International Journal of Innovative Pharmaceutical Sciences and Research

Transcription

1 International Journal of Innovative Pharmaceutical Sciences and Research FORMULATION AND DEVELOPMENT OF VALSARTAN IMMEDIATE RELEASE TABLET 1 M.Usha*, 2 Y.Raya Jaya Rao, 3 P.Prem Kumar, 4 M.Manohar Babu, 5 N.Sabitha, Sims Institute of Pharmacy, Guntur, AP, INDIA Abstract Immediate release t a b lets are uncoated tablets intended to be d i s s o l v e immediately in 0.1N HCL after administration giving a homogeneous dispersion and there by improves the dissolution and absorption of water insoluble drugs. In the present research work Valsartan Immediate release tablets were prepared using croscarmellose sodium Crosspovidone and sodium starch glycolate as super disintegrants and they have an objective of disintegration, fast dissolution and quick on set of action etc. Valsartan Immediate release tablets prepared were evaluated for number of parameters like weight variation, hardness, friability, disintegration time, drug content uniformity, drug polymer interaction and in-vitro drug release studies. Invitrodrug release studies were carried, results showed that more than 90% of the drug was released from all the batches and the tablets of the batch VL6 consisting of 8mg Crosspovidone shows a maximum released i.e. 99.9% of the drug within 5min. And the T70 value for the same tablets was 2.8min. Key words: Valsartan Immediate release tablets superdisintegrant. Corresponding Author: M.USHA, SIMS College of Pharamacy, Guntur, AP, INDIA m.usha039@gmail.com Mobile: Available online: July Issue 1402

2 INTRODUCTION Solid dosage forms like tablet and capsule are most popular and preferred drug delivery system because they have high patient compliance, relatively easy to produce, easy to market, accurate dosing, and good physical and chemical stability [1]. From past decade, there has been an increased demand for more patient-friendly and compliant dosage forms.as a result, the demand for developing new technologies has been increasing day by day [2]. US Food and Drug Administration, Center for Drug Evaluation and Research (CDER) defines, in the Orange Book an ODT as a solid dosage form containing medicinal substances, which disintegrates rapidly, usually with a matter of seconds, when placed upon the tongue [3].Many patient find difficulty to swallow tablet and hard gelatin capsule, consequently they do not take medication as prescribed. It is estimated that 50% of the population is affected by this problem which result high incident of incompliance and ineffective therapy [4]. The difficulty is experienced in particular by pediatric and geriatric patients, but it also applied to people who are ill in bed and those active working patients who are busy or traveling, especially those who have no access to water [5].European Pharmacopoeia described orally disintegrating tablets as uncoated tablets intended the placed in the mouth where they disperse rapidly before being swallowed and as tablets which should disintegrate within 3 min [6]. There are two different types of dispersible tablet which have to be distinguished, one dosage form disintegrates instantaneously in the mouth, to be swallowed without the need for drinking water, while other tablet formulation can readily be disperse in water, to form dispersion, easy to ingest by the patient [7].In an effort to develop drug products that are more convenient to use and to address potential issues of patient compliance for certain product indications and patient populations, recent developments in technologies have come out with Immediate release tablets (FDT) that can be ingested simply by placing them on the tongue. FDT is a solid dosage form that dissolves or disintegrates within a minute in the oral cavity without the need of water and has a pleasant taste. FDT is also known as orally Available online: July Issue 1403

3 disintegrating tablet, fast-dissolving tablet, fast-melting tablet, mouth melting tablet or fastdisintegrating tablet [8]. Orally disintegrating tablets are also called as orodispersible tablet, quick disintegrating tablets mouth dissolving tablets. Fast integrating tablets, Immediate release tablets, rapid dissolving tablets, porous tablets and rapimelt. European pharmacopoeia has used the term orodispersible tablet for tablet that disperse readily and within 3 min in mouth before swallowing [9].United State Food and Drug Administration (FDA) defined ODT as a solid dosage form containing medicinal substance or active ingredients which disintegrate rapidly usually within a matter of second when placed upon the tongue [10]. Valsartan is an angiotensin II receptor blocker that shows high affinity for the angiotensin II receptor type 1 (AT1), with a binding affinity 3000 times greater for AT1 than AT2. It has the longest half-life of any ARB (24 hours) and the largest volume of distribution. In addition to blocking the RAs, Valsartan acts as a selective modulator of peroxisome proliferator-activated receptor gamma (PPAR-γ), a central regulator of insulin and glucose metabolism. It is believed that Valsartan s dual mode of action may provide protective benefits against the vascular and renal damage caused by diabetes and cardiovascular disease (CVD). MATERIAL Valsartan is obtained as gift sample from Cipla Pharma R & D, Vikhroli, Croscarmellose sodium, Crospovidone and Sodium starch glycolate from HiMedia Laboratories Ltd, Mumbai, Microcrystalline cellulose from Merck Specialties limited., Mumbai, Magnesium stearate from Oxford Laboratory., Mumbai, Talc from NR Chem, Mumbai. And Lactose from Merck Specialties limited, Mumbai. METHOD PRECOMPESSION STUDY [11, 12, 13] Available online: July Issue 1404

