71 P a g e International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 2(6): November-December 213 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89*** ICV 3.*** Pharmaceutical Sciences RESEARCH ARTICLE!!! FORMULATION DEVELOPMENT AND EVALUAVATION OF AMOXICILLIN TRIHYDRATE AND POTASSIUM CLAVULANATE IMMEDIATE RELEASE TABLETS A.NAVEL KISHORE SINGH *, M. SEKAR, V. VISWANATH, HUSSAN REZA DEPARTMENT OF PHARMACEUTICS, SANTHIRAM COLLEGE OF PHARMACY, KEYWORDS: Amoxicillin, Potassium Clavulante, Sodium starch glycolate, Crosspovidone, HPC, PVP K-3, Immediate release Tablets. For Correspondence: A.NAVEL KISHORE SINGH* Address: Department Of Pharmaceutics, Santhiram College Of Pharmacy, Nandyal. Email-ID: anavelkishoresingh@gma il.com NANDYAL ABSTRACT The aim of the current investigation is to design oral immediate release dosage form of Amoxicillin Trihydrate and Potassium Clavulanate used as antibiotics used for treatment of pharyngitis/tonsillitis, respiratory tract infections and some microbial infections, which release the drug within 2 minutes and match with the desired drug release profile. The tablets were prepared by the Wet Granulation Method, Dry Granulation Method, and Moist Activated Granulation Method using different polymers in different concentrations. The interference of the polymers was ruled out by FT- IR Spectroscopy studies. The powder blends of tablets and drug were evaluated for their physical properties like the angle of repose, bulk density, compressibility index, and Hausner ratio. The manufactured tablets were evaluated for in process and finished product quality control tests including appearance, thickness, weight variation, hardness, friability, drug content, and in vitro drug release. Among all formulations F3 shows better dissolution profile and is considered as most successful formulation.
- 72 - P a g e International Standard Serial Number (ISSN): 2319-8141 INTRODUCTION: Immediate Release Tablets are those tablets which are designed to disintegrate and release their medication with no special rate controlling features, such as special coatings and other techniques. Recently immediate release tablets have started gaining popularity and acceptance as a drug delivery system, mainly because they are easy to administer, has a quick onset of action is economical and lead to better patient compliance. Advantages of Immediate Release Tablets: Quick onset of action. Improved stability and bioavailability. Provides some advantages of liquid dosage forms. Disadvantages of Immediate Release Tablets: Sometimes may require more frequency of administration. Dose dumping may occur. Mechanism of drug release: On exposure to aqueous fluids, hydrophilic matrices take up water and the polymer starts hydrating to form a gel layer. Drug release is controlled by diffusion barriers by surface erosions. An initial burst of soluble drug may occur due to surface leaching. When a matrix containing a swellable glassy polymer comes into contact with an aqueous medium, there is an abrupt change from a glassy to rubbery state associate with swelling process with time, water infiltration deep into a case increasing the thickness of the gel layer. The outer layer becomes fully hydrated and starts dissolving or eroding. When water reaches the center of the system and the concentration of the drug falls below the solubility value, the release rate of the drug begins to reduce. Antibiotic: An antibacterial is a compound or substance that kills or slows down the growth of bacteria. A chemical substance derivable from a microorganism or by chemical synthesis that kills or inhibits microorganisms and cures infections known as an antibiotic. A broad-spectrum antibiotic can be used to treat a wide range of infections. Antibiotics are drugs used to kill or harm organisms such as bacteria, viruses, funguses and protozoon in living organisms. Since their discovery in the 193s, antibiotics have made it possible to cure diseases caused by bacteria such as pneumonia, tuberculosis and meningitis- saving the lives of millions of people around the world. Some antibiotics