FORMULATION AND EVALUATION OF ACECLOFENAC MATRIX TABLETS USING ETHYL CELLULOSE AND CELLULOSE ACETATE PHTHALATE

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1 M. Vijaya Laxmi et al. / JGTPS/ 5(3)-(2014) ISSN: (Research Article) Journal of Global Trends in Pharmaceutical Sciences Journal home page: FORMULATION AND EVALUATION OF ACECLOFENAC MATRIX TABLETS USING ETHYL CELLULOSE AND CELLULOSE ACETATE PHTHALATE M. Vijaya Laxmi* Vamshi Krishna. J Department of Pharmaceutics, Teegala Krishna Reddy College of Pharmacy, Hyderabad, India ABSTRACT The objective of this investigation was to formulate modified release matrix tablets of Aceclofenac, a BCS class II drug by wet granulation method, using Ethyl cellulose (EC) and Calcium Acetate Phthalate (CAP). This combination was taken into consideration to minimize initial release of the drug in gastric region to avoid irritation. A total of 12 formulations were formulated, among which three were prepared only with EC in three different proportions to know to what extent an initial release of drug takes place in the absence of enteric polymer (CAP) and the rest were formulated in three different proportions to EC and CAP where, EC acts as sustained release polymer and CAP as a ph dependent polymer. The combination of EC and CAP gave in vitro release in such a way that as the concentration of EC increased, the prolongation of drug release was achieved and at the same time as the concentration of CAP increased, initial release was minimized. Among the formulations, F 9 was adjudged as the best formulation since it minimized the initial drug release of the drug to the maximum extent compared to other formulations and prolonged for 14 h. Keywords: Modified release, ph dependent, Ethyl Cellulose, Calcium Acetate Phthalate, Aceclofenac. INTRODUCTION Non steroidal anti inflammatory drugs (NSAIDs) are considered to be the first line drugs in the symptomatic treatment of rheumatoid arthritis, osteoarthritis and spondylitis, Aceclofenac is one of them 1. It is a newer derivative of Diclofenac with low gastrointestinal complications. The short biological half life (3 4h) and dosing frequency more than one per day make Aceclofenac an ideal candidate for sustained release. To reduce the frequency of administration and to improve patient compliance, an once daily sustained release formulation of Aceclofenac is desirable. Matrix tablets composed of drug and release retarding polymer like EC offer the simplest approach in designing a sustained release system. Controlled release preparations have been reported to reduce the gastro irritant and ulcerogenic effects of non steroidal anti-inflammatory drugs. In the present study, an attempt was made to develop matrix tablet-based controlled release formulations of ibuprofen, using ethyl cellulose as the rate-controlling polymer. Cellulose acetate phthalate (CAP) is a commonly employed enteric coating polymer in pharmaceutical industry. In combination with cellulose acetate butyrate, CAP has been employed for preparing enteric matrix microspheres by emulsion solvent evaporation technique. Detailed literature search revealed only one report on the use of CAP in tablet based matrix systems of macromolecular diffusion due to their porous gel state that may be controlled through specific coating procedures 2, 3. Address for correspondence M. Vijaya Laxmi* Teegala Krishna Reddy College of Pharmacy, Hyderabad MATERIALS & METHODS: Materials: Aceclofenac, Calcium Acetate phthalate and Povidone K-30 were obtained as gift samples from Rexer Pharma Ltd.; Ethyl Cellulose was purchased from S D Fine Chem Limited. All other chemicals and reagents used in the investigation were of analytical grade. Preparation of Matrix Tablets: The experimental batches of the tablets were prepared using wet granulation technique. Then, these granules were compressed with 7 mm punch with a target compression weight of 150 mg containing 100 mg active dose. The accurately weighed quantity of Aceclofenac was mixed with the EC and CAP and blended, the binder solution prepared by dissolving the Povidone in purified water was then added slowly to above mixture to form a damp mass, which was then passed through the coarse sieve (20 screens). The obtained coarse granules were dried at 50 C for 20 min, and then dried granules were mixed with glidant and lubricant followed by mixing. These granules were passed through sieve #30 before compression 5, 6. Calibration Curves of Aceclofenac: 100 mg of Aceclofenac was taken and dissolved in small amount of acidic buffer of ph 1.2 and further diluted up to 100 ml with the same buffer. This gives standard solution of Aceclofenac (1mg/ml) which can be used for further dilutions. From the standard solution, samples of different concentrations are prepared, and 1804

