International Journal of Innovative Pharmaceutical Sciences and Research

Transcription

1 International Journal of Innovative Pharmaceutical Sciences and Research FORMULATION AND EVALUATION OF TENOFOVIR DISOPROXIL FUMARATE IMMEDIATE RELEASE TABLETS 1 Farha Amna Shaik*, 2 Shubhrajit Mantry 1 M.Pharmacy Scholar, Kottam Institute of Pharmacy, Mahaboobnagar, AP, INDIA 2 Assistant Professor, Kottam Institute of Pharmacy, Mahaboobnagar, AP, INDIA Abstract This investigation is undertaken with an aim to develop pharmaceutically equivalent, stable, cost effective and quality improved formulation of Tenofovir Disoproxil Fumarate immediate release tablets. The current study involves formulation and evaluation of Tenofovir Disoproxil Fumarate tablets, comparison of dissolution rate of optimized formula with innovator s product and estimation of similarity and difference factors. The similarity and dissimilarity factor obtained for Tenofovir Disoproxil Fumarate was found to be within the limits. The formulation F-8 exhibited similar release profile to that of innovators product at each time point. Hence, F-8 was considered as the best formulation. Key words: Tenofovir Disoproxil Fumarate, Immediate release tablets, Wet granulation method. Corresponding Author: Farha Amna Shaik Department of Pharmaceutics, Kottam Institute of Pharmacy, Erravally X Roads, Andhra Pradesh farha.khatoon@gmail.com Telephone: Available online: October Issue 252

2 INTRODUCTION Active pharmaceutical compounds (drugs) are used for the treatment of a disease or for prophylactic purpose. An Active Pharmaceutical Ingredient (API) may exist in solid, liquid or semisolid form. They are rarely prescribed to the patients as such i.e. without adding excipients, since the desired effect may not be obtained. Earlier, it was thought that excipients are inert in nature but, in recent time it is well known that excipients can greatly modify the intended effect of a drug. The API and excipients are suitably processed in pharmaceutical industry to convert them into dosage forms such as tablet, capsule, suspension, solution, etc. The selection of excipients and processing of drug excipients mixture is as important as API itself. Patient acceptability can be improved by controlling the organoleptic properties. Dosage form provides desired therapeutic level of a drug. Preparation method of tablet [1-2] Direct Compression The term direct compression is defined as the process by which tablets are compressed directly from powder mixture of API and suitable excipients. No pre-treatment of the powder blend by wet or dry granulation procedure is required. Manufacturing steps for direct compression Direct compression involves comparatively few steps: i) Milling of drug and excipients. ii) Mixing of drug and excipients. iii) Tablet compression Wet Granulation The most widely used process of agglomeration in pharmaceutical industry is wet granulation. Wet granulation process simply involves wet massing of the powder blend with a granulating liquid, wet sizing and drying. Available online: October Issue 253

3 Steps involved in the wet granulation i) Mixing of the drug(s) and excipients ii) Preparation of binder solution iii) Mixing of binder solution with powder mixture to form wet mass. iv) Coarse screening of wet mass using a suitable sieve (6-12 screens) v) Drying of moist granules. vi) Screening of dry granules through a suitable sieve (14-20 screens) vii) Mixing of screened granules with disintegrant, glidant, and lubricant. Coating [3] Coated tablets are defined as tablets covered with one or more layers of mixture of various substances such as natural or synthetic resins,gums,inactive and insoluble filler, sugar, plasticizer, polyhydric alcohol,waxes,authorized colouring material and sometimes flavouring material. Coating may also contain active ingredient. Substances used for coating are usually applied as solution or suspension under conditions where vehicle evaporates. Immediate release [3] The term immediate release pharmaceutical formulation includes any formulation in which the rate of release of drug from the formulation and/or the absorption of drug, is neither appreciably, nor intentionally, retarded by galenic manipulations. In the present case, immediate release may be provided for by way of an appropriate pharmaceutically acceptable diluents or carrier, which diluents or carrier does not prolong, to an appreciable extent, the rate of drug release and/or absorption. Thus, the term excludes formulations which are adapted to provide for modified, controlled, sustained, prolonged, extended or delayed release of drug. In this context, the term release includes the provision (or presentation) of drug from the formulation to the gastrointestinal tract, to body tissues and/or into systemic circulation. For gastrointestinal tract release, the release is under ph conditions such as ph=1 to 3, especially at, or about, ph=1. In one aspect of the invention a formulation as described herein with a compound of formula (I), or an acid addition salt thereof, in crystalline form releases drug under a range of ph conditions. In another aspect of the invention a formulation as described herein with a compound of formula (I), or an acid addition salt thereof, releases drug under ph conditions such as ph=1 to 3, Available online: October Issue 254

