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Indo American Journal of Pharmaceutical Research, 2015 ISSN NO: 2231-6876 FORMULATION AND EVALUATION OF BILAYER TABLET OF FAMOTIDINE WITH ANTACID LAYER Kamal Kumar Bhatt*, shivani kala, Divya juyal Himalayan Institute of Pharmacy & Research Rajawala, Dehradun (Uttarakhand). ARTICLE INFO Article history Received 05/09/2015 Available online 30/09/2015 Keywords Bilayer Tablet, Famotidine, Antacid, HPMC K100M, HPMC K4M. ABSTRACT In the present study bilayer tablet of famotidine with antacids (aluminium hydroxide and magnesium hydroxide) layer are prepared. The inner sustained release layer of famotidine consist controlee release polymer HPMC K4 M and HPMK100M at different concentration .and the combination of citric acid ,tartaric acid and sodium bi carbonate used as a effervescent for outer immediate release layer of antacid .The inner layer of famotidine shows the sustained release effect up to 9 hrs. And the immediate release layer of antacids shows rapid dispersion time between 8-12 seconds. The prepared tablets were evaluated for their post compression parameters, physical characteristics and in-vitro release study. The drug content of famotidine was found between the ranges of 98.25-99.30. The Cumulative percent drug release of optimized formulation (FB5) after 10 hours were found to be 98.03 %. Fitting the in-vitro drug release data in to krosmeyer-peppas model the n value found to be approx 1 that shows that all the six formulations followed the mechanism of diffusion. FB5 0 0 formulations were selected for stability studies stored at 30 C±2 C, 65 ± 5% RH and subjected to stability studies up to 90 days. Drug content and cumulative percent drug release after stored formulation for 45 days of optimized formulation FB5 were found to be 98.90. The % similarity of cumulative percent drug release before and after was found to be 87%. It showed that the formulations are physically and chemically stable. Copy right © 2015 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. www.iajpr.com Page Please cite this article in press as Kamal Kumar Bhatt et al. Formulation And Evaluation of Bilayer Tablet of Famotidine With Antacid Layer. Indo American Journal of Pharmaceutical Research.2015:5(09). 2982 Corresponding author Kamal Kumar Bhatt Himalayan Institute of Pharmacy & Research Rajawala, Dehradun (Uttarakhand). kamal [email protected] Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 INTRODUCTION Famotidine is an oral drug that blocks the production of acid by acid producing cells present in the stomach. Famotidine promote the healing of stomach and prevent ulcer when given at low dose for long period. For the quick relief to peptic ulcer pain and to promoting the healing of peptic ulcer antacids are prescribed for the treatment of gastric ulcer. The oral treatment of gastric disorders with an H2 receptor antagonist such as Famotidine with combination of antacids promotes local delivery of these drugs to the receptor of parietal cell wall. Therefore, in this investigation attempt has been made to prepare S.R. tablet of Famotidine, so that tablets are retained in the stomach for a longer period and local delivery of drug increases due to the contact of drug with its absorption site at a constant rate for extend period of time and thus the bioavailability of the drug also increased . and also increases the efficacy of drugs to reduce gastric acid secretion. Hence, this principle may improve systemic as well as local delivery of Famotidine. H2 receptor antagonist used for the treatment of peptic ulcer or used in case of too much acid production in the stomach by the approach of bi layer technique of Famotidine and antacid. the immediate layer of antacid neutralize the excessive acid present in the stomach and then the sustained layer of Famotidine release and Famotidine bind with the H2 receptor located in the Basolateral membrane of parietal cells and block the effect of histamine that control the excessive acid production in the stomach BILAYER TECHNOLOGY In last two decade