive strength, in vitro dissolution pattern after the stability tasting for one month. KEYWORDS: Gastroretentive mucoadhesive tablet, Famotidine, mucoadhesive strength, in-vitro drug release, stability study, factorial design. Introduction The pharmaceutical research is being steadily shifted from the development of new chemical entities to the development of Novel Drug Delivery System (NDDS) of existing drug molecule to maximize their effectiveness in terms of therapeutic action and patient protection. Extensive efforts have recently been focused on targeting a drug or drug delivery system in a particular region of the body for extended periods of time, not only for local targeting of drugs but also for better control of systemic drug delivery. There are various routes of drug administration like oral, parenteral, transdermal, nasal, rectal, intravaginal, ocular etc. Amongst these various routes of drug administration, oral route is the most preferred for its ease in administration and patient compliance (Yadav et al., 2010; Baviskar and Jain, 2012). The development of oral controlled release systems has been a challenge to formulation scientists due to their inability to restrain and localize the system at targeted areas of the gastrointestinal (GI) tract. Under such conditions, one of the most feasible approach for achieving a prolonged and predictable drug delivery profile in GIT is to control the gastric residence time by designing a delivery system that is able to reside in stomach or preferably prior to absorption window that would increase the absorption of drugs. The retention of oral dosage forms in the upper GIT causes prolonged contact time of drug with the GI mucosa, leading to higher bioavailability and hence therapeutic efficacy, reduced time intervals for drug administration, potentially reduced dose size and thus improved patient compliance. These considerations have led to development of unique controlled release dosage forms with gastroretentive properties (Jain et al., 2013; Kumar et al., 2012). Mucoadhesive Drug delivery are the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the Gastro intestinal tract (GIT) is to control the gastric residence time (GRT). The term mucoadhesive describes material that bind to biological substrate, such as mucosal layer. Adhesion of bioadhesive drug delivery devices to the mucosal tissue 2955

2 2956 Int J Pharm Sci Nanotech Vol 8; Issue 3 July September 2015 offers the possibility of creating an intimate and prolonged contact at the site of administration. This increased residence time can result in enhanced absorption and in combination with a controlled release of drug also improve patient compliance by reducing the frequency of administration. In the present study we tried to enhance the bioavailability of famotidine by formulating it in the form of gastroretentive mucoadhesive drug delivery system for controlled release which is expected to be a better dosage form when compared to conventional or immediate dosage form. Therefore, the aim of the present work is to formulate gastro-retentive mucoadhesive tablets for famotidine (Gudigennavar et al., 2013; Rathee et.al., 2012). Famotidine is a histamine H2-receptar antagonist. It is prescribed widely in Active Duodenal ulcers, Gastric ulcers, Zollinger-Ellison syndrome, Gastro Esophageal Reflux Disease (GERD) and Erosive Esophagitis. It has a low biological half-life of hr. The current recommended adult oral dosage of famotidine is 20 mg twice daily or 40 mg once daily. The low bioavailability (40-45 %) and short biological half-life ( hr) of famotidine following oral administration favors development of a sustained release formulation. The gastroretentive drug delivery system can be retained in the stomach and assist in improving the oral sustained delivery of drugs (Tripathi, 2010). The main objectives of the present work is to formulate famotidine mucoadhesive tablets by using Carbopol 940 as a primary polymer and HPMC K4M, HPMC K15M, and HPMC K100M as a secondary polymers in different proportions, with other tablet excipients and lubricants to give good compressibility by direct compression method, which can provide constant effective drug release for 12 hours. This approach offer better opportunities for and broader applicability to highly variable and challenging drugs and therapy of various gastrointestinal disorders. Materials and Methods Materials The drug famotidine was procured as gift sample from Sehat Pharma Pvt. Ltd. At. Savgadh, Himatnagar, India, Carbopol 940 and HPMC grades were procured from S. D. Fine Chem. Ltd. Mumbai. All other chemicals purchased were of analytical grade. For determining mucoadhesive strength, sheep gastric mucosa was obtained from a local slaughter house. Method Standard plot of famotidine in 0.1N HCl: An accurately weighed quantity of Famotidine (100 mg) was dissolved in small amount of 0.1N HCl and made up to 100 ml with 0.1N HCl to generate a primary stock solution having a concentration of 1 thousand mcg/ml. 1 ml of primary stock solution was further diluted to 100 ml to produce a secondary stock solution having a concentration of 10 μg/ml. Pipette out 0.2, 0.4, 0.6, 0.8 and 1.0 ml from secondary stock solution were further diluted to 10 ml to