are produced from live organisms such as bacteria and funguses. Other antibiotics are totally or partially produced synthetically. Antibiotics act via two mechanisms: they kill the microorganisms (bactericide action) and prevent them from reproducing (bacteriostatic action). Amoxicillin Trihydrate and Potassium Clavulanate Dosage forms: Amoxicillin/clavulanate is a widely prescribed combination of beta-lactam antibiotic and betalactamase inhibitor available in different conventional dosage forms for per oral delivery and is considered as a broad-spectrum antibiotic for the treatment of a wide range of bacterial infections,
- 73 - P a g e International Standard Serial Number (ISSN): 2319-8141 including upper and lower respiratory tract infections and infections of the skin and soft-tissue structures. The Potassium Clavulanate component inhibits beta-lactamase-mediated inactivation, thereby maintaining amoxicillin s bactericidal activity. This broadens the spectrum of activity of amoxicillin to include amoxicillin sensitive and beta-lactamase-producing (amoxicillin resistant) bacterial strains. The daily parenteral (IV) therapeutic dose in adults ranges up to 12 g/12 mg Amoxicillin/Clavulanate. Amoxicillin absorption is rate and site dependent in the gastrointestinal tract. The drug is well absorbed in the duodenum and jejunum, with no significant differences in absorption when administered as a bolus or IV infusion, but absorption is decreased and rate dependent in the ileum. The main reason for this is tablets represent unit dosage forms in which one usual dose of the drug accurately placed. Liquid oral dosage forms such as syrups, suspensions, emulsions, solutions and elixirs are usually designed to contain one dose of medication in 5 to 3 ml. Such dosage measurements are typically error by a factor ranging from 2 to 5% when the drug is self administered by the patient. METHODS OF FORMULATING IMMEDIATE RELEASE TABLETS- In general, the choice of method for the manufacture of tablets is dependent on a number of factors like the physical and chemical stability of the therapeutic agent during manufacturing process, the availability of the necessary processing equipment, the cost of the manufacturing process and the excipients are used to formulate the product. 1) Direct Compression:- Direct compression method is the simpler granulation technique where the powdered material is compressed directly into the tablet without the physical nature being modified. 2) Wet granulation Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems. 3) Dry Granulation:- Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation requires drugs or excipients with cohesive properties, and a 'dry binder' may need to be added to the formulation to facilitate the formation of granules. At last powdered
- 74 - P a g e International Standard Serial Number (ISSN): 2319-8141 lubricants are added. 4) Moisture Activated Dry Granulation (MADG) In this method moisture is used to activate the granule formation but the granules drying step is not necessary due to moisture absorbing material such as MCC. The moisture-activated dry granulation process consists of two steps, wet agglomeration of the powder mixture followed by moisture absorption stages. A small amount of water (1 4%) is added first to agglomerate the mixture of the API, a binder, and excipients. Moisture absorbing material such as MCC and potato starch is then added to absorb any excessive moisture. After mixing with a lubricant, the resulting mixture can then be compressed directly into tablets. Hence, this process offers the advantage of wet granulation is that eliminates the need for a drying step. MATERIALS: Amoxicillin Trihydrate and Potassium Clavulanate was a gift samples from Aurobindo Pharma ltd Hyderabad, Crosspovidone, PVP-K3 are from ISP technologies, sodium starch glycolate from DMV International, HPC, Opadry white are from Colorcon Asia Ltd, MCC from FMC biopolymer, Collidal Silicon dioxide from Degusser, Magnesium sterate from Ferro industry chemicals. METHODS: 1. WET GRANULATION METHOD: Sift the Amoxicillin