the interest in layer technology of tablet increase because of the one or more active ingredient in a single dose provides better treatment of disease and it provide control release of drug and improve the effect of therapy. Biayer tablet is the new area for control release formulations. Bilayer tablet suitable for the sustained effect of tablet in which one layer is immediate release and second is maintained dose. By the use of bilayer technology the drug re-administration or plasma fluctuation also be minimized. Bilayer tablet is helpful design that reduce problem which are associated with the single layered tablet. Bilayer tablets provide one of the important approaches where incompatible drugs, with different indication, and same drug with different release rate can be added in a single unit. Bilayer tablet is suitable for sequential release of two drugs in combination, that individualized two antipathetic substances or ingredient and also for sustained release tablet in which one layer is immediate release as starting dose and next layer is maintenance dose. Many different types of compression are used to formulate bilayer tablets, like as simple single-sided press to highly sophisticated equipment such as the courtoy-R292F [1] Advantages of bilayer tablet • Reduce cost of drug • Minimizing dose dumping • Suitable for large scale production • Taste masking technique of bitter drugs or substance • Separate physically or chemically incompatible ingredients [2,3] Disadvantage of bilayer tablet Drug have bitter taste and objectionable odour or sensitive with oxygen require encapsulation or coating In case of children difficult to swallow and unconcision patient Drug have poor solubility, slow dissolution high absorption in GIT may be difficult to formulate. Insufficient hardness. The possibility of cross contamination between two layers [4,5] MATERIAL & METHODS MATERIAL USED: Materials that are used in the formulation of bilayer tablet are purchased from various vendors or suppliers are listed below. NAME Famotidine Aluminium hydroxide Magnesium hydroxide Citric acid Magnesium stearate Aerosil Maize starch Methocel k4m Methocel k 100m Calcium hydrogen phosphate Mannitol Microcrystalline cellulose ph101 Tartaric acid Sodium bi carbonate CATEGORY Active Antacid Antacid Effervescent Lubricant Glidant Binder Polymer Polymer Lubrication Diluent Filler Effervescent Effervescent www.iajpr.com VENDOR/SUPPLIER Rakshit drug pvt.ltd. Central drug house, Delhi Central drug house, Delhi Signet Chemical Corp. Pvt. Ltd Nikita pharmaceutical Evanik industries Mulji motha & sons Pvt. Ltd. Colorcon Pvt. Limited Colorcon Pvt. Limited Canton laboratories M/S Roquette frères DFE pharm India Signet Chemical Corp. Pvt. Ltd Central drug house, Delhi Page S.N. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 2983 Table 1 list of material used in formulation of double layer tablet. Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 PREPARATION OF BILAYER TABLET Preparation of Granules of Immediate release Outer Layer (Antacid) The ingredient listed in table.2 was weight accurately and passed through the sieve no 60. Aluminium hydroxide, magnesium hydroxide, maize starch, citric acid and sodium bi carbonate were mixed homogeneously; aerosil and magnesium stearate was added as a lubricant. Preparation of Granules of Inner Layer Wet granulation method: - Granules were prepared by using wet granulation technique. Microcrystalline cellulose, maize starch, Hydroxypropyl methylcellulose and the active ingredients were mixed homogeneously. Water (quantity sufficient) was used as a granulating agent. The granules were dried in fluid bed dryer. The dried granules were sieved through 40/60 meshes. Magnesium stearate, colloidal anhydrous silica was added as a lubricant and the granules were compressed in to 65 station tablet punching machine. Compression of both layers to form bilayer tablet The granules of inner layer were weight accurately and introduced in to the die size 12.8manually with the help of spatula. The granules were allowed to punch and