produce standard solutions having concentrations of 2, 4, 6, 8 and 10 μg/ml. The absorbance of the solutions was measured at nm using double beam UV-Visible spectrophotometer against 0.1N HCl as blank. The plot of absorbance vs. concentration (μg/ml) was plotted and data was subjected to linear regression analysis in Microsoft Excel (Masih, 2012). Fig. 1. Standard calibration curve of Famotidine in 0.1N HCl. TABLE 1 Formula of famotidine mucoadhesive tablet. Ingredient (mg) Formulation code F1 F2 F3 F4 F5 F6 F7 F8 F9 Famotidine Carbopol HPMC K4M HPMC K15M HPMC K100M Lactose Talc Magnesium stearate Total weight Compatibility study using FT-IR Infrared Spectrophotometry is a useful analytical technique utilized to check the chemical interaction between the drug and other excipients used in the formulation. 1 mg of the sample was powdered and intimately mixed with 10 mg of dry powdered potassium bromide. The powdered mixture was taken in a diffuse reflectance sampler and the spectrum was recorded by scanning in the wavelength region of cm 1 in an FTIR spectrophotometer. The IR spectrum of the drug compared with that of the physical mixture to check for any possible drug-excipient interaction (Sharma, 2009; Chatwal and Sham, 2007; Lambert, 1987). Preparation of mucoadhesive tablets Mucoadhesive tablets of famotidine were prepared by direct compression technique using variable concentration of different polymers like Carbopol 940, HPMC K4M, HPMCK15M and HPMC K100M. The entire excipients except talc were blended uniformly in glass mortar and pestle for a suitable time period. After sufficient mixing of drug with other excipients, talc was added and blend was further mixed for 2-3 minutes, the tablets (250 mg, gross wt.) were compressed with 9 mm punch. The weight of the tablets was kept constant (Paul et. al., 2012).

3 Vishal et al: Development and Evaluation of optimized Gastroretentive Muscoadhesive Tablets of Famotidine for Fig. 2. IR spectrum of pure drug. Fig. 3. IR spectrum of formulation. 120 HPMC K100m 100 % drug release Time in hours F1 F2 F3 F4 F5 F6 F7 F8 F9 Fig. 4. Time vs % drug release of factorial batches.

4 2958 Int J Pharm Sci Nanotech Vol 8; Issue 3 July September 2015 Where, Y is the dependent variables, b0 is the arithmetic mean response of the nine runs, and b1 is the estimated coefficient for the factor X1. The main effects (X1 and X2) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X1X2) show how the response changes when two factors are simultaneously changed. The polynomial terms (X1 and X2) are included to investigate non-linearity (Kshirsagar et al., 2011). Fig. 5. Modified physical balance for Mucoadhesive strength measurement. Factorial Design A 3 2 full factorial design was constructed to study the effect of independent variables, i.e., amount of Carbopol 940(X1) and HPMC K100(X2) on dependent variables i.e., Mucoadhesive strength and % Drug release. The levels of the two factors were selected on the basis of preliminary studies carried out before implementing the experimental design. Tables 2 and 3 Summarizes the experimental runs, their factor combinations and the translation of the coded levels to the experimental units used in the study. A statistical model (see equation) incorporating interactive and polynomial terms was utilized to evaluate the responses. 2 2 Y = b0 + b1x1 + b2x2 + b12x1x2 + b11x 1 + b22x 2 TABLE 2 Factor combinations as per the chosen experimental 3 2 full factorial design. Trial No. Coded factor levels X1 X2 F F F F F F F7-1 0 F8 0-1 F9 0 0 TABLE 3 Translation of coded value in an actual unit. Coded level X1 Carbopol 940 (mg) X2 HPMC K100M (mg) Evaluation Parameters Pre-compression parameters All formulation batches were evaluated for Precompression parameters such as angle of repose, bulk density, tapped density, Carr s index and Hausner s ratio as per the official methods (Subrahmanyam, 2010; Mantry et al., 2012). Post-compression parameters The tablets were evaluated for thickness, hardness, friability, weight variation test, drug content, Swelling index, In-vitro dissolution study, in-vitro bioadhesion study, Ex-vivo mucoadhesive measurement. All prepared sustained release tablets were evaluated for the following official and unofficial parameters (IP, 2007; Lachman et al., 1987). Thickness Thickness was measured using a vernier caliper. Five tablets of the formulation were picked randomly and thickness was measured individually. Hardness Hardness was measured using Monsanto hardness tester. The hardness expressed in kg/cm 2. For each batch three tablets were tested. Friability Twenty tablets were weighed and placed in the Roche friabilator and apparatus was rotated at 25 rpm for 4 minutes. After revolutions, the tablets were dedusted and weighed again. The percentage friability was measured using formula, % F = {1 (Wt/W)} 100 Where, % F = Friability in percentage W = Initial weight of tablets Wt = Weight of tablets after revolution. Weight variation Twenty tablets were randomly selected from each batch and individually weighed. The average weight and standard deviation of 20 tablets was calculated. The batch passes the test for weight variation test if not more than two of the individual tablet weight deviate from the average weight.