4 The drug powder was evaluated for the following parameters Angle of repose, bulk density, tapped density and percentage porosity. Construction of calibration curve in 0.1 N HCL [14, 15] Standard Solution: 100mg of pure drug transferred into 100ml of 0.1 N HCl in a volumetric flask to give a concentration of 1 mg/ml. Stock Solution: From the standard solution a stock solution was prepared to give a concentration of 100 mcg/ml in 0.1 N HCl. Aliquots of 0.4, 0.6, 0.8, 1.0, 1.2 and 1.4ml of stock solution was pipetted out in 10 ml volumetric flasks. The volume was made up to mark with solvent. The dilution gives 4g/ml, 6g/ml, 8g/ml, 10g/ml, 12g/ml, 14g/ml. of Valsartan respectively. The absorbance of prepared solution of Valsartan in HCl was measured at 296 nm in PG instruments UV\visible spectrophotometer against 0.1N HCl as blank. The absorbance data for standard data for calibration curve yields a straight line, which shows that drug obeys Beer s law in the concentration range of 4-14 mcg\ml. The results are given in table-2 and figure-1 Fig. 1: Standard plot of Valsartan in 0.1 N HCL at λmax 249nm Table 1: Standard plot of Valsartan in 0.1 N HCL at λmax 249nm Sl. No Concentration (µg/ml) Absorbance Available online: July Issue 1405

5 DRUG AND EXCEPIENT COMPATIBILITY STUDIES Drug- excipient compatibility studies lay the foundation for designing a chemically stable formulation for clinical and commercial development. Drug excipient compatibility studies are conducted during preformulation to select the most appropriate excipients. It is clear from the below observation of the below values of characteristics absorption bands for different functional groups and bonds of the drug and its polymer that is most of the cases there is no appreciable change in the position of the bands. Even if negligible deviations exist, it s due to the different types of the polymers used for the study. IR spectra for pure drug, formulations Valsartan, Crospovidone and VL6 were recorded in a Fourier transform infrared (FTIR) spectrophotometer (Shimadzu Corporation 8600, Japan) with KBr pellets Preparation of Valsartan Immediate release tablet [14] Valsartan Immediate release tablet VL1 to VL12 were prepared by direct compression method and the detailed tablet composition was given. A total of tablets were prepared in every batch and the quantity for each tablet is given in table-1. Method All the ingredients were passed through 60 mesh sieve separately. Then drug and diluents separately taking small portion of both each time and blending it thoroughly to get uniform mixture. The granules were compressed using 8 mm size to get a tablet of 220 mg tablet weight using Rimek mini press machine Table 1: Composition of various formulations Ingredient (mg) VL1 VL2 VL3 VL4 VL5 VL6 VL7 VL8 VL9 VL1 VL1 VL Valsartan Crospovidone Available online: July Issue 1406

6 Croscarmellose sodium Sodiumstarch glycolate Microcrystalline cellulose Lactose Talc Mg stearate Total Tablet Properties: Hardness test: Tablets require a certain amount of strength, or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packaging and shipping. The hardness of the tablets was determined using Monsanto Hardness tester. It is expressed in Kg/cm2. Three tablets were randomly picked from each formulation and the mean and standard deviation values were calculated. Friability test: It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of lamination or breakage when subjected to mechanical shock or attrition. % Friability of tablets less than 1% is considered acceptable. F = Initial weight- x100 Initial weight Weight variation test [12] The tablets were selected randomly from each formulation and weighed individually to check for weight variation. The U.S Pharmacopoeia allows a little variation in the weight of a tablet. The following percentage deviation in weight variation is allowed. Available online: July Issue 1407