collected separately. Now the granules of outer layer were weight separately and allowed to introduce in to die size 12.8, previously punched inner layer was also introduced in to the die cavity and allowed to punch PREFORMULATION STUDIES: Preformulation is the first step in the rational formulation of an active pharmaceutical ingredient (API). It is an investigation of the physical-chemical properties of the drug substance, alone and in combination with excipients. Assessment of possible incompatibilities between the drug and different excipients is an important part of preformulation. Identification test: The drug sample was authenticated using FT-IR and Melting Point test apparatus. Organoleptic characteristics of the drug was observed and recorded by using descriptive terminology. a. Physical Appearance: b. Solubility c. Melting Point test d. FT- IR Characterization e. Determination of analytical wavelength f. Drug- excipient Compatibility study Physical appearance Physical appearance of drug was examined by organoleptic properties, colour, odour, taste, state. [6,7] Solubility Small amount of the drug was mixed with solvent in screw capped glass tube. The solution was examined physically for the absence or presence of drug particles. [6] Melting Point test Melting point of Famotidine was determined by using digital auto melting point apparatus. A capillary fused at one end was taken and a small quantity of famotidine was pushed in through the free end of capillary. The capillary was then placed in the well provided space in digital melting point apparatus. The temperature at which the drug started to melt was noted. [6-8] Determination of analytical wavelength: Determination of λ max and Preparation of Standard Curve Page Standard solution: The stock solution was diluted subsequently with 0.1N HCl to get a series of dilutions containing 2, 4, 6, 8 and 10 mg/ml. One single dilution was selected and scanned in the wavelength range 200- 400 nm to get the UV spectrum and record the characteristic peak, λmax. All other dilutions were then analyzed at that particular λmax to determine their absorbance for the preparation of calibration curve of famotidine in 0.1 N HCl. Linearity, accuracy and precision were determined [9] 2984 Stock solution: 100 mg of famotidine was dissolved in sufficient amount of 0.1N HCl in a 100 ml volumetric flask and the solution was made up to the mark with 0.1N HCl. www.iajpr.com Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 FT- IR Characterization The IR spectrum of drug was recorded using Fourier Transform Infra-Red Spectrophotometer (FT-IR) instrument. Nearly 1 mg of sample was thoroughly mixed with 100 mg of finely powdered KBr. The diffuse reflectance spectrum was recorded which is similar to the transmittance spectra. [9,10]. Drug- excipient Compatibility study The study of drug–excipients compatibility represents an important phase in the preformulation stage for the development of all dosage forms. In fact, potential physical and chemical interactions between drugs and excipients can affect the chemical nature, stability and bioavailability of drugs and, consequently, their therapeutic efficacy and safety. The ratio of drug to excipients used in the study is often left to the discretion of the formulator, although some authors recommend the ratio encountered in the final formulation. Often a 1:1 ratio is used to maximize the likelihood of interaction taking place and thus help in easier detection of incompatibilities (El- Shattawy, 1984). Hence 1:1 ratio was selected in this study. The study was conducted in order to ensure that the list of excipients used in the formulation does not cause any potential stability or compatibility problem. [10]. FORMULA FOR THE FORMULATION OF INNER LAYER TABLET Table 2 List of ingredient required for formulation of famotidine S.R. tablet. S.N. 1 2 3 4 5 6 7 8 INGRIDIENT Famotidine Microcrystalline cellulose Starch Methocel k4m Methocel k 100m Calcium hydrogen phosphate Magnesium stearate Aerosol TOTAL F1 40 120 20 10 5 3 2 200 FORMULATION F2 F3 F4 F5 40 