through mesh # 14 sieve and also sift the micro crystalline cellulose, Crosspovidone, Sodium starch Glycolate through mesh # sieve. Load the shifted materials Amoxicillin, Micro crystalline cellulose, Crosspovidone, Sodium starch glycolate to Rapid Mixer Granulator and mix. Dilute the Hydroxyl Propyl Cellulose with water and add diluted HPC add it RMG and knead the wet mass. Dry the wet mass at inlet temperature 5 ± 5 C. Screen the dried granules of Amoxicillin using Oscillating Granulator with a 1. mm screen and Sift the screened granules through mesh # 18 sieve using vibratory sifter. Dry the extra granular materials Crosspovidone & Colloidal silicon dioxide except Clavulanate Potassium + Microcrystalline cellulose mixture in VTD at 5 ± 5 C. Sift together Clavulanate Potassium + Microcrystalline cellulose, Crosspovidone & Colloidal silicon dioxide through mesh # sieve.resift the blend through mesh # 18 sieve and sift magnesium state through mesh # 6 sieves using Vibratory sifter. Load the intragranular material and extragranular into low shear blender and blend for 2 minutes. Add sifted magnesium state initial low shear blender and blend for 5. Compress the Amoxicillin and Potassium Clavulanate blend is compressed into tablets using Cadmach 3 station single rotary press. Load the compressed tablet in to coating pan at 5 ± 5 C intermittent to get the desired temperature. Start coating at 5 ± 5 C after coating about to get weight build up of 2 % w/w
- 75 - P a g e International Standard Serial Number (ISSN): 2319-8141 check the exhaust air RH & temperature during coating. Exhaust RH should be less than 1 % and exhaust temperature should be between 45 C and 49 C. 2. DRY GRANULATION METHOD: Sift the Amoxicillin through mesh # 14 sieve, sift the Microcrystalline cellulose, Sodium starch glycolate, PVP K-3 through mesh # sieve using Vibratory Sifter. Sift the extragranular materials like Clavulanate potassium + microcrystalline cellulose, Crosspovidone & colloidal silicon dioxide through mesh # sieve using Vibratory sifter. Load the shifted materials Amoxicillin, Microcrystalline cellulose, Sodium starch glycolate, and extragranular materials Clavulanate Potassium + Microcrystalline cellulose, crosspovidone, Colloidal silicon dioxide to Octagonal Blender and blend it. Compact the blend into a solid compact or sheet so called as flakes. The flakes are reduced in size of desired granules using oscillating Granulator machine with 1 mm screen at medium speed. Then sift the granules through mesh # 18 sieve using vibratory sifter. Load the blend into octagonal blender and add Magnesium sterate and blend it for 5 minutes. The amoxicillin and Potassium Clavulanate blend is compressed into tablets using Cadmach 3 Station Single rotary tablet press. Load the compressed tablet in to coating pan at 5 ± 5 C intermittent to get the desired temperature. Start coating at 5 ± 5 C after coating about to get weight build up of 1.5% w/w check the exhaust air RH & temperature during coating. Exhaust RH should be less than 1 % and exhaust temperature should be between 45 C and 49 C. 3. MOIST ACTIVATED DRY GRANULATION TECHNIQUE: Sift the Amoxicillin through mesh # 14 sieve using Vibratory Sifter. Sift the Micro crystalline cellulose, Sodium starch glycolate, PVP K-3 through mesh # sieve using Vibratory Sifter. Load the sifted materials to Rapid Mixer Granulator and mix for 2 minutes. Spray the water slowly to the blend while mixing for 5 minutes at slow speed. Mix the blend for 1 minutes. Sift the extragranular material like Potassium Clavulanate, Crosspovidone, Aerosil through mesh # sieve using Vibratory sifter. Add aerosil to the intragranular blend to remove the excess of moisture present. Load the intragranular blend, extragranular blend to the Octagonal blender and blend it for 5 minutes. Add the lubricant Magnesium Sterate to the blend and blend it in an octagonal blender for 5 minutes. Compress the Amoxicillin and Potassium Clavulanate blend is compressed into tablets using Cadmach 3 station single rotary press. Load the compressed tablet in to coating pan at 5 ± 5 C intermittent to get the desired temperature. Start coating at 5 ± 5 C after coating about to get weight build up of 1% w/w check the exhaust air RH & temperature during coating. Exhaust RH should be less than 1 % and exhaust temperature should be between 45 C and 49 C.
