FORMULATION AND EVALUATION OF DICLOFENAC SODIUM TABLETS BY USING MELT GRANULATION TECHNIQUE Malla Vasavi Chandrika *, M. Prasanthi 1, N. Rinny Havilah 1, M. Gopi 1 Department of pharmaceutics, St. Ann s College of pharmacy, Chirala, A.P, India Abstract: The main of the present work is to formulate Diclofenac sodium by using melt granulation technique. Here we have formulated three formulations by using melt granulation technique by taking PEG 8000 as a polymer. Formulations prepared with drug : polymer ratio of 1:0.125 (F 1 ), 1:0.5 (F 2 ), 1: 0.75 (F 3 ) by taking along with the super disintegrating agent SSG. All the three formulations were compared with the formulation (F 4 ) prepared by using direct compression technique. The formulations prepared with melt granulation is having better drug release than compared with the formulation prepared with direct compression technique. F 3 was considered as best formulation among the three formulations prepared by melt granulation technique. 93.45% of drug release was observed within 15 minutes for the formulation F 3. The work proves that increase in the concentration of polymer ratio may lead to increase in the drug release pattern. All the four formulations shows first order release pattern. The dissolution kinetics was presented in Table 5. The dissolution rate followed first-order kinetics as the graphs drawn between log % drug unreleased vs time were found to be linear. The dissolution rate of diclofenac sodium was found to be effected by the concentration of the PEG 8000 used in the preparation of tablets. Based on the dissolution rate, the order of drug release for the four formulations was F3> F2> F1> F4. The formulation prepared with 1:0.75 (F3) was offered relatively rapid release of diclofenac sodium when compared with other concentrations employed in this investigation. Key words Diclofenac sodium, PEG 8000, SSG, Melt Granulation Technique. Corresponding author Malla Vasavi Chandrika Department of pharmaceutics, St. Ann s College Of pharmacy, Chirala, A.P, India INTRODUCTION Diclofenac sodium is a non-steroidal antiinflammatory drug (NSAID). It is used for relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and relief of mild to moderate pain and is used in chronic and acute conditions of pain and inflammation. As its serum concentrations and analgesic effect are correlated, rapid absorption of diclofenac sodium could be a prerequisite for the quick onset of its action. Rate of bioavailability of Diclofenac sodium is highly variable due to their low aqueous solubility [1]. The major problems with drug are its very low solubility in biological fluids and its short biological half-life of 1.2-2 h.1 Melt granulation is one of the novel granulation technology. Melt granulation is the process by which granules are obtained through addition of either molten binder (or) a solid binder which melts during process. This process is known as melt granulation and thermoplastic Advanced Journal of Pharmacie and Life science Research 16
Adv J Pharm Life Sci Res, 20164;2:16-22 granulation [2]. Principle of melt granulation consists of combination of three phases wetting & nucleation, coalescence step and attrition, breakage. During nucleation step the binder comes into contact with the powder and some liquid bridges are formed, leading to the formation of small agglomerates [3,4]. In distribution method a molten binding liquid is distributed on to surfaces of fine solid particles. coalescence step involves nuclei that have residual surface liquid to promote successful fusion of nuclei. Attrition and breakage refer to the phenomenon of granulation fragmentation in that are solidified by tray cooling to ambient temperature without the need for drying by tumbling process. Materials and Methods: Diclofenac sodium is a gift sample from Sarvotham care Ltd, Hyderabad, Sodium starch glycolate, PEG 8000 are procured from LOBA chem. pvt Ltd, Mumbai. Magnesium stearate was procured from S.D. Fine chem. Ltd, Mumbai. A single punch tablet press (Cadmach machinery Co. Pvt. Ltd., Ahmedabad); disintegration test apparatus (2-USP-305), Camphbell electronics, Mumbai); dissolution test apparatus (DT 03071009, lab India- Mumbai, 2000); and UV-visible spectrophotometer (SL159, Elico Ltd., Hyderabad) were used in research work. Preparation of Diclofenac sodium tablets by Melt Granulation Technique Different batches of tablets were prepared by Melt granulation technique. Three