5 Vishal et al: Development and Evaluation of optimized Gastroretentive Muscoadhesive Tablets of Famotidine for Compatibility studies The drug-excipients compatibility studies were carried out using Fourier Transform Infrared spectrophotometer (FTIR). Infra-red spectra of pure drug and mixture of drug and excipients were recorded. A base line correction was made using dried potassium bromide and then the spectra of the dried mixture of drug, formulation mixture and potassium bromide were recorded on FTIR. Drug content uniformity 5 Tablets are weighed and powdered, from it average weight equivalent is weighed and added into 100 ml volumetric flask, this powder is dissolved in 0.1N HCl and sonicated for 10 min (Shaikh et al., 2013). From the above solution 1 ml is taken and diluted to 10 ml with 0.1N HCl to get concentration of 20 μg/ ml. Then this solution is analyzed on UV Spectrophotometer using nm wavelengths. Swelling index study For each formulation batch, one tablet was weighed and placed in a beaker containing 200 ml of buffer media (Singh et al., 2010). After each interval the tablet was removed from beaker and weighed again up to 12 hr. The swelling index was calculated using following formula. Swelling Index %(S.I.) = (wt wo)/wo 100 Where, S.I. = Swelling index Wt = Weight of tablet at time t Wo = Weight of tablet before placing in the Beaker. TABLE 4 Pre-compression parameters. Formulations Tapped Density (gm/cm 3 ) Bulk Density (gm/cm 3 ) Carr s Index (%) Hausner s Ratio (%) Angle of Repose (degree) F ± ± ± ± ± 1.10 F ± ± ± ± ± 1.36 F ± ± ± ± ± 1.26 F ± ± ± ± ± 2.77 F ± ± ± ± ± 1.40 F ± ± ± ± ± 0.58 F ± ± ± ± ± 0.99 F ± ± ± ± ± 0.17 F ± ± ± ± ± 2.96 NOTE: The value represents mean ± SD TABLE 5 Post-Compression Parameters. Formulations code Weight Variation (mg) (n=20) Hardness (kg/cm 2 ) (n=5) Thickness (mm) (n=5) Friability (%) Drug Content (%) F ± ± ± % % F ± ± ± % % F ± ± ± % % F ± ± ± % % F ± ± ± % % F ± ± ± % % F ± ± ± % % F ± ± ± % % F ± ± ± % % NOTE: The value represents mean ± SD TABLE 6 Swelling index, % drug release and Ex-vivo mucoadhesive measurement. Formulations code Swelling index (%) Drug release (%) Mucoadhesive strength (gm) Force of Adhesion (N) F F F F F F F F F

6 2960 Int J Pharm Sci Nanotech Vol 8; Issue 3 July September 2015 % Swelling index % swelling index Fig. 6. Swelling index. Time in hours F1 F2 F3 F4 F5 F6 F7 F8 F9 In-vitro release study In vitro release of famotidine from mucoadhesive tablets were determined using USP dissolution apparatus (paddle type, apparatus 2) in 900 ml of 0.1N HCl at constant temperature of 37 ± 0.5 o C at 50 rpm (Paul et al., 2012). Aliquots (5 ml) of the solutions were withdrawn from the dissolution apparatus at different periodic intervals and replaced with fresh dissolution medium to maintain sink condition. Samples thus obtained were filtered through Whattman filter paper. The absorbance of these solutions was measured by using a double beam ultra-violet spectrophotometer at nm. The release data of best selected formulation obtained was fitted to zero order, first order, Higuchi and Korsmeyer-papas equation to determine the corresponding release rate and mechanism of drug release from the mucoadhesive tablets of famotidine. In-vitro bioadhesion study The mucoadhesive properties of the tablets were evaluated by an in vitro bioadhesion testing method known as wash off method. Pieces of stomach mucosa were mounted on the glass slides were connected with suitable support. About 2 tablets attached on the glass slide and the support was hung on the arm of a USP tablet disintegrating machine was given as slow regular up and down movement in the 0.1N HCl at 37 o C. The time of detachment of both the tablets was noted down. TABLE 7 In-vitro