- 76 - P a g e International Standard Serial Number (ISSN): 2319-8141 NOTE: The quantity of amoxicillin USP is based on % W/W assay value and 14.6 % water content. The quantity of Clavulanate Potassium is based on 19.2 % w/w value (on anhydrous basis). Calculate actual quantity of amoxicillin and potassium clavulante required: Quantity required = Label claim EVALUATION TESTS: % w w assay on an hydrous basis % w water content w Assay by HPLC: 1 mg of drug is dissolved in water. One ml of sample is collected and diluted to 2 ml and filtered the solution with whattman paper. The filtrate solution about 2 ml / min was injected to in to the column. The column was run with mobile phase- 9 : 5 : 5 ( water : buffer : menthol ). Then the amount of drug present in the sample was calculated from absorption value at wavelength of 22 nm using uv-detector Drug polymer interaction by Fourier-transform infrared spectroscopy: The drug polymer and polymer interaction were studied by FTIR spectrometer. Two percent (w/w) of samples with respect to potassium bromide disc was mixed with dry KBr. The mixture was ground into a fine tablet using an agate mortar and compresses into KBr discs in a hydraulic press at a pressure of psi. Each KBr disc was scanned and resolution characteristic peaks were recorded. PRECOMPRESSION STUDIES: 1. Angle of repose: The flow properties of the blend were evaluated by determining the angle of repose and the compressibility index. The angle of repose (θ) was calculated by using the Eqn: Tan θ = h/r; Where, θ = Angle of repose; h = Height of the heap; r = Radius of heap 2. Bulk density: It is the ratio of the total mass of powder to the bulk volume of powder. The bulk density is calculated according to the formula mentioned below. It is expressed in g/cc and is given by: D b = m/v o ; Where, m = mass of the powder 3. Tapped density: It is the ratio of the total mass of powder to the tapped volume of powder. It is expressed in g/cc and is given by: Dt = m/vi Where, m= mass of the powder, V i = tapped Volume of the powder. Both loose bulk density (LBD) and tapped bulk density (TBD) were determined by using tap density tester. LBD and TBD were calculated using the following Formula: LBD = weight of the powder / volume of the packing TBD = weight of the powder / tapped volume of the packing 4. Compressibility index: The flowability of powder can be evaluated by comparing the loose Bulk density (LBD) and Tapped bulk density (TBD) of powder and the rate at which its packed down. Compressibility index of the powder was determined by Carr s compressibility index as given by following eqn. Carr s index (%) = [(TBD LBD) x ]/TBD
- 77 - P a g e International Standard Serial Number (ISSN): 2319-8141 5. Hausner ratio: It is the ratio of tapped to loose bulk density was calculated by using the following eqn. Hausner ratio = TBD)/ LBD POST COMPRESSION PARAMETERS: a) Shape of Tablet: Compressed tablets were examined under the magnifying lens. b) Tablet Dimensions: Thickness and diameter were measured using Vernier calipers. c) Hardness: Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. It is expressed in kg/cm 2. d) Friability test: It is expressed in percentage (%). Twenty tablets were initially weighed (W 1 ) and transferred into friabilator. The friabilator was operated at 25 RPM for 4 minutes or run up to revolutions. The tablets were weighed again (W 2 ). The % friability calculated by % Friability = (W 1 -W 2 ) / W 1 X where W 1 = Weight of tablets before test W 2 = Weight of tablets after test e) Weight Variation Test: Twenty tablets were selected randomly from each batch and weighed individually to check for weight variation. f) In vitro Dissolution: The dissolution test is carried out in a dissolution apparatus (paddles type), one tablet is placed in each vessel containing 9 ml of water maintained at temperature 37 C and rotate paddles with 75 rpm for 3 minutes. Collect the sample at every 5 minutes of interval time and filter the sample through whattman filter paper. The filtrate is used for HPLC analysis. The filtrate solution about 2 ml / min was injected to in to the column. The column was run with mobile phase- 9 : 5 : 5 (water : buffer : menthol ). The ph of the solution is adjusted to 3.