different batches of tablets are prepared by taking PEG 8000 as a polymer. Formulations prepared with drug : polymer ratio of 1:0.125 (F 1 ), 1:0.5 (F 2 ), 1: 0.75 (F 3 ) along with superdisintegrant sodium starch glycolate of fixed concentration 10 mg, of each and compare with fourth batch of tablets prepared by direct compression technique with same concentration of super disintegrating agent. The required quantity of binder was heated in a water bath until it gets converted into liquid state. Then the specified amount of drug was added to the molten mass in order to produce damp mass. The granules were formed by passing the damp mass through sieve no: 16. The granules were dried at 35 0 c for 20 minutes and to this dried granules specified amount of SSG was added and was lubricated with magnesium stearate and compressed into tablets using the Cadmach single punch (round shaped, 7mm thick) machine. Thus the three batches were prepared in different concentrations as shown in the table 1. Advanced Journal of Pharmacie and Life science Research 17
Table I Composition of ingredients for Diclofenac tablets by Melt Granulation Technique S.No Ingredients F 1 F 2 F 3 F 4 1 Diclofenac sodium (mg) 100 100 100 100 2 PEG 8000 (mg) 0.125 0.5 0.75-3 Sodium starch glycolate (mg) 10 10 10 10 4 Magnesium stearate (mg) 2.875 2.5 2.125 3 5 Total weight (mg) 113 113 113 112 Table II: Micrometric properties for formulation blends Formulation code Bulk density (gm/cm3 ) Tapped density (gm/cm3 ) Carr s index (%) Hausner s ratio F 1 0.441 0.512 14.48 1.12 F 2 0.451 0.511 13.21 1.14 F 3 0.480 0.510 14.22 1.16 F 4 0.439 0.502 13.01 1.20 Table III: Physical parameters of Diclofenac sodium fast dissolving tablets Sl.No Parameters F 1 F 2 F 3 F 4 1 Average weight(mg) 113±0.2 113±0.1 113±0.1 113±0.2 1 Disintegration time(sec) 162 149 125 180 3 Friability (%) 0.67 0.87 0.89 0.71 4 Hardness(kg/sqcm) 3.9 3.7 4.0 4.5 Table IV: In-vitro dissolution data of Diclofenac sodium tablets Sl.No Sampling time (min) Percentage of drug released ( ± S.D.) F 1 F 2 F 3 F 4 1 0 0.00 0.00 0.00 0.00 2 5 26.35 31.78 66.64 29.84 3 10 64.40 69.03 81.77 33.15 4 15 83.23 90.52 97.81 33.35 5 20 92.12 96.32-63.68 6 25 97.88 99.84-67.88 7 30 - - - 80.32 Advanced Journal of Pharmacie and Life science Research 18
Table V: In-vitro dissolution kinetics of Diclofenac sodium tablets Formulation T 50 (min) T 90 (min) DE 15 (%) K (min -1 ) Correlation coefficient values Zero First Order order F 1 13.07 43.45 44.13 0.053 0.982 0.985 F 2 8.05 26.77 48.70 0.086 0.825 0.994 F 3 6.66 22.14 66.44 0.104 0.927 0.969 F 4 23.1 76.76 44.68 0.003 0.788 0.860 EVALUATION OF DICLOFENAC SODIUM TABLETS Weight variation test [5] : Weight variation test was done by weighing 20 tablets individually, calculating the average weight and comparing the individual tablet weight to the average weight. Disintegration Time [6,7] : The disintegration time was determined in distilled water at 37±0.50 C using disintegration test apparatus USP ED-2L (Electro lab, Mumbai). Friability [8] : Roche friabilator was used to determine the friability. Pre weighed tablets were placed in friabilator and rotated at a speed of 25 rpm for 4 minutes or up to 100 revolutions. The tablets are dropped from a distance of 6 inches in each revolution. The tablets were then reweighed after removal of fines and the percentage of weight loss was calculated % friability= Wt before friabilation - Wt after friabilation X 100 Wt before friabilation *Wt Weight Hardness [9, 10] : Hardness of the tablet was determined using the Monsanto hardness tester. The lower plunger was placed in contact with the tablet and a zero reading was taken. The plunger was then forced against a spring by tuning threaded bolts until the tablet fractured. Then the final reading was recorded. The hardness was computed by deducting the initial pressure from the final pressure. [11, Dissolution studies 12] : Dissolution studies for Diclofenac sodium tablets were performed in ph 6.8 phosphate buffer using USP dissolution test apparatus (Electrolab, Mumbai, India) with a paddle stirrer. The paddles are allowed to rotate at speed of 100 Advanced Journal of Pharmacie and Life science Research 19