40 40 40 110 100 120 110 20 20 20 20 20 30 10 20 5 5 5 5 3 3 3 3 2 2 2 2 200 200 200 200 F6 40 100 20 30 5 3 2 200 FORMULA FOR THE FORMULATION OF OUTER LAYER TABLET Table 3 List of ingredient required for formulation of antacid tablet. S.N. 1 2 3 4 5 6 7 INGRIDIENT Aluminium hydroxide Magnesium hydroxide Magnesium stearate Tartaric acid Citric acid Maize starch Aerosil Sodium bi carbonate TOTAL QUANTITY (mg) 357 340 16.600 7.5 7.5 63.520 27.88 10 830 Angle of repose The angle of repose of the powdered blend was determined by the funnel method. The accurately weight granules were taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the heap of the granules. The granules were allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured using the following equitation. Ø = tan-1 (h/r) www.iajpr.com Page Flow Properties – For the determination of frictional force, bulk density, tapped density, Measures of Powder Compressibility (cars index or Hauser’s Ratio) or measurement of flow ability the Preformulation Parameters are needed before formulation. 2985 PRE-COMPRESSION PROPERTIESMost of the formulation include one or more combination of chemicals that are effect the preformulation parameters of main active ingredient that are needed for compression. That’s why the precompression parameters evaluation is needed before final compression according to the standard procedure. Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 Table 4 shown the value of Ø equal their flow property. Angle of repose(Ѳ) <25 25-30 30-40 >40 Where, h and r are the height and radius of the powder pile respectively. Flow Excellent Good Passable Very poor Bulk density Both loose bulk density (LBD) and tapped density were determined, A quantity of the powder from each formula, previously lightly shaken to break any agglomerates formed, was introduced into a 10 ml measuring cylinder, After the initial volume was absorbed, the cylinder was allowed to fall under its one weight onto a hard surface. From the height of the 2.5 cm. LBD and TBD were calculated using the following formulas. LBD = weight of powder / volume of the packing. TBD = weight of powder / tapped volume of the packing. Compressibility index The compressibility of the powdered blend was determined by Carr’s compressibility index. Carr’s index (%) = (TBD - LBD) / TBD × 100 Table 5 Carr’s index Value (as per USP). Carr’s index 5 – 15 12 – 16 18 – 21 2 – 35 33 – 38 >40 Properties Excellent Good Fair to Passable Poor Very Poor Very Very Poor Hausner’s Ratio The hausner’s ratio of the powder blend was determined by following formula. HR = TBD / LBD POST COMPRESSION PROPERTIESFor ensuring the tablet strength or uniformity in weight, uniformity in thickness of the tablet or various parameters such as drug dissolution rate and amount of drug present in a single tablet (drug content) or dispersion time of tablet ,swelling property the post compression parameters evaluation are require and their procedure and equipment used in evaluation are given below. Hardness 2 The strength of tablet is expressed as tensile strength (Kg/cm ). The tablet crushing load, which is the force required to break a tablet into pieces by compression. It was measured using a tablet hardness tester (Monsanto hardness tester). Page Where, w0 is the weight of the tablets before the test and w is the weight of the tablets after the test. 2986 Friability The friability of the tablets was determined using Roche friabilater. This device subjects the tablets to the combined effect of absorption and shocks in a plastic chamber revolving at a height at 6 inches in each revolution. Pre-weighted sample of taste was placed in the friabilater and were subjected to 100 revolutions. Tablets were degusted using a soft muslin cloth and reweighted. The friability (F) is gives by the formula. F = (1-w0/w) × 100 www.iajpr.com Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 Weight Variation Test Randomly selected 20 tablets were weighed individually and together in a single pan balance. The average weight was noted and standard deviation was