bioadhesion study. Formulation code Sr. No. of tablet Detachment time (min) Average (min) F F F F F F F F F Ex-vivo mucoadhesion measurement Mucoadhesive strength of the tablets was measured on the modified physical balance. The apparatus consist of a modified double beam physical balance in which the right pan has been replaced by a glass slide with copper wire and additional weight, to make the right side weight equal with left side pan. A taflone block of 3.8 cm diameter and 2 cm height was fabricated with an upward portion of 2 cm height and 1.5 cm diameter on one side. This was kept in beaker filled with buffer media 0.1N HCl ph 1.2, which was then placed below right side of the balance. Sheep stomach mucosa was used as a model membrane and buffer media 0.1N HCl ph 1.2 was used as moistening fluid. The sheep stomach mucosa was obtained from local slaughter house and kept in a Krebs buffer during transportation. The underlying mucous membrane was separated using surgical blade and wash thoroughly with buffer media 0.1N HCl ph 1.2. It was then tied over the protrusion in the Teflon block using a thread. The block was then kept in glass beaker. The beaker was filled with 0.1N HCl ph 1.2 up to the upper surface of the sheep stomach mucosa to maintain stomach mucosa viability during the experiments. The one side of the tablet was attached to the glass slide of the right arm of the balance and then the beaker was raised slowly until contact between sheep mucosa and

7 Vishal et al: Development and Evaluation of optimized Gastroretentive Muscoadhesive Tablets of Famotidine for mucoadhesive tablet was established. A preload of 10 mg was placed on the slide for 15 min (preload time) to establish adhesion bonding between mucoadhesive tablet and sheep stomach mucosa. The preload and preload time were kept constant for all formulations. After the completion of preload time, preload was removed from the glass slide and water was then added in the plastic bottle in left side arm by peristaltic pump at a constant rate of 100 drops per min. The addition of water was stopped when mucoadhesive tablet was detached from the sheep stomach mucosa. The weight of water required to detach mucoadhesive tablet from stomach mucosa was noted as mucoadhesive strength in grams. Force of adhesion was calculated from this test by using the following formula. Force of adhesion (N) = Mucoadhesive strength Data Analysis article To analyze the mechanism of release and release rate kinetics of the dosage form, the data obtained were fitted into Zero order, First order, Higuchi matrix, Pappas and Hixson Crowell model using PCP-DISSO v3 software. Based on the R-value, the best-fit model was selected (Brahmankar and Jaiswal, 2009; Arvapally et al., 2013). Stability Studies of Optimized Formulation In the present study, stability studies were carried out at 40 o C and 75% RH for a specific time period up to 30 days for selected formulations. For stability study, the tablets were sealed in aluminum packaging coated inside with polyethylene. These sample containers were placed in desiccators maintained at 75% RH (Kendre et.al., 2010). Mucoadhesive strength (gm) Mucoadhesive strength F1 F2 F3 F4 F5 F6 F7 F8 F9 Formulation code Fig. 7. Mucoadhesive strength (gm). Force of Adhesion (N) Adhesion (N) F1 F2 F3 F4 F5 F6 F7 F8 F9 Formulation code Fig. 8. Force of adhesion. Design-Expert Software Factor Coding: Actual mucoadhesive strength (gm/cm2) Design points above predicted value Design points below predicted value X1 = A: carbopol 940 X2 = B: hpmc k 100m mucoadhesive strength (gm/cm2) B: hpmc k 100m (mg) A: carbopol 940 (mg) Fig. 9. A response surface plot showing effect of concentration of independent variables on the Mucoadhesive strength.