2 analyzed spectrophoto-metrically at 268 nm. Observations are tabulated in Table 1 and standard graph is represented in Figure 1. Table 1: Concentration and absorbance values of Aceclofenac in Acidic Buffer (ph 1.2) S. No Concentration (µg/ml) Absorbance Figure 2: Standard curve of Aceclofenac in Phosphate Buffer (ph 6.8) Drug Excipient Compatibility: In tablets, drug is in intimate contact with one or more excipients, which could affect the stability of the drug. The knowledge of drug-excipients interaction is therefore essential for selecting appropriate excipients. This was studied using FT-IR spectrophotometry. FTIR Spectra are represented in Figures 3 and Transmittance [%] Wavenumber cm-1 Figure 3: FTIR Spectrum of Pure Drug Figure 1: Standard curve of Aceclofenac in Acidic Buffer (ph 1.2) 100 mg of Aceclofenac was taken and dissolved in small amount of phosphate buffer of ph 6.8 and further diluted up to 100 ml with the same buffer. This gives standard solution of Aceclofenac (1mg/ml) which can be used for further dilutions. From the standard solution, samples of different concentrations are prepared, and analyzed spectrophoto-metrically at 275 nm. Observations are tabulated in Table 2 and standard graph is represented in Figure 2. Table 2: Concentration and absorbance values of Aceclofenac in Phosphate Buffer (ph 6.8) S. No Concentration (µg/ml) Absorbance Transmittance [%] Wavenumber cm Figure 4: FTIR Spectrum of Drug-Polymer Mix The principle FTIR absorption peaks of Aceclofenac at cm 1 ( NH stretch) , cm-1 (C-O stretch), cm-1 (stretch aromatic), cm -1 (stretch), were observed in Aceclofenac as well as the Drug-Polymer mixture. Thus the FTIR studies indicated that there were no drugexcipient interactions. Evaluation of Granules: Angle of Repose: The angle of repose was determined bythe funnel method. The accurately weighed 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 and angle of repose was calculated using the following equation θ = tan 1 (h/r) Where; h and r are the height and radius of the powder pile respectively. The results are shown in Table

3 Bulk Density Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. A quantity of 2 g of 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 observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 second intervals. The tapping was continued until no further change in volume was noted. LBD and TBD were calculated using the following formulae. LBD = Weight of the Powder/Volume of the packing TBD = Weight of the Powder/ Tapped volume the packing Compressibility Index & Hausner Ratio: In recent years the compressibility index and the closely related Hausner ratio have become the simple, fast, and popular methods of predicting powder flow characteristics. The Carr s compressibility index was found by the equation Carr s Index (%) = (TBD LBD)/TBD X 100 Hausner Ratio = TBD/LBD The results are tabulated in Table 5. Drug Content: Three tablets were weighed and average weight was calculated. All tablets were crushed. The powder equivalent to 50 mg of drug was weighed and dissolved in phosphate buffer (ph 6.8) and the volume was made up to 50 ml with phosphate buffer (ph 6.8) 7. This is considered as stock solution. 1 ml of this solution was suitably diluted with phosphate buffer (ph 6.8) and the drug content was determined spectrophotometrically at 275 nm. Drug content values of different formulations were reported in Table 5. Evaluation of Tablets Thickness The thickness of the tablets was determined by using vernier callipers. Five tablets from each batch were used and average values were calculated. The results are reported in Table 5. Uniformity of Weight To study weight variation, 20 tablets of each formulation were weighed using an electronic balance and the test was performed according to the official method. The results are reported in Table 5. Hardness and Friability The resistance of tablet for shipping or breakage, under conditions of storage, transportation and handling, before usage, depends on its hardness. Friability is the measure of tablet strength. For each formulation, the of hardness and friability of tablets was determined using the Monsanto Hardness tester and the Roche friabilator respectively. The results are reported in Table 5. In Vitro Release Studies The release profile of Aceclofenac from modified release tablets was determined using USP dissolution testing apparatus II (paddle type) at 75 rpm. The dissolution test was performed for first 2 h using acidic buffer (ph 1.2) at 268 nm. Further dissolution test was carried out for a period of 12 h using phosphate buffer (ph 6.8) at 275 nm. The temperature of the dissolution medium was maintained at 37 ± 0.5 C. 1 ml of the sample was withdrawn at regular intervals and replaced with the same volume of pre-warmed fresh dissolution medium. The withdrawn samples were made up to 10 ml using Acidic Buffer (ph 1.2) for first 2 h and the rest with phosphate buffer (ph 6.8) 8. After filtration, the amount of drug release was determined from the standard calibration curve of pure drug. The results are tabulated in Table 6. Stability Studies: Stability testing of drug product begins as a part of drug discovery and ends with the demise of the compound or commercial product. To assess the drug and formulation stability, short term stability studies were carried out. The short term stability studies were carried out for the most satisfactory formulation. As per ICH guidelines, The most satisfactory formulation was sealed in aluminum packaging and kept in humidity chamber maintained at 30 ± 2 C / 65 ± 5% RH and 40 ± 2 C / 75 ± 5% RH for two months 9. The results are tabulated in Table 7. RESULTS AND DISCUSSION: Micrometric Properties: Angle of Repose: The values of the angle of repose for F 1,F 2 and F 3 formulations were ranged from to (Table 5) and the angle of repose to be in the range between (Table 3) which indicates Good/Fair flow properties of granules. Table 3: Flow properties & corresponding Angles of repose Flow Property Angle of Repose ( 0 ) Excellent Good Fair (aid not needed) Passable (may hang up) Poor (must agitate, vibrate) Very poor