calculated. IP limit for weight variation in case of tablets weighting up to 120 mg is ± 10%, 120 mg to 300 mg is ± 7.5% and more than 300 mg is ± 5%. PD= (W ) – (W avg ) / (W initial avg ) x 100 Where PD= Percentage deviation, W = Average weight of tablet, avg W initial = Individual weight of tablet. Table 6 shown the average weight of tablet and acceptable range. Average Weight Of A Tablet 80 mg or less More than 80 mg and less than 250 mg 250 mg or more Percentage Deviation 10 7.5 5 Swelling Index The swelling of tablet involves the absorption of a liquid resulting in an increase in weight and volume. Liquid uptake by the polymers results to saturation of capillary spaces within the polymer chain or hydration of macromolecule. To determine the extent of matrix swelling, three tablets from each batch were weighed and placed in a Petri-dish containing 25 ml of 0.1N hydrochloric acid. After each 2 hrs interval the tablets were removed from media, excess of media was wiped off by using filter paper and weighed again up to 12 hrs. The swelling index was calculated using following formula. [11,12]. Swelling index= Final weight – initial weight/ Final weight x 100 Drug content Ten randomly selected tablets were weight and average weight was calculated, then tablet were crushed then 10mg weight and dissolve in 10ml of 0.1NHCL with the help of magnetic stirrer. This was the stock solution from which 1ml sample was withdrawn and diluted to 10ml methanol. The content of each formulation was determined spectrophotometrically at 265 nm. [9] In-vitro Dispersion Time The USP device to test Dispersion uses 6 glass tubes that are 3 inches long open at top held against a 10 mesh screen at the bottom end of the basket rack assembly. The tablets remain 2.5 cm below the surface of the liquid on their upward movement and descend not closure than 2.5 cm from bottom of beaker. Tablet was placed in each of six tubes of the basket and apparatus was operated at 28 to 32 cycles per minute. The temperature was maintained at 37 0 C ±20 C .The disintegration time was noted. In- vitro Dissolution Study The drug release studies were carried out using USP dissolution test apparatus at 100 rpm, 37 0 C ±0.50 C in 0.1 N HCL for 810 hrs. At different time interval 5 ml of sample were withdrawn and replaced with 5 ml of drug free dissolution medium. The sample withdrawn were analyzed by UV spectrophotometer. Sample was analyses at 265 nm using UV-VIS spectrophotometry. [9] www.iajpr.com Page ZERO ORDER MODELS: Drug dissolution from dosage form that do not disaggregate and release the drug slowly can be represented by the equation: Q0 –Qt =K0t Rearrangement of the equation yields: Qt=Q0+K0t Where Qt is the amount of drug dissolved in time t Q0 is the initial amount of drug in the solution K0 is the zero order release constant expressed in units of concentration/time. 2987 KINETIC RELEASE (MATHEMATICAL MODELLING) The data obtained from in-vitro release studies was treated by various conventional mathematical models (zero-order, firstorder, higuchi and korsmeyer-peppas) to determine the release mechanism from the designed double layer formulation. Selection of a suitable release model was based on the values of R (correlation coefficient), k (release constant) and n (diffusion exponent) obtained from the curve fitting of release data. Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 FIRST ORDER MODEL: This model has been used to describe absorption and elimination of some drugs, although it is difficult to conceptualize this mechanism on a theoretical basis. This release of the drug which followed first order kinetics can be expressed by the equation: LogC=logC0-Kt/2.303 Where, C0 is the initial concentration of drug. K is the first order rate constant, and t is the time. The data obtained are plotted as log cumulative percentage of drug remaining vs. time which would be straight line with a slope of – K/2.303. KORSMEYER-PEPPAS MODEL Korsmeyer derived a simple relationship which described drug release from a polymeric system equation to find out the mechanism