8 2962 Int J Pharm Sci Nanotech Vol 8; Issue 3 July September 2015 Design-Expert Software Factor Coding: Actual mucoadhesive strength (gm/cm2) Design Points mucoadhesive strength (gm/cm2) X1 = A: carbopol 940 X2 = B: hpmc k 100m B: hpmc k 100m (mg) A: carbopol 940 (mg) Fig. 10. A counter plot showing relationship between various levels of independent variables to gain fixed value of Mucoadhesive strength. Results and Discussion Standard plot of Famotidine in 0.1N HCl Calibration curve shows the absorbance reading of Famotidine standard solution containing 2 10 μg/ml of drug in Acidic ph 1.2. The maximum wavelength selected is 265 nm. And calibration curve for Famotidine with slope, intercept and regression co-efficient. The calibration curve shows a linear straight line which shows it follows Beer`s law. Compatibility studies Compatibility study were performed using FT-IR spectrophotometer. The FT-IR spectrum of pure drug and physical mixture of drug and different polymers were studied. And it has been observed that there is no chemical interaction between drug and the polymers used. From the Figure, it was observed that there were no changes in these main peaks in FT-IR spectra of mixture of drug and polymers, which shows there were no physical interactions because of some bond formation between drug and polymers. So it was concluded that all the polymers are compatible with drug. Pre-compression parameters Blend of all tablet formulation were subjected for various evaluation such as Angle of repose, Bulk and Tapped density, Compressibility, Hausner s ratio, Carr s index. Result of all Precompression parameters shows good flow characteristics and compressibility index. Post-compression parameters Uniformity of thickness: Thickness of the tablets was measured using calibrated dial calipers by picking tablets randomly from all the batches. Formulation F1 to F9 tablet have thickness in range 3.11 mm to 3.15 mm respectively. Result shows that Tablets showed standard concave surfaces with circular shape. Tablets were white in color and uniformity in thickness. Hardness test: Hardness or crushing strength of all batches was found to be optimum in order to withstand during transportation. From trial 9 batches, F8 shows hardness about 5.8 kg/cm 2 containing Carbopol 940 and HPMC K100M. The optimized formulation F6 shows a relatively good hardness of 6.52 kg/cm 2. Friability test: Friability values of all batches F1 to F9 were found 0.08 to 0.40 %. The obtained results were found to be well within the approved range (<1%) in all the designed formulations. That indicated tablets possess good mechanical strength. Weight variation test: Weight variation or uniformity of content was found to within standard range as per IP. All the tablets of trial and optimized batches passed the weight variation test, i.e., average percentage weight variation was found within the pharmacopoeia limits. Drug Content Uniformity Active drug content of tablets is determined by UV- Visible spectrophotometry. The drug content was found to be from range 97.78% to 99.20%. The drug content uniformity test performed in order to determine the amount of active drug present. The drug content uniformity was examined as per I.P specification. The trial and optimized batches were found to comply with the standards. Swelling index study Swelling index or Water uptake test is performed to determine the swelling ability of tablets. The data obtained optimized batches (F1-F9) is from to respectively. Swelling index or water uptake test was performed to check the swelling property of tablets. Swelling study is carried out for 12 hr performed on trial as well as optimized batches. Swelling index is calculated through a graph of swelling index (%) against the time (hr). The trial study shows that high swelling index was found for F1 batch containing Carbopol 940 with HPMC K4M. The optimized study reveals that formulation F3 (Carbopol 940 and HPMC K100M) exhibits 92.73% swelling index. Thus viscosity of the polymer had major influence on swelling process, matrix integrity as well as adhesion capacity. Results showed that polymers with higher concentration and viscosity had lower swelling index due to fact that polymer concentration and viscosity restricts the movement of polymers.