4 The values of angle of repose for F 4,F 5 and F 6 formulations were ranged between to (Table 5) and the angle of repose to be in the range between (Table 3) which indicates Excellent/Good flow properties of granules. The angle of repose of F 7, F 8 and F 9 formulations were ranged from to (Table 5) and the angle of repose to be in the range from 25 to 35 which indicates Excellent/Good flow properties of granules. Table 4: Formulation Development; Compositions of various formulations Ingredients E 1 E 2 E 3 F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9 Ethyl Cellulose (14 cps); mg Cellulose Acetate Phthalate; mg Povidone K-30; mg Purified water (ml) Lactose; mg Magnesium Stearate; mg Talc; mg Total weight of tablet; mg Code Angle of repose ( ) **Equal amount of drug was used in all the above formulations Table 5: Different evaluation parameters of all the formulations Carr s Index (%) Hausner Ratio Hardness (kg/cm²) Thickness (mm) Weight variation (% deviation) Drug Content (%) Friability (% Loss) E ± E ± E ± F ± F ± F ± F ± F ± F ± F ± F ± F ± Table 6: Cumulative % drug release of all the formulations Time (min) E 1 E 2 E 3 F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F

5 Figure 5: Dissolution profiles of formulations E 1, E 2 and E 3 Figure 6: Dissolution profiles of formulations F 1, F 2 and F 3 Figure 7: Dissolution profiles of formulations F 4, F 5 and F 6 Figure 8: Dissolution profiles of formulations F 7, F 8 and F

6 Table 7: Stability studies of formulation F 9 (optimized batch) Time (Days) Hardness (kg/cm 2 ) Drug content (%) Drug release at the end of 840 minutes A B C D A, C = 30 ± 2 C / 65 ± 5% RH; B, D = 40 ± 2 C / 75 ± 5% RH Compressibility index: The compressibility index values of F 1, F 2 and F 3 formulations were ranged from to (Table 5) and the compressibility index was found to be in the range of (Table 8). These findings indicated that the mixture of F 1 formulation exhibited Good/Fair flow properties. Table 8: Flow properties & corresponding Compressibility indices Flow Property Compressibility Index Excellent 10 Good Fair Passable Poor Very poor The compressibility index values of F 4, F 5 and F 6 formulations were ranged from to (Table 5) and the compressibility index was found to be in the range of (Table 8). These findings indicated that the F 4 formulation exhibited Fair flow properties. The compressibility index values of F 7, F 8 and F 9 formulations were found to be to (Table 5) and the compressibility index was found to be in the range of (Table 8). These findings indicated that the mixture of F 7, F 8 and F 9 formulations exhibited flow properties. Hausner Ratio: The Hausner ratio values of F 1, F 2 and F 3 formulations were ranged from 1.13 to 1.33 (Table 5) and the Hausner ratio was found to be in the range of (Table 9). These findings indicated that the mixture of F 1 formulation exhibited Good/Fair flow properties. Table 9: Flow properties & corresponding Hausner ratio Flow Property Hausner Ratio Excellent Good Fair Passable Poor Very poor The Hausner ratio values of F 4, F 5 and F 6 formulations were ranged from 1.21 to 1.5 (Table 5) and the Hausner ratio was found to be in the range of (Table 9). These findings indicated that the mixture of F 4 formulation exhibited Fair flow properties. The Hausner ratio value of F 7, F 8 and F 9 formulations were ranged from 1.31 and 1.41 (Table 5) and the Hausner ratio was found to be in the range of (Table 9). These findings indicated that the mixture of F 7 formulation exhibited Poor flow properties. Physicochemical Parameters: The tablets of different batches were found to be uniform with respect to thickness (3.5 to 3.58 mm) and hardness (4.76 to 7.86 kg/cm2). The friability (%) and weight variation of different batches of tablets were found within the prescribed limits (friability: 0.25 to 0.53%; deviation of weight variation test: 0.2 to 1.5%). Good and uniform drug content (>98%) was observed within the batches of different tablet formulations. In Vitro drug release: The formulations F 1, F 2, F 3 containing 10 mg EC and 2.5mg, 5.0mg, 7.5 mg CAP, respectively gave initial drug release ranged from 9.11 ± 1.09 to ± 0.91% for first 2hr and eventually complete release of the drug, ranged from ± 0.55 to ± 0.55% within 9hr. The formulations F 4, F 5, F 6 containing 15 mg EC and 2.5 mg, 5.0mg, 7.5mg CAP, respectively gave initial drug release of 8.74 ± 1.09 to ± 2.78% for first 2hr and eventually complete release of the drug, ranged from ± 1.11 to ± 0.73% for 11hr. The formulations F 7, F 8, F 9 containing 20mg EC and 2.5mg, 5.0mg, 7.5mg CAP, gave initial drug release of 4.98 ± 0.55 to 9.11 ±1.09% for first 2hr and eventually complete release of the drug, ranged from ±.93 to ± 0.83% for 14hr. With regard to the effect of polymer concentration, decrease in drug release rate was observed when polymer content in the matrix was increased. This may be due to the reason that the polymer in higher concentrations in the tablets might have produced dense matrix around the drug particles, providing more barriers for them to escape and dissolve. As the concentration of Ethyl Cellulose increased from 10 to 20 mg, the drug release rate decreased significantly. The results indicate that, formulations where 10 mg of EC is used, could not sustain the release for longer periods of time, as complete 1809