of drug release, first 60% drug release data were fitted in korsmeyer-peppas model. Mt/M∞ =Ktn Where, Mt/M ∞ is a fraction of drug released at time t, K is the release rate constant and n is the release exponent. Then n value is used to characterize the release mechanism of drug. Table 7 Diffusion exponent and mechanism of diffusional Release from Swellable controlled-release System[13]. Slab 0.5 >0.5-<1.0 1.0 >1.0 >>1.0 Cylinder 0.45 >0.45-<0.89 0.89 >0.89 >1.0 Sphere 0.43 >0.43-<0.85 0.85 >0.85 >1.0 Drug release Mechanism Fickian diffusion Non Fickian Zero-order release Case II transport Super Case II transport STABILITY STUDIES The stability studies were conducted for satisfactory formulation for 3 month. The satisfactory formulation sealed in aluminium packaging and stored at 30±2°C with 65±5% RH for 3months.Samples were analyzed for physical parameters and drug content. RESULTS RESULT OF PREFORMULATION STUDIES Result of Physical appearance Table 8 Physical appearance of famotidine. Description Colour Odour Taste State 1 2 3 4 5 A white to pale yellowish white crystalline powder White powder Odourless Bitter Fine powder RESULT OF SOLUBILITY STUDIES SOLVENT Distilled water 0.1N HCL Methanol Mineral acid Glacial acetic acid &Diamethyl Formamide Ethanol OBSERVED SOLUBILITY Very slightly soluble Slightly soluble Slightly soluble Slightly soluble Freely soluble Insoluble Page S.N. 1 2 3 4 5 6 2988 Table 9 solubility study of Famotidine. www.iajpr.com Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 RESULT OF MELTING POINT DETERMINATION Table 10 Melting point determination of famotidine. SAMPLE NO. 1 2 3 MELTING POINT (0C) 161-162 161-162 161-162 AVERAGE MELTING POINT(0C) 161.5 DETERMINATION OF ANALYTICAL WAVELENGTH Determination of absorption maximum (λ ) in 0.1NHCL: max For determination of absorption, stock solution of 10ug/ml was prepared. The solution was scanned in the range of 200-400 nm in UV/visible spectroscopy. The λmax was found to be at 265nm. Figure 1 Standard curve of famotidine. RESULT OF IDENTIFICATION OF DRUG (FAMOTIDINE) THROUGH FTIR Figure 2: FTIR scanning of famotidine. 1 2 3 4 WAVE NUMBER(cm-1) 1800-1600 1600-1400 1200-1000 1000-800 PEAK (REFERENCE) 1639 1601,1533 1146,1321 904 www.iajpr.com PEAK (SAMPLE) 1638.23 1601.59,1534.1 1146,1321 903.487 Page S.NO 2989 Table 11 FTIR Spectra Range of Standard and Sample of Famotidine. Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 The drug sample as identified with FTIR spectroscopy and studies against standard famotidine. The peak of the sample was identical as compare to standard and there was no major difference observed in absorbance peaks which shows the sample is pure and free from impurities. RESULT OF COMPATIBILITY STUDIES: Figure 3 FT-IR spectrum of famotidine with polymers. Table 12 FTIR spectrum of famotidine with polymer (HPMC K4M+HPMCK100M). S.NO 1 2 3 4 WAVE NUMBER(cm-1) 1800-1600 1600-1400 1200-1000 1000-800 PEAK(REFERENCE) 1639 1601,1533 1146,1321 904 PEAK (FAMOTIDINE+HPMCK4M+K100M) 1638.23 1601.59,1534.1 1146,1321 903.487 Figure 4 FT-IR spectrum of famotidine with mixture of excipient. WAVE NUMBER (cm-1) 1 2 3 4 1800-1600 1600-1400 1200-1000 1000-800 PEAK (REFERENCE) 1639 1601,1533 1146,1321 904 PEAK (FAMOTIDINE+MIXTURE OF EXCIPIENTS) 1634 1601.59,1534.1 1146,1321 901.97 Page S.N. 2990 Table 13 FTIR spectrum of famotidine with mixture of Excipients. www.iajpr.com Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 RESULT OF EVALUATION OF PRECOMPRESSION STUDIES FLOW PROPRTIES: Table 14 flow properties of granules of inner layer. S.N. 1 2 3 4 5 6 Formulation Code F1 F2 F3 F4 F5 F6 Bulk Density Tapped Density 0.60 0.58 0.60 0.57 0.56 0.61 0.72 0.71 0.72 0.68 0.66 0.71 Carr’s Index 16.66 18.42 16.66 16.17 15.15 14.08 Hausner’s Ratio 1.20 1.22 1.20 1.19 1.17 1.16 Angle Of Repose 23.60 22.90 23.58 24.20 22.50 24 Table 15 Flow properties of granules of outer layer. S.N. 7 Formulation Code F7 Bulk Density Tapped Density 0.75 0.82 Carr’s Index 8.53 Hauser’s Ratio 1.09 Angle Of Repose 28.20 RESULT OF EVALUATION OF POST COMPRESSION PARAMETER There