9 Vishal et al: Development and Evaluation of optimized Gastroretentive Muscoadhesive Tablets of Famotidine for In vitro release study The dissolution study is performed in order to check the drug release from the all batches as per standards. Disso study shows drug release found in range to respectively. Dissolution apparatus USP type II paddle method was used to carry out in-vitro drug release studies on the prepared trial Mucoadhesive tablets with stirring speed of 50 rpm at 37 o C ± 0.5 in 900 ml 0.1N HCl (ph 1.2) for 12 hours. Formulations F1, F2, and F3 with HPMC K4M exhibited 93.14, and 87.25% of drug release in 9, 9 and 11 hours respectively. Formulations F4, F5 and F6 with HPMC K15M exhibited 91.67, and 85.29% of drug release in 10, 11 and 11 hours respectively. Formulations F7, F8 and F9 with HPMC K100M exhibited 94.12, and 88.73% of drug release in 11, 12 and 12 hours respectively. Formulation F1 to F9 contains varying concentration of HPMC grades. As the concentration of HPMC grades increases the release pattern was found to be in a sustained manner. Out of all 9 formulations batch F8 containing HPMC K100M shows maximum drug release in a sustained manner as compared to other HPMC grades i.e., HPMC K4M and K15M. The dissolution of optimized batches also carried out and it shows a better drug release. Formulations F1, F2, and F3 with HPMC K100M exhibited 94.61, and 90.2 of drug release in 12, 12 and 9 hours respectively. Formulations F4, F5 and F6 with HPMC K100M exhibited 88.24, and 98.04% of drug release in 12 hours respectively. Formulations F7, F8 with HPMC K100M exhibited 93.14, of drug release in 12, 10 hours respectively. Formulation F1 to F8 contains varying concentration of HPMC K100M and Carbopol 940. Out of all formulations batch F6 shows maximum drug release. This was considered as best optimized batch. Design-Expert Software Factor Coding: Actual drug release (%) Design points above predicted value Design points below predicted value X1 = A: carbopol 940 X2 = B: hpmc k 100m drug release (%) B: hpmc k 100m (mg) A: carbopol 940 (mg) Fig. 11. A response surface plot showing effect of concentration of independent variables on the % drug release. Design-Expert Software Factor Coding: Actual drug release (%) Design Points drug release (%) X1 = A: carbopol 940 X2 = B: hpmc k 100m B: hpmc k 100m (mg) A: carbopol 940 (mg) Fig. 12. A counter plot of showing relationship between various levels of independent variables to gain fixed value of % drug release.

10 2964 Int J Pharm Sci Nanotech Vol 8; Issue 3 July September 2015 % Drug Released Release Profile Time in hours Actual Zero 1st Matrix Peppas Hix.Crow. Fig. 13. In vitro drug release data analysis of optimized batch F6. TABLE 8 Result of ANOVA. Response model Sum of square Degree of freedom Mean square F value P value R square Ade. precision Mucoadhesive strength % drug release TABLE 9 In vitro Drug release data Analysis of optimized batch F6. Batch Zero order First order Matrix Korsmaver-papas Hixson-crowell F6 R Slope R Slope R Slope R Slope R Slope n k TABLE 10 Stability study of optimized formula F6. Condition Time (month) Hardness (Kg/cm 2 ) Friability (%) Drug content (%) Mucoadhesive strength (gm) Drug release (%) At room temp 25 o C to 30 o C Ex-vivo mucoadhesion measurement Ex vivo mucoadhesion study was performed to determine mucoadhesion strength. The mucoadhesion strength was found in range between 17 gm to 24.2 gm respectively. Whereas mucoadhesive force (N) data is obtained in between to range. Ex vivo mucoadhesion study was performed for trial and optimized tablets on modified analytical balance. The main objective of the test is to determine mucoadhesion strength. The detachment strength of trail batches was found to be in the range of 10 to 18.5 gm, also the optimized batches shows detachment strength about 17 to 24.2 gm suggesting that all the formulations have sufficient bioadhesive strength to remain intact with gastric mucosa for long time to release the drug for longer period of time. The test revealed that as the concentration of Carbopol 940 increases also the mucoadhesive strength increases hence provide good mucoadhesive property. The optimized formulation F6 shows optimum mucoadhesive strength. In vitro bioadhesion study In-vitro bioadhesion study or wash off test was performed. The detachment time was found in range min. In-vitro bioadhesion study or wash off test was performed on trial and optimized batches of Famotidine tablets. The data obtained suggesting that all the formulations have sufficient mucoadhesive strength to remain intact with gastric mucosa for long time to release the drug in a controlled manner. Searching for optimum formulation The targeted response parameter were statistically analyzed by applying one way ANOVA at significant level and the significance of the model was calculated by Design and Expert software. Which given in (Table #08) The individual parameter evaluated by using F test and mathematical relationship was generated between the factor dependent variables and independent variables for determining the level of factor which give optimum mucoadhesive strength and dissolution rate.