4 especially at, or about, ph=1. Thus, formulations of the invention may release at least 70% (preferably 80%) of active ingredient within 4 hours, such as within 3 hours, preferably 2 hours, more preferably within 1.5 hours, and especially within an hour (such as within 30 minutes), of administration, whether this be oral or parenteral. MATERIALS AND METHODS Methods used in the formulation of TDF immediate release tablets: 1. Direct compression method & 2. Wet granulation method Procedure for f-1(direct compression): All the ingredients were weighed except Magnesium stearate and the mix was passed through #40 mesh, and then mixed for 5 min in s blender. The above mixture was then lubricated with Magnesium stearate which was initially passed through sieve no 12 in blender for 2 mins. Then the lubricated blend was compressed using 16.5 x 8mm size punches. Procedure for f-2 to f-8(wet granulation): API, MCC ph 101, Lactose monohydrate, Crospovidone were weighed and passed through #40 meshes. The above mixture was mixed in a poly bag for 10 minutes. PG starch was added to sufficient quantity of purified water by stirring. The binder solution was added to the dry mixture within 2 minutes with impeller speed fast (600rpm). The wet mass was mixed for 1min with impeller and chopper fast (600rpm). The obtained wet mass was passed through #12 mesh. The sieved mixture was dried using FBD and the temperature was maintained at 60 C. until the moisture content in the blend comes to 1.0 to 2.0 % The dried blend was passed through #18 mesh and then pre lubricated using MCC ph 102, crospovidone for 5 minutes and then lubricated with Magnesium stearate in bender for 2mins. Physical characteristics of the lubricated blend were carried out. Available online: October Issue 255

5 Then finally the lubricated blend was compressed using 16.5x8mm size, oval shape punches. The obtained tablets were coated using opadry II blue coating solution Table no.1 formulation table of TDF immediate release tablets F1 F2 F3 F4 F5 F6 F7 F8 Materials (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) Tenofovir disoproxil fumarate Microcrystalline cellulose Lactose anhydrous Lactose monohydrate Crospovidone(intragranular) Croscarmellose sodium(intragranular) Pregelatinized starch Water - Q.S Q.S Q.S Q.S Q.S Q.S Q.S Microcrystalline cellulose(ph 102) Crospovidone(extragranular) Croscarmellose sodium(extragranular) Magnesium stearate Core tablet weight Opadry blue II coat (2.3%) Coated tablet weight Available online: October Issue 256

6 RESULTS & DISCUSSIONS: Table.No.2 Standard calibration data of TDF in 0.1 HCL Concentration (mcg/ml) Absorbance (260 nm) Fig.No.1 Standard graph of Tenofovir Disoproxil Fumarate Fourier Transforms Infrared Spectroscopy (FTIR) Studies: The pure drug, physical mixtures and optimized formulations were subjected for FTIR analysis. The samples were prepared on KBr-press (Sipra laboratories, Hyd). The samples were scanned over a range of cm-1 using Fourier transformer infrared spectrophotometer Spectra were analysed for drug polymer interactions. Available online: October Issue 257

7 Transmittance [%] Tab no.3 FTIR interpretation of Pure drug and excipients S.No Formulation C=C Stretching Cm -1 C=O Stretching Cm -1 N-H Stretching Cm -1 C-H Stretching Cm -1 1 T+CCNa T+MCCPH T+PS T+LM T+MCC 5 PH T+ALL T+OB Drug(TDF) D:\IR DATA\.279 DRUG - TDF T SOLID 9/19/2013 Fig.No.2 FTIR Spectrum of Pure Drug Tenofovir Disoproxil Fumarate Available online: October Issue 258

8 Transmittance [%] Transmittance [%] D:\IR DATA\.271 T+CCNa SOLID 9/19/2013 Fig.No.3 FTIR Spectrum of TDF+Croscarmellose sodium 0 D:\IR DATA\.272 T+MCCPH-101 SOLID 9/19/2013 Fig.No.4 FTIR Spectrum of TDF+Microcrystalline cellulose D:\IR DATA\.273 T+PS SOLID 9/19/2013 Fig.No.5 FTIR Spectrum of TDF+Pregelatinized starch Available online: October Issue 259

9 Transmittance [%] Transmittance [%] Transmittance [%] D:\IR DATA\.275 T+LM SOLID 9/19/2013 Fig.No.6 FTIR Spectrum of TDF+Lactose monohydrate 0 D:\IR DATA\.276 T+MCC-102 SOLID 9/19/2013 Fig.No.7 FTIR Spectrum of TDF+Microcrystalline cellulose D:\IR DATA\.278 T+OB SOLID 9/19/2013 Fig.No.8 FTIR Spectrum of TDF+Opadry ii blue Available online: October Issue 260