are 6 formulation of double layer tablet which are prepared and they are evaluated for precompression and post compression studies. Table 16 Post compression parameters of inner core tablet. S.N. 1 2 3 4 5 6 Formulation Code F1 F2 F3 F4 F5 F6 Uniformity of Weight (mg) 201 200 202 204 201 199 Thickness (mm) 3.41 3.42 3.37 3.40 3.35 3.42 Hardness (kg/cm2) 5.40 5.42 5.40 5.38 5.33 5.42 %Friability 0.59 0.50 0.56 0.54 0.49 0.62 Table 17 post compression parameter of bilayer (both inner or outer layer or complete) tablet. S.N. 1 2 3 4 5 6 Formulation Code FB1 FB2 FB3 FB4 FB5 FB6 Uniformity of Weight (mg) 1031 1029 1031 1028 1031 1032 Hardness (kg/cm2) 3.46 3.45 3.42 3.50 3.52 3.55 %Friability 0.61 0.62 0.63 0.60 0.59 0.61 Thickness (mm) 12.6 12.6 12.6 12.6 12.5 12.5 SWELLING INDEX OF INNER LAYER 1 2 3 4 5 6 7 8 9 F1 10.6 17.2 26 34.8 40.2 48.5 56 61.2 - F2 16.8 25.7 34.6 42.6 49.8 53.2 59.6 65.7 69.3 F3 19.3 32.7 41.7 42.8 53.9 62.8 70.8 77 83 Formulation code F4 F5 F6 12.7 18.7 23.2 18.6 28 35.6 30.8 38.1 44.5 39.2 45.9 48.9 44 49.7 56.5 51.6 54.5 63.8 58 61 71 63.8 65 80.5 70.2 86.2 www.iajpr.com Page Time in hrs 2991 Tablet 18 swelling index of inner core of tablet. Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 Figure 5 swelling index of inner layer. DISPERSION TIME Table 19 dispersion time of outer layer. S.N. 1 2 3 4 5 6 Formulation Code FB1 FB2 FB3 FB4 FB5 FB6 Dispersion Time(Sec.) Outer layer 10 9 11 10 8 12 Figure 6 dispersion time of inner layer. RESULT OF DRUG CONTENT Formulation code FB1 FB2 FB3 FB4 FB5 FB6 Drug content Inner layer 98.65 98.55 99.30 98.76 99.25 98.99 www.iajpr.com Page S.N. 1 2 3 4 5 6 2992 Table 20 drug content of inner layer. Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 RESULT OF IN –VITRO DISSOLUTION STUDIES Table 21 In –Vitro Dissolution Studies of Famotidine. Time in hours 1 2 3 4 5 6 7 8 9 10 F1 16.09 28.72 43.78 56.23 69.04 80.24 88.71 95.22 97.17 _ F2 11.88 25.50 41.96 53.55 64.10 75.03 82.33 90.27 95.97 97.30 % Release F3 F4 10.15 15.30 23.21 26.09 36.62 38.71 48.99 54.20 61.49 68.00 73.21 79.59 79.98 90.79 89.36 94.17 94.57 96.26 96.91 _ F5 10.69 23.47 36.75 49.64 60.19 73.34 85.45 91.83 95.61 98.08 F6 9.75 22.95 36.88 47.04 62.53 69.83 83.89 88.71 92.61 96.52 Figure 7 Cumulative % drug release of inner layer (famotidine). RESULTS OF STABILITY STUDIES The optimized formulation (batch F5) stored at 40 ± 2°C/75 ± 5% was found stable. After storage at 40 ± 2°C/75 ± 5%, cumulative percentage drug release, and % drug content were nearly similar to the initial results. So, it was clear that the drug and the formulation were thermally stable as well as not affected by the high humidity at 40 ± 2°C/75 ± 5%. The similarity factor of the batch after the stability study was found to be 87%when compared with the initial drug release profile. The comparative dissolution profile of batch FB5 after stability study is shown table 1.17. Table 22 stability studies of formulation FB5. Duration of period Three month Friability Drug content 98.90 0.60 Dispersion time(sec.) 11 Thickness 12 Table 23 Dissolution profile of formulation FB5 after three months. 1 10.52 2 22.48 3 34.40 4 50 5 58.16 6 71.16 7 82.91 8 92.1 9 97.16 10 - 2993 Time in hours FB5% Release Page Formulation code FB5 www.iajpr.com Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 Figure 8 compression of cumulative % release profile of formulation FB5 after or before 3 month. DISCUSSION The Bilayer Tablet was formulated by using Famotidine as Inner Layer and Antacid combination (Aluminium Hydroxide & Magnesium hydroxide) as outer layer. There are 6 formulation are formulated and evaluated. Preformulation studies Solubility-famotidine was Slightly soluble in 0.1N HCL and Methanaol and freely soluble in glacial acetic acid and insoluble in ethanol Melting point-the melting point range of famotidine between 161-162. Identification of drug through FTIR-The drug sample as identified with FTIR spectroscopy and studies against standard famotidine. The peak of the sample was identical as compare to standard and there was no major difference