±.1. The amount of drug present in the sample was calculated from absorption value at wavelength of 22 nm using uv-detector Calculation: The % of drug release of Amoxicillin Trihydrate and potassium clavulante by using the formula: (label claim: Amoxicillin: 5Mg; Potassium Clavulante: 125Mg) % of drug release: test. area / absorbance std. dilution std. area / absorbance test. dilution potency label. claim
- 78 - P a g e International Standard Serial Number (ISSN): 2319-8141 ILLUSTRATIONS: FORMULATION TABLE METHOD Wet Granulation Dry Granulation Dry Granulation Method Moist Activated Dry Granulation Method INGREDIENTS F1 F2 F3 F4 F5 F6 F7 F8 F9 Intragranular Material Amoxicillin 574 574 574 574 574 574 574 574 574 trihydratre Microcrystalline 6 61 45 41 36 46 2 2 2 cellulose Crosspovidone 7-8.5 - - - - - - Sodium starch 7 1 8.5 12.5 15 12.5 5 1 12.5 glycolate Hydroxypropyl 1 1 1.5 - - - - - - cellulose PVP-K 3 - - - 25 25 2 1 1 2 Water Q.S Q.S Q.S - - - 3% 3% 3% Extragranular Material Clavulanate 149 149 149 149 149 149 149 149 149 Potassium Microcrystalline 149 149 149 149 149 149 45 35 15 cellulose Crosspovidone 7-8.5 12.5 15 12.5 5 1 12.5 Sodium starch - 1 - - - - - - - glycolate Magnesium sterate 1 1 1 1 1 1 1 1 1 Colloidal Silicon 7 7 7 1 1 1 35 35 35 Dioxide Opadry 2% 2% 2% 1.5% 1.5% 1.5% 1% 1% 1% white(coating solution ) Total Weight (Mg) 15 15 15 Table No: 1
- 79 - P a g e International Standard Serial Number (ISSN): 2319-8141 FIGURES: HPLC CHROMATOGRAM PEAKS: FIGURE NO: 1 FTIR SPECTRA OF AMOXICILLIN TRIHYDRATE FIGURE NO: 2 FTIR SPECTRA OF POTASSIUM CLAVULANATE FIGURE NO: 3 FTIR SPECTRA OF AMOXICILLIN TRIHYDRATE AND POTASSIUM CLAVULANATE FIGURE NO: 4
percentage of drug release percentage of drug release - 8 - P a g e International Standard Serial Number (ISSN): 2319-8141 FTIR SPECTRA OF AMOXICILLIN TRIHYDRATE AND POTASSIUM CLAVULANATE AND ALL EXCIPIENTS FIGURE NO: 5 Dissolution study for Amoxicillin Trihydrate for F1-F3 12 8 6 2 Dissolution study for F1-F3 1 2 3 time (minutes) FIGURE NO: 6 Dissolution study for Amoxicillin Trihydrate for F4-F6 12 8 6 2 Dissolution study for F4-F6 1 2 3 5 time (minutes) FIGURE NO: 7
percentage of drug release percentage of drug release percentage f drug release - 81 - P a g e International Standard Serial Number (ISSN): 2319-8141 Dissolution study for Amoxicillin Trihydrate for F7-F9 12 8 6 2 Dissolution study for F7-F9 1 2 3 time (minutes) FIGURE NO: 8 Dissolution study for Amoxicillin Trihydrate for F1-F9 12 8 6 2 Dissolution study of Amoxicillin Trihydrate of all fomulations 1 2 3 5 time (minutes) FIGURE NO: 9 Dissolution study for Potassium Clavulanate for F1-F3 12 8 6 2 Dissolution study for F1-F3 1 2 3 time (minutes) FIGURE NO: 1
percentage of drug release percentage of drug release percentage of drug release - 82 - P a g e International Standard Serial Number (ISSN): 2319-8141 Dissolution study for Potassium Clavulanate for F4-F6 12 8 6 2 Dissolution study for F4-F6 1 2 3 5 time (minutes) FIGURE NO: 11 Dissolution study for Potassium Clavulanate for F7-F9 12 8 6 2 Dissolution study for F7-F9 1 2 3 5 time (minutes) FIGURE NO: 12 Dissolution study for Potassium Clavulanate for F1-F9 Dissolution study of Potassium Clavulanate of all 12 fomulations 8 6 2 1 2 3 5 time(minutes) FIGURE NO: 13