rpm. The dissolution medium was maintained at a temperature of 37+0.5 OC and samples are withdrawn at an interval of every 5 min the volume of the withdrawn samples are replaced by fresh dissolution medium in order to kept the volume of the dissolution medium as constant. The withdrawn samples are filtered and absorbance was measured at absorption maxima of 283 nm using UV-visible spectrophotometer. In-vitro dissolution kinetic studies [13, 14] : The drug release data were plotted and tested with zero order (cumulative % drug released Vs time), First order (Log % remained Vs time). The in vitro dissolution kinetic parameters, dissolution rate constants (K), correlation coefficient (r), the times (t50) for 50 % drug released (half-life) and dissolution efficiency [D.E]. were calculated. From the slopes of linear plots, the dissolution rates were calculated. RESULTS AND DISCUSSION Micromeritic properties: Micromeritic properties of the blends were studied and results were shown in Table II. All the blends exhibited good flow properties. % drug release 200 0 0 20 40 Time (min) Figure I: In-vitro dissolution profile of Diclofenac Sodium tablets formulated with different concentrations of PEG 8000 Influence of PEG 8000 on Diclofenac sodium tablets: To study the influence of PEG 8000 on the performance of diclofenac sodium, a set of four formulations (F 1 to F 4 ) were prepared using three different concentrations of PEG 8000. Formulations prepared with drug: polymer ratio of 1:0.125 (F 1 ), 1:0.5 (F 2 ), 1: 0.75 (F 3 ) by taking along with the super disintegrating agent SSG respectively. The formulated tablets were subjected to various quality control tests and the results were shown in Table III. All the tablets complied with the pharmacopoeial standards. The dissolution data was presented in Table IV and Figure 1. The In-vitro dissolution kinetics was presented in Table V. The dissolution rate followed first-order kinetics (Figure 2) as the graphs drawn between log % drug unreleased vs time were found to be linear. The dissolution rate of diclofenac sodium was found to be effected by varying concentrations of PEG 8000 used in the preparation of tablets. The formulation F1 F2 F3 F4 Advanced Journal of Pharmacie and Life science Research 20
prepared with PEG 8000 was offered relatively rapid release of diclofenac sodium when compared with other formulations used in this investigation. Log % drug unreleased Figure II: First order plots of Diclofenac Sodium tablets formulated with different concentrations of PEG 8000 REFERENCES: 1.Erno A. van Schaik, Philippe Lechat, Bart M M. Remmerie, Grant Ko, Kenneth C. Lasseter, Eric Mannaert. Pharmacokinetic Comparison of Fast-Disintegrating and Conventional Tablet Formulations of Risperidone in Healthy Volunteers. Clinical Therapeutics 2003; 25(6):1687-1699. 4 2 0-2 0 20 40 time (min) 2.Suresh Bandari. Orodispersible tablets: An over view. Asian J Pharm. 2008;2(1) :1-5. 3.Bogner RH,Wilkosz MF. Fast Dissolving Tablets New Dosage Convenience for Patients, US Pharm 2002; 27: 34-43. 4. Habib W, Khankari R, Hontz J. Fast Dissolve Drug Delivery Systems. Crit Rev Therap Car Sys 2000; 17: 61-64. F1 F2 F3 F4 5.A.Martin and J.Swarbrick, Physical pharmacy, 3 rd edition, Mumbai: Varghese publishing house, 1993, Pg. No. 444-447. 6. Indian pharmacopoeia 2007, Vol 3, Monographs on dosage forms, The Indian pharmacopoeia commission, Ghaziabad, 2007,182-183. 7.Tapan Kumar Giri, Hemant Badwaik, Amit Alexander, Dulal Krishna Tripathi. Solubility enhancement of ibuprofen in the presence of hydrophilic polymer and surfactant. Int j applied Biology and Pharmaceutical Technology 2009; 2(2 ),119-130. 8.Indian pharmacopoeia 2007, Vol 3, Monographs on dosage forms, The Indian pharmacopoeia commission, Ghaziabad, 2007, 177-178. 9.Indian pharmacopoeia 2007, Vol 3, Monographs on dosage forms, The Indian pharmacopoeia commission, Ghaziabad, 2007,183-184. 10. USP 27/NF 22, Asian edition, General test procedures, U.S. Pharmacopoeial convention, Rockville MD, 2000,1677-1678. 11. Battue S K,Repay M.A, Maunder S, Rio M Y. Formulation and evaluation of rapidly disintegrating tablet Fenoverine tablets: Effect of superdisintegrants. Drug. Dev. Ind. Pharm 2007;33: 1225-1232. Advanced Journal of Pharmacie and Life science Research 21
Adv J Pharm Life Sci Res, 20164;2:16-22 12. Sunada H, Yonezawa Y, Danjo K, Otsuka A, Iida K. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. Chem Pharm Bull (Tokyo) 1996 ; 44: 2121-2127. 13. Gohel.M.C, Bansal.G, Bhatt.N, Formulation and evaluation of orodispersible taste masked 14. tablets of Famotidine. Pharma Boil world 2005;3: 75-80. ********** Advanced Journal of Pharmacie and Life science Research 22