11 Vishal et al: Development and Evaluation of optimized Gastroretentive Muscoadhesive Tablets of Famotidine for The model F-value for mucoadhesive strength was found to be and for % drug release 1.75 which imply model is significant. Polynomial equation for mucoadhesive strength is Y = X X X1X X X22 Polynomial equation for % Drug Release is Y = X X2 0.12X1X X X22 The response surface diagram gives knowledge to understand contribution of the variables and their interaction. The response curve map is shown for both variables have effect on the mucoadhesive strength and % drug release. The mucoadhesive strength increases with increase in concentration of Carbopol 940. Data Analysis Dissolution data treatment of optimized formulation To analyze the mechanism of release and release rate kinetics of the dosage form, the data obtained were fitted into Zero order, First order, Higuchi matrix, Pappas and Hixson Crowell model using PCP-DISSO v3 software. Based on the R-value, the best-fit model was selected. The in-vitro dissolution data was fitted to Korsmaver equation, values of exponent n was found to be indicating that the drug release is by non-fickian diffusion mechanism. The in-vitro release data was subjected to goodness of fit test by linear regression analysis according to zero order, first order kinetic equations, higuchi equation, korsmeyer papas and Hixson-crowell models to ascertain the mechanism of drug release. The results of linear regression analysis of data including regression coefficient are summarized in appendix. When the regression coefficient r value of Matrix and korsmeyer papas plots were compared, it was observed that the r values of matrix was found to be whereas the r values of korsmeyer papas plot was found to be indicating drug release from optimized formulation was found to follow Korsmaver papas kinetics. The in-vitro dissolution data was fitted to Korsmaver equation, values of exponent n was found to be indicating that the drug release is by non-fickian diffusion mechanism. Stability studies of optimized formulation Stability study is carried out on optimized batch (F6). The tablet did not show any physical changes during the study period and the drug content was found to be 98.36% and drug release 97.83% for famotidine at the end of 1 month. Conclusions The aim of the study was development and evaluation of optimized gastroretentive mucoadhesive tablet for gastro reflux disorder. The present research work reveals following conclusions Famotidine mucoadhesive tablet were prepared by direct compression technique and found to be good without chipping, capping and sticking. From the above IR study and physical observation it can be conclude that there is no significant Drug-Excipients interaction. So we conclude that drug and other excipients are compatible with each other. Trial and optimized tablets of famotidine were formulated well in terms of hardness, thickness, weight variation, content uniformity. The in-vitro dissolution profiles of all prepared mucoadhesive formulations of Famotidine were found to be stable in GIT and extend the drug release up to 12 hours and release can be extended for longer period over 12 hours by increasing the concentration of polymers. 