7 Drug content uniformity [13] Twenty tablets were weighed and crushed in a mortar. Then weighed powder contain equivalent to 100mg of drug transferred in 100ml of 0.1 N HCL. Its concentration 1000 mcg/ml. 10ml from this stock solution taken and diluted to 100ml of 0.1N HCL, it makes 249nm. In vitro disintegration time The process of breakdown of a tablet into smaller particles is called as disintegration. The in-vitro disintegration time of a tablet was determined using disintegration test apparatus as per I.P. specifications. I.P. Specifications: Place one tablet in each of the 6 tubes of the basket. Add a disc to each tube and run the apparatus using 0.1 N HCL maintained at 37 ±2 C as the immersion liquid. The assembly should be raised and lowered between 30 cycles per minute in the 0.1 N HCL maintained at 37 ±2 C. The time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured and recorded. In vitro dissolution studies: Dissolution rate was studied by using USP type-ii apparatus (DR-6. Campbell Apparatus, Dissolution Test Apparatus using 900ml of 0.1 N HCl as dissolution medium. The speed of basket paddle was maintained at 50rpm Temperature of the dissolution medium was maintained at 37 ±0.5 C, aliquot of dissolution medium was withdrawn at every 1 min interval and filtered. 5ml of sample was withdrawn and it was replaced with 5ml of buffer solution. The absorbance of filtered solution was measured by UV spectrophotometric method at 249 nm and concentration of the drug was determined from standard calibration curve. The results are given in respective tables. RESULT & DISCUSSION Available online: July Issue 1408

8 Table-2: Granule Parameters for Valsartan Formulation Formulation Code Bulk Density gm/cc True Density Angle Repose =h/r of Percentage Porosity VL VL VL VL VL VL VL VL VL VL VL VL Formulation code Table 3: Physical parameters of dosage form Hardnesss (Kg/cm 2 ) Friability (%) Disintegration time(sec) weight variation Drug Content uniformity VL VL VL VL VL VL VL VL VL VL VL Available online: July Issue 1409

9 VL Drug Polymer Interaction Study The probability/possibility of drug polymer interaction was studied by Infrared Spectroscopy using KBr pellet method. The Infrared Spectra of Pure drug Valsartan shows a characterstic peak at different frequencies which are as follows. Peak at cm-1 is due to C=O stretching. Peak at 1422 cm-1 is due to C=N stretching. Peak cm-1 is due to C-H stretching. Peak at cm-1 is due to C=C stretching. The spectra of the formulation scanned showed following peaks. Peak at cm-1 is due to C=O stretching. Peak at cm-1 is due to C=N stretching. Peak at cm-1 is due to C-H stretching. When the peaks of the formulation spectra compared with the peak of Valsartan Pure Drug Spectra, the characteristic peak of Pure Drug were retained indicating the intactness of the drug in the formulation prepared. Fig 2: FTIR SpectrumIR Spectrum of Fig 3: FTIR SpectrumIR Spectrum Available online: July Issue 1410

10 Crospovidone of Pure Drug Valsartan Fig 4: FTIR SpectrumIR Spectrum of Formulation VL6 Table-4: In-vitro Drug Release of Valsartan Immediate release Tablets Time in Minute VL1 VL2 VL3 VL4 VL5 VL6 VL7 VL8 VL9 VL10 VL11 VL Available online: July Issue 1411

11 Fig 5: Dissolution Profile of Formulations Table 5: Time required dissolving 70% of the drug with various Valsartan Immediate release tablet Sr No. Formulation Code T70%(min) 1 VL VL VL VL VL VL VL VL VL VL VL VL CONCLUSION Valsartan is a new angiotensin II receptor antagonist and is used for the treatment of essential Hypertension only. Croscarmellose sodium, Crospovidone and Sodium starch glycolate alone and in combination were used in different concentration to prepare immediate release tablets. All the formulations prepared were evaluated for Precompression parameters like Bulk density, True density, and Angle of Repose and Percentage porosity and are given in table. The angle of repose for the all formulation was found to be less than 30 indicating free flowing granules. All the Immediate release tablets were found to be elegant without any chipping, capping and sticking. Immediate release tablets so prepared were evaluated for post-compression parameters like Hardness, Friability, Drug content uniformity, weight variation, In-Vitro Dispersion, Drug Available online: July Issue 1412