10 Transmittance [%] D:\IR DATA\.277 T+ALL SOLID 9/19/2013 Fig.No.9 FTIR Spectrum of TDF+Mixture of Excipients Differential scanning calorimetry (dsc): Approximately 2-6 mg of pure drug (TDF) and selected formulations were taken in aluminum pan, sealed with aluminum cap and kept under nitrogen purging (atmosphere). The samples were scanned from C with the scanning rate of 30 C/min using differential scanning calorimeter. Fig.No.10 DSC Thermogram of Pure drug Tenofovir Disoproxil Fumarate Fig.No.11 DSC Thermogram of Best formulation F-8 Available online: October Issue 261

11 Pre-Formulation Parameters [4, 5, 6] Precompression parameters such as bulk density, tapped density, angle of repose, Carr s index and Hausner ratio which are evaluated for prepared tablets are given in following table: Evaluation of tablet: [7, 8] Weight variation: Twenty tablets were randomly selected from each batch individually weigh, the average weight and standard deviation of 20 tablet calculated (Krishanaiah et al., 2003). Table no-6 Thickness: The thickness of the tablet was measured by using digital venire caliper, twenty tablets from each batch were randomly selected and thickness was measured (The British Pharmacopoeia, 2005). Hardness: Hardness was measured using Pfizer hardness tester, for each batch three tablets were tested (The United State of Pharmacopoeia, 1995). (Table no-6) Friability: Twenty tablets were weight and placed in the Roche friabilator and apparatus was rotated at 25 rpm for 4 min. After revolution the tablets were dusted and weighed. (Chaudhari PD, 2005). In-vitro disintegration test: The test was carried out on 6 tablets using Tablet disintegration tester. Distilled water at 37 C± 2 C was used as a disintegration media and the time in seconds taken for complete disintegration of the tablet with no palable mass remaining in the apparatus was measured. Table.No.4 Post-compression parameters for F-1to F-8 Formula Average weight(mg) Thickness (mm) Hardness (Kg/cm 2 ) Friability (%) Disintegration Time F min 21sec F min 19sec F min 14sec F min 56sec F min 49sec F min 31sec F min 29sec F min 58sec Available online: October Issue 262

12 Table.No.5 Dissolution profile of formulations (F-1 to F-8) Time(min) F-1 F-2 F-3 F-4 F-5 F-6 F-7 F Fig.No.12 In-vitro dissolution profile of Fig.No.12 In-vitro dissolution profile of TDF formulations F-1 to F-4 TDF formulations F-5 to F-8 Table.No.6 Comparision of In-vitro Drug release profile of (Tenofovir Disoproxil Fumarate) best formulation F-8 with Marketed product TIME %CDR OF %CDR OF F-8 INNOVATOR Available online: October Issue 263

13 Fig.No.14 Plot for comparison of In-vitro Drug release F-8 with marketed product CONCLUSION: Drug and excipient compatibility studies by FTIR reveal that there is no chemical or physical interaction. Pre formulation studies of Tenofovir Disoproxil Fumarate are within the acceptable literature limits. The hardness, friability, thickness, average weight, in-vitro disintegration time and in-vitro release were uniform and reproducible. Based on the results of the above mentioned tests F8 was selected as the best formulation as it showed drug release profile matching with the Innovator product. Stability studies were performed for this batch under accelerated testing conditions. The product was evaluated for assay and dissolution and the results obtained were found to be within the specified limits indicating the product is stable. The Tenofovir Disoproxil Fumarate immediate release tablets showed fickian mechanism following zero order kinetics. ACKNOWLEDGMENT The authors are thankful to by Kottam institute of pharmacy Erravally X road, Mahaboobnagar (A.P.) INDIA, for completion of this work. REFERENCES: 1. Himanshu Dilip M. KS, Basuri T, Thakkar JH, Patel CA. Recent advances in granulation technology. Int J Pharm Sci Rev Res 2010;5(3): Optimization of binder level in moisture-activated dry granulation using absorbent starch to distribute moisture. 2011;19(2): Available online: October Issue 264

14 3. A review on Immediate release drug delivery system- Int.Journ. of Pharmaceutical research and research and bioscience.- IJPRBS,2012; volume:1(5): Subramanyam CVS. Textbook of Physical Pharmaceutics, Vallabh Prakashan, 2nd ed; Mehta RM. Pharmaceutics-I, Vallabh Prakashan, 2nd ed; The United States Pharmacopoeia-National Formulary ed, Rockville: The United States Pharmacopoeial Convention; Vol-I, Gwen MJ and Joseph RR and Rhodes CT. Modern Pharmaceutics, Marcel Dekker, Inc., New York, 72(3), 1996, Goldstein J L, Femilial hypercholesterolemia, in the metabolic and molecular bases of coronary heart disease, Basic research cardiol, 98 (2001) Available online: October Issue 265