- 83 - P a g e International Standard Serial Number (ISSN): 2319-8141 RESULTS: HPLC CHROMATOGRAM PEAK STUDY: AT DAD A : 22 NM Retention Area Area height Height Theoretical Resolution Asymmetry Name time % % plates 5.943 99234 4.5 667 6.71 2748 1.21 Potassium Clavulanate 7.133 234977 95.95 84378 93.29 151 2 1.12 Amoxicillin trihydrate Totals 2448941 9445 ASSAY: Table No: 2 SL.N TEST DRUG NAME LIMITS RESULTS 1 Assay Amoxicillin NLT 9 % - 97.5 % NMT 11 % 2 Assay Potassium NLT 9 % - 96.7 % Clavulanate NMT 11 % Table No: 3 PRECOMPRESSION STUDIES: Formulation B.D(gm/ml) T.D(gm/ml) C.I (%) H.R Angle of Repose Property F1.581.781 24.37 1.33 37.64 passable F2 F3 F4 F5 F6 F7 F8 F9.593.787 24.657 1.3 38.72 passable.571.783 23.188 1.29 37.61 passable.588.754 22.52 1.27 37.83 passable.596.789 28.121 1.35 38.86 passable.598.763 22.299 1.29 38.14 passable.579.769 24.638 1.31 36.66 passable.62.783 24.657 1.29 38.26 Passable.583.795 29.38 1.41 38.45 passable Table No: 4
- 84 - P a g e International Standard Serial Number (ISSN): 2319-8141 PHYSICAL EVALUVATION OF TABLETS: TESTS SPECIFICATION F1 F2 F3 F4 F5 F6 F7 F8 F9 Appearance White oval shaped coated tablets Passes Passes Passes Passes Passes Passes Passes Passes Passes Identification test Should pass Passes passes Passes Passes Passes Passes Passes Passes Passes POST COMPRESSION STUDY: Table No: 5 TEST F1 F2 F3 F4 F5 F6 F7 F8 F9 AVERAGE WEIGHT 2 997 3 996 998 1 148 152 146 HARDNESS [kp] 16.2 16.7 15.9 18.6 19.2 18.9 17.5 17.2 17.3 FRIABILITY %.3.1.2.3.4.3.3.2.3 LENGTH[mm] 15.1 15.4 15.2 15.2 15.1 15.2 15.5 15.6 15.5 THICKNESS[mm] 6.77 6.54 6.62 6.71 6.79 6.72 6.99 7.2 6.85 DISINTEGRATION TIME 5 25 4 5 4 3 8 1 Table No: 6 7 7 55 5 35 5 1 Dissolution study for Amoxicillin Trihydrate: Method Wet granulation method Dry granulation method M.A.D.G method Time F1 F2 F3 F4 F5 F6 F7 F8 F9 5 5 5 64.8% 7.9% 86.2% 65.2% 58.4% 68.5% 7.6% 79.67% 67.6% 1 78.4% 79.1% 97.4% 69.5% 69.7% 76.4% 82.4% 88.3% 78.9% 15 82.8% 85.4% 99.5% 74.2% 74.4% 78.4% 9.3% 96.4% 84.8% 2 88.49% 91.6% 11.7% 8.9% 79.3% 88.3% 94.2% 99.7% 88.5% 25 97.5% 96.9% 85.6% 87.6% 91.2% 98.6% 11.2% 93.5% 3 11.6% 98.3% 91.3% 93.2% 96.7% 12.6% 97.6% 35 12.3% 95.6% 97.4% 99.3% 11.5% 98.7% 98.3% 11.5% 45 11.3% 12.4% Table No: 7
- 85 - P a g e International Standard Serial Number (ISSN): 2319-8141 Dissolution study for Potassium Clavulanate: Method Wet granulation method Dry granulation method M.A.D.G method Time F1 F2 F3 F4 F5 F6 F7 F8 F9 5 61.6% 64.8% 85.2% 61.3% 58.4% 62.1% 68.7% 75.5% 66.2% 1 7.6% 73.5% 96.3% 7.9% 69.7% 78.3% 81.5% 84.7% 75.9% 15 85.5% 83.9% 98.3% 79.1% 74.4% 88.5% 91.5% 93.5% 86.8% 2 93.7% 92.8% 11.2% 85% 79.3% 95.6% 97.6% 98.6% 91.2% 25 97.2% 97.5% 91.6% 85.6% 99.7% 99.4%.5% 99.2% 3 99.5% 99.9% 98.9% 93.2%.7%.8% 12.5% 35 12.6% 11.2% 11.1% 98.7% 12.1% 11.5% Table No: 8 Stability studies of Amoxicillin and Potassium Clavulanate tablets at 3 C / 75% RH for formulation F-3 Sl.No Tests Limits Initial result One month results Two months results 1 Appearance White colour Passes Passes Passes 2 Identification test should pass the Passes Passes Passes test 3 Average weight ± 1% from target 995.7.4 997.5 weight 4 Hardness 16 18.5 kp 16.6 kp 16.5 kp 16.8 kp 5 Amoxicillin 95-11 % of 99.6% 99.3% 98.6% trihydrate (assay) labeled amount 6 Amoxicillin NLT 85% of.5% 99.6% 99.14% trihydrate (dissolution study) labeled amount dissolved in 3 7 Potassium Clavulanate(assay) 95-11 % of labeled amount 99.2% 98.5% 98.31% 8 Potassium Clavulanate (dissolution study) NLT 85% of labeled amount dissolved in 3 11.4 99.5% 99.1% Table No: 9
- 86 - P a g e International Standard Serial Number (ISSN): 2319-8141 DISCUSSION: In the present study, various formulations of immediate release Amoxicillin trihydrate and Potassium Clavulanate were prepared. In order to achieve the development of immediate release dosage form three different methods like Wet granulation method, Dry Granulation Technique and Moist Activated Dry Granulation Technique has been used. At first characterization of API was followed by its incompatibility studies with various excipients. The formulation was studied for various pre-compression parameters like Bulk density, Tapped density, Carr s index, Hausners ratio, porosity and angle of repose. The formulation was also studied for various post compression studies like hardness, weight variation, friability, disintegration time, content uniformity and in-vitro dissolution were analyzed and the results were compared. Dissolution studies for all the formulations from F1 F9 are