3 2 full factorial design and Optimization technique successfully used in the development of mucoadhesive formulation of CARBOPOL 940 and HPMC K100M. Optimization Famotidine tablets carried out by CARBOPOL 940 and HPMC K100M in the ratio of +1:-1 give successful result in terms of mucoadhesive strength and Cumulative % drug release. Optimized formulation F6 tablet containing CARBOPOL 940 and HPMC K100M shows 98.04% drug release in 12 hr. And shows sustained release pattern. On the basis of mucoadhesive strength studies formulation F4 shows maximum mucoadhesive strength 24.2 gm but it release only % drug in 12 hr. so it fail to achieve maximum drug release. But formulation F6 shows gm mucoadhesive strength and % drug release in 12 hr which is selected as an optimized batch. References Arvapally S., Kumar A. B., Dr. Rao V.U., Kiran S., Supraja S (2013). Formulation and evaluation of floating bioadhesive tablets of Ciprofloxacin HCl using natural polymers. Int. J. Advances in Pharma. Sci. 4(4): Brahmankar D. and Jaiswal S (2009). Biopharmaceutics and Pharmacokinetics A Treatise. 1st edition. Vallabh Prakashan. New Delhi Chatwal G.R and Sham K. A (2007). Instrumental methods of chemical analysis. 5th revised edition. Himalaya publishing house Dr. Baviskar D.T and Dr. Jain D.K (2012). Novel drug delivery systems.1 st edition, Nirali Prakashan Gudigennavar A. S., Vijapur L.S., Patil C.C. and Kulkarni R.V (2013). Development and evaluation of gastro-retentive drug delivery systems of cefuroxime axetil. African J. Pharm. Pharmacology. 7(20): Indian Pharmacopoeia (2007). Government of Indian Ministry of Health and Welfare. Delhi. 1: Jain M., Sharma N., Khinchi M.P., Agrawal D (2013). A Review On Mucoadhesive Tablets As Controlled Drug Delivery System. Asian J. Pharm. Res & Development. 1(1):

12 2966 Int J Pharm Sci Nanotech Vol 8; Issue 3 July September 2015 Kendre P.N., Lateef S.N., Godge R.K., Chaudhari P.D., Fernandes S. L. and Vibhute S.K (2010). Oral Sustained Delivery of Theophylline Floating Matrix Tablets- Formulation and In-vitro Evaluation. Int. J. Pharm. Tech. Res. 2(1): Kshirsagar S.J., Wadekar S.B., Bhalekar M.R., Ughade P.B. and Madgulkar A.R (2011). Gastroretentive drug delivery system of hydrochlorothiazide: formulation, optimization and in vivo evaluation. Asian J. Pharma. Sci. 6(3-4): Kumar S., Jamil F., Rajput M. and Sharma S (2012).Gastro Retentive Drug Delivery System: Features and Fact. Int. J. Res Pharm & Biomedical Sci. 3(1): Lachman L, Liberman H.A. and Kranig J.L (1987). The Theory and Practice of Industrial pharmacy. 3rd edition. Mumbai, Varghese publishing house Lambert J.B (1987). Introduction to Organic Spectroscopy. Macmillan publication. New York.1-6. Mantry S, Patnaik A, Satish S.M. and Mishra S (2012). Formulation and evaluation of gastroretentive floating bioadhesive tablet of Tinidazole. Int. J. Pharma. Industrial Res. 2(4): Masih D (2012). Development and Evaluation of Floating Dosage Form Containing Atenolol. Int. J. Pharma. Innov. 2(5): Paul Y., Kumar S. and Sehrawat R (2012). Design, Development and Characterization of Mucoadhesive Tablets of Atenolol. Int. J. Pharma. Bio. Sci. 3(1): Rathee P., Jain M., Rathee S., Nanda A. and Hooda A (2012). Gastroretentive Drug Delivery Systems: A Review of Formulation Approaches. The Pharma Inno. J. 1(8): Shaikh DM., Shende M.A and Shaikh A.M (2013). Formulation Development and Evaluation of Gastro Retentive Mucoadhesive Tablets Using Synthetic Polymers. Int. J. Res Pharm Biomedical Sci. 4(4): Sharma Y.R (2009). Elementary organic Spectroscopy. 4th edition, published by S. Chand Singh S.K., Bothara S.B., Singh S., Patel R. and Dodia R (2010). Formulation and evaluation of mucoadhesive tablet: Influence of some hydrophilic polymer on the release rate and in vitro evaluation. Int. J. Pharma. Sci. Nanotech. 3(3): Subrahmanyam C.V.S (2010). Textbook of Physical pharmaceutics. 2nd edition, published by Vallabh Prakashan, Delhi Tripathi KD (2010). Essential of Medical Pharmacology. Sixth edition, Jaypee brother s medical publishers Address correspondence to: Suryavanshi Vishal, Department of Pharmaceutics, Ali Allana College of Pharmacy Akkalkuwa, District Nandurbar, Maharashtra, India. Mob: ; suryawanshiv10@gmail.com