7 release occurred within 9 hrs. The formulations where 20 mg of EC is used, could sustain the release for longer periods of time, as complete release occurred up to 14 hrs. CONCLUSION A total 12 formulations of modified release matrix tablets of Aceclofenac were prepared by wet granulation technique. The prepared formulations were evaluated for the precompression parameters such as angle of repose, bulk density, tapped density, % compressibility, Hausner ratio and post compression parameters such as weight variation, thickness, hardness, friability, drug content. First three formulations were prepared by using only ethylcellulose in order to know to what an extent drug releases in the absence of CAP. As the concentration of EC increased there was less initial release and prolonged for 14 h. Then a combination of EC and CAP were tried in different proportions with an ideal of minimal initial release in gastric ph and then prolonging it for longer duration. As the concentration of both EC and CAP increased, the initial release was minimized and the matrix tablets prolonged the release for 14 h. Different kinetic models were fitted for dissolution profile of best formulation to know the release mechanism. The best formulation F 9 followed controlled and Non-Fickian mechanism of release. The stability studies were carried out for the most satisfactory formulation F 9 which showed no major change in physicochemical parameters, like hardness, drug content and in vitro dissolution profile. ACKNOWLEDGEMENTS The authors are sincerely thankful to Rexer Pharma Ltd., for providing the gift samples of Aceclofenac, CAP and Povidone K-30. Authors also thank the management of Teegala Krishna Reddy College of Pharmacy, Hyderabad, India for providing the facilities to carry out this research work. REFERENCES 1. Tripathi.K.D, Essentials of medical pharmacology, 6th Edition, 2009, J.P. Publication Joseph W and Nairn JG. Some factors affecting the microencapsulation of pharmaceuticals with cellulose acetate phthalate. J. Pharm. Sci. (1986) 75: Wan LSC and Chui WK. Deviation of the ratio of drugs in a two-component mixture encapsulated in cellulose phthalate microspheres. J. Microencapsul. (1995) 12: Chandran S, Laila FA and Mantha N, Design and evaluation of Ethyl Cellulose Based Matrix Tablets of Ibuprofen with ph Modulated Release Kinetics, Indian Journal of Pharmaceutical Sciences, September-October 5. Thiruganesh Ramasamy et al, Evaluation of Chondroitin Sulphate Tablets of Aceclofenac for Colon Targeted Drug Delivery, Iranian Journal of Pharmaceutical Research (2012), 11 (2): Lachman L, Lieberman HA, Kanig JL, editors. 3rd ed. Mumbai: Varghese Publishing House; pp (The Theory and Practice of Industrial Pharmacy). 7. Chourasia MK, Jain SK. Pharmaceutical approaches to colon targeted drug delivery systems. J. Pharm. Pharamaceut. Sci. 2003;6: Swarbrick J. Encyclopedia of Pharmaceutical Technology. 2000; Vol. 6: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products, Annex 2, WHO Technical Report Series, No. 953, Ritger PL, Peppas NA. A simple equation for the description of solute release, I: Fickian and non- Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Control Rel. 1987; 5: Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharm. 1983; 15: Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC) Adv. Drug Deliv. Rev. 2001; 48: Roxin P, Karlsson A, Singh SK. Characterization of cellulose acetate phthalate (CAP) Drug Dev Ind Pharm. 1998;24: Beyger JW, Nairn JG. Some factors affecting the microencapsulation of pharmaceuticals with cellulose acetate phthalate. J Pharm Sci. How to cite this article: M. Vijaya Laxmi*, Vamshi Krishna. J: Formulation and Evaluation of Aceclofenac Matrix Tablets using Ethyl Cellulose and Cellulose Acetate Phthalate: A Review, 5(3): (2014) All are reserved by Journal of Global Trends in Pharmaceutical Sciences. 1810