compared. The release profile for Amoxicillin Trihydrate and Potassium Clavulanate for formulation F-3 is 11.7 % and 11.2 % respectively. The formulation F-8 prepared by Process Optimization technique Moist Activated Dry Granulation method also showed fast release of the drug in 25 minutes. But the disintegration time for F3 formulation is less than the time taken for F8 formulation to disintegrate. Hence F3 is considered as best formulation. The Best formulation F-3 was kept for stability studies. The Short stability studies were performed for three months as per ICH guidelines at 37 C±3 C / 75% RH±5% RH and parameters like percentage drug content, hardness, disintegration time, and in-vitro dissolution studies were evaluated and found to be stable. CONCLUSION: Immediate release tablets are those which are designed to disintegrate and release their medication with no special rate controlling features. The success of in vitro drug release studies recommends the product for further in vivo studies, which improve patient compliance. In the present study different type of polymers like superdisintegrants Sodium starch glycolate, Crospovidone were used. Hydroxy propyl cellulose and PVP K-3 were used as binder. By using these polymers nine formulations were prepared by three different methods. From the results formulation F-3 is selected as best formulation among all other formulations as it provides better disintegration and in-vitro drug release. The formulation F-3 prepared by the wet granulation method had passed the short term stability studies. So F3 formulation prepared by Wet Granulation method is concluded as the best method for the manufacturing of Amoxicillin and Potassium Clavulanate Immediate Release tablets. REFERENCES 1. K.Mallikarjuna Rao, K.Gnanaprakash, K.B. Chandra Sekhar, C. MadhusudhanaChety, Formulation and in-vitro characterization of floating microspheres of amoxicillin trihydrate against. pylori, Journal of Pharmacy Research, 211,4, pp. 836-8.
- 87 - P a g e International Standard Serial Number (ISSN): 2319-8141 2. JayeshParmar, Ph. D., Siahboomi, Ph. D., Formulation of Extended Release Multiparticulate Systems uses Ethylcellulose, Pharma Times, April 21, 42, pp. 34-39. 3. AmnonHoffmana, Haim D. Danenbergb, IfatKatzhendlera, RivkaShuvala, Dalia Gilhar, Michael Friedman, Pharmacodynamic and pharmacokinetic rationales for the development of an oral controlled-release amoxicillin dosage form, Journal of Controlled Release, 1998, 54, pp. 29 37. 4. Singhal M., Gupta V., Jindal S., Sharma A., Surenderkaswan, NituBishnoi, Design and Development of Extended Release Oral Solid Dosage Form of Perfenazine, Journal of NaturaConscientiaMarch 211, 2, pp. 35-362 5. Shiva Kumar Yellanki, Jeet Singh, Jawad Ali Syed, RajkamalBigala, SharadaGoranti, Naveen Kumar nerella, International Journal of Pharmaceutical Sciences and Drug Research, 21, 2, pp. 112-114 6. Grimmettet al, Tablet containing a coated core, U S patent 683894B2, 21, Smithkline Beecham p.l.c. 25. 7. Ramarajuet al, Multi-layered modified release formulation comprising amoxicillin and clavulanate, U S patent 211/28 A1, 27, Ranbaxy Laboratories Limited, 211. 8. Gregory E. Amidon, PhD, Proposed New USP General Information Chapter, Excipient Performance (159), Pharmacopeial Forum, Nov. Dec. 27, 33, 1311-1323. 9. Igor Legen, atja Z., MatejaSalobir, Janez Ker C, The evaluation of some pharmaceutically acceptable excipients as permeation enhancers for amoxicillin, International Journal of Pharmaceutics, 26, pp. 84 89. 1. M. K. Goyal Preparation and evaluation of calcium silicate based floating microspheres of amoxicillin, Journal of Applied Pharmaceutical Science, 211, pp. 137-141. 11. Raxit Y. Mehta, Sandip B. Tiwari, The Utility of Ultra-High Viscosity Hypromellose in Extended Release Matrix Formulations, Colorcon, Inc., 21. 12. Kultida Songsurang, Jatuporn Pakdeebumrung, Narong Praphairaksit, and Nongnuj Muangsin, Sustained Release of Amoxicillin from Ethyl Cellulose-Coated Amoxicillin/Chitosan Cyclodextrin-Based Tablets, American Association of Pharmaceutical Scientists, March 211, 12, pp. 35 45.