observed in absorbance peaks which shows the sample is pure and free from impurities. Compatability studies-The drug polymer compatibility studies are preformed with the help of FTIR spectrometry and there was no major difference was show. Thus the polymers were compatible with drug. Friability studiesThe % friability of bilayer tablet was found between 0.49-0.62. Dispersion studiesThe dispersion time of outer layer of antacid was performed in 0.1N HCL.The time range between 8-12 sec. (0.8-0.12 min.) that indicates the rapid dispersion time of outer layer. Drug contentThe drug content of famotidine was found to be in range between 98.25 - 99.30 %. In vitro drug release studiesIn the drug release studies of famotidine it was observed that increasing the amount of polymer decrease the drug release and observed stability in drug release. Page 2994 Model Fitting of drug Release-the drug release profile of bilayer tablet of famotidine (inner layer) in 0.1 N HCL R2 value of zero order for inner layer found to be 0.974. to 0.999. R2 value of first order for inner layer found to be 0.951 to 0.979. R2 value of Higuchi release for inner layer found to be 0.901 to 0.933. n value of Korsmeyer Peppas for inner layer found to be 0.993 to 1.175. The n value of korsmeyer-peppas near about 1 and that’s indicates the drug release mechanism of the diffusion through swellable matrix follows case II trsnsfer or super Case II transfer. www.iajpr.com Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 Stability studies – The best formulation FB5 was taken for stability studies to see the effect of temperature and humidity in the formulation for 3 month. The stability result are satisfactory the % drug content were nearly similar to the initial results and The% similarity factor of the batch FB5 after the stability study was found to be 87%when compared with the initial drug release profile. And there are no difference is seen in drug physical appearance colour, size or shape. So, it was clear that the drug and the formulation were thermally stable as well as not effected by the high humidity at 40 ± 2°C/75 ± 5%. In the double layer tablet the outer layer is composed by antacid and inner layer contain famotidine the outer layer formulation contain effervescent combination of sodium bi carbonate, citric acid and tartaric acid that release the outer layer as a faster rate and inner layer contain sustained release polymer .so it was necessary that the dispersion time of outer layer are rapid and then the inner layer show sustained release effect. CONCLUSION In the present study the bi layer tablet of Famotidine with antacid were designed, prepared and evaluated. The aim of the study was to reduce and control of excessive acid production by the acid producing cells present in the stomach. Excessive acid in the stomach cause various disease such as erosive esophagitis, gastric ulcer, zollinger-Ellison-syndrome, duodenal ulcer .Famotidine is a H2 receptor antagonist used for the treatment of peptic ulcer or used in case of too much acid production in the stomach. By the approach of bi layer tablet of Famotidine and antacid that control the excessive acid production in the stomach Famotidine bind with the H2 receptor located in the basolateral membrane of parietal cells and block the effect of histamine .and the immediate layer of antacid neutralize the excessive acid present in the stomach or give immediate relief from acidity. Page 2995 ACKNOWLEDGEMENT Author is thankful to Sharon Bio Medicine Ltd. Dehradun for providing all the facilities related for this research Project. www.iajpr.com Vol 5, Issue 09, 2015. Kamal Kumar Bhatt et al. ISSN NO: 2231-6876 REFERENCES 1. Barthwal Priyamvada and Kothiyal Preeti, Bilayer: A review international journal of pharmaceutical and chemical sciences Dec 2013, 1788-1797. 2. Singh KP and Kumar S. Bilayer and Floating Bioadhesive Tablets: Innovative Approach to Gastro retention. Journal of Drug Delivery and Therapeutics. 2011,32-35. 3. Kulkarni A. and Bhatia M. 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