12 intactness and In-Vitro Drug release studies, etc. Hardness of the three tablets of each batch were checked by using Monsanto hardness tester and the results were shown in the table 9. The results showed that the hardness of the tablet is in the Kg/cm2. Tablets of each batch were evaluated for percentage friability and the results were given in table 10. The results suggest that the friability will withstand the rigors which occurred during packing, transportation and shipping etc. Because of their low percentage friability is less than one. Drug content uniformity study was carried out on the tablets of every batch and the results were shown in the 15. The results were showed that there was uniform distribution of the drug throughout the batch. When the peaks of the formulation spectra compared with the peak of Valsartan Pure Drug Spectra, the characteristic peak of Pure Drug were retained indicating the intactness of the drug in the formulation prepared. Tablets of every batch were subjected to weight variation test, difference in weight and percent deviation was calculated for each tablet was shown in the table 12 to 15. The average weight of the tablet is approximately 160mg and it is in between mg. So the permissible limit is ± 7.5%. The results of the of the test showed that, the tablets were weighing in the range of limit. Three tablets of each batch were evaluated for In-Vitro Dispersion time test. The results showed that the tablets so prepared were disintegrating and dispersing in the time range of 15 to 110 seconds. The tablets of the batch VL6 prepared using 8mg of Crospovidone showed Faster disintegration is within 15 seconds. Finally, the tablets were evaluated for In-Vitro drug release studies for a perod of 10 minutes and the results were shown in the table In all the cases a minimum of 91% of the drug was released within 10 minutes, among the various formulation prepared the batch/tablets of the composition drug Valsartan and Crospovidone (8mg) VL6 released 99% of the drug within 5minute.The improved drug release was mainly due to the increased In-Vitro dispersion which is due due to the addition /inclusion of super disintegrant. t70% value of the drug was relasd within a minimum time of 3 minutes REFERENCE 1. Sameer G, Late, Yi-Ying Yu, Ajay K. Effect of disintegration- promoting agent, lubricants and moisture treatment on optimized fast disintegrating agent. Int J Pharm. 2008:1-8.Shojaei AH. A systemic drug delivery via the buccal mucosal route, Pharm. Tech. 2001; Available online: July Issue 1413

13 2. Bhushan S.Y., Sambhaji S.P. Anant R.P., Mandik K.R. new drug delivery system for elderly, Indian drugs 2003; 37 : Patel VM, Prajapati BG, Patel MM. Design and characterization of chitosan containing mucoadhesive buccal patches of propranolol hydrochloride. Acta pharm. 2007; 57: United States food and drug administration. CDER Data standards manual Abdelbary G, Prinderre P, Eouani C, Joachim J, Reynier.J.P. The preparation of orally disintegrating tablets using a hydrophilic waxy binder. Int. j pharm. 2004; 278: Chang R, Guo X, Burnside B. A review of Immediate release tablets. Pharm Tech. 2000; 24(6): European pharmacopoeia.strasbourg, France 2006; Schiermeier S, Schmidt PC. Fast dispersible ibuprofen tablets. Eur j Pharm Sci. 2002: Chien YW. Novel drug delivery systems. New York Marcel Dekker Inc., 2nd ed Bandari S, Mittapalli RK, Gannu R, Rao MY. Orodispersible tablets: An overview. Asian J Pharm. 2008: Pebley, W.s., Jager N.E., Thompson, S.j.,Rapidly disintegrating tablets US patent No. 5,298,261, Manavalan R and Ramaswamy L. Physiccal Pharmaceutics 1st Edn, Vighnesh Publishers. P.No Subramanyan CVS. Text book of Physical Pharmaceutics. 1st Edn., Published by Vallabh Prakash. P. No Alfred Martin. Text book of Physical Pharmacy 4th Edn., B.I Wavesly Pvt Lts. P.No K.V. Chaudhari, P.D. Gaikwad, V.H Bankar, S.P. Pawar. Development and Validation for simultaneous estimation of Valsartan and Atorvastatin Calcium in bulk and tablet dosage form. International Journal of Pharmacy and Technology June2010:Vol.2.P.No Naman Doshi; Avani Sheth; Tejas Patel,J B Dave, C.N.Patel. Spectrophotometric absorption factor method development and Validation for estimation of Rovastatin calcium and Valsartan in solid dosage form. Journal of Chemical and Pharmaceutical Research 2010,2(3);15-24 Available online: July Issue 1414