FORMULATION AND EVALUATION OF ACECLOFENAC LOADED SR MATRIX PELLETS: EXTRUSION SPHERONIZATION

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1 Academic Sciences International Journal of Pharmacy and Pharmaceutical Sciences ISSN Vol 5, Suppl 3, 2013 Research Article FORMULATION AND EVALUATION OF ACECLOFENAC LOADED SR MATRIX PELLETS: EXTRUSION SPHERONIZATION ABSTRACT PRASHANT K. PURANIK, FARHAN M. KHAN* Government College of Pharmacy, Aurangabad (M.S.), India. Received: 28 Jun 2013, Revised and Accepted: 21 July 2013 Objective: The major objective of this study was to prepare and evaluate Once- Daily Sustained Release Matrix Pellets Formulation of Aceclofenac by using Extrusion-Spheronization technique. Methods: The sustained release matrix pellets of Aceclofenac were prepared by industrially applied extrusion spheronization technique. The different formulations were prepared using HPMC K100M LVCR as hydrophilic matrix polymer, PEG 400 as potential plasticizer in different concentration, MCC PH101 as a spheronization aid and HPMC K4M (2% w/w) as binder. The prepared pellets were evaluated for parameters like Flow Properties, Morphological characteristics, Drug Content and In vitro drug release study in ph 6.8 phosphate buffer. Experimental design technique was used to select optimized formulation releasing drug for 24 hr. Results: The Aceclofenac SR matrix pellets composed of HPMC K100M LVCR 11 % and PEG % was selected as optimised. The evaluated parameters of optimised batch were found within the limits. Drug release of optimized batch (F3) at 2 hr was found to be less than 30 % (25.43 %) and at 24 hr more than 80 %( 98.32%). Conclusion: The results from this study showed that combination of HPMC K100M LVCR as hydrophilic matrix polymer and PEG 400 as potential plasticizer is effective and useful for sustaining the Aceclofenac release. And hence Extrusion-Spheronization technique can be promising approach for the preparation of pellets which assure its applicability for large scale manufacturing. Keywords: Aceclofenac, Extrusion-Spheronization, Hydroxypropyl Methylcellulose, Matrix Pellets. INTRODUCTION Aceclofenac is a new generation NSAID showing effective Antiinflammatory and Analgesic properties and a good tolerability profile in a variety of painful conditions like Ankylosing spondylitis [1,2], Rheumatoid Arthritis [3], and Osteoarthritis [4]. It directly blocks the prostaglandin s synthesis and has less GI complications. It has a short biological half life of approx 4 h and a dosing frequency of 200 mg daily in two divided doses [5, 6]. This necessitates multiple daily dosing for maintenance of its plasma concentration within the therapeutic index. Hence, there is impetus for developing sustained release multiple-unit dosage form that maintains therapeutic plasma drug concentration for long period compared to conventional dosage forms. Several matrix based sustained release products of aceclofenac utilizing hydrophilic and hydrophobic polymers have been reported [7, 8]. Polymer matrix systems have the advantages of prolonging drug release and reducing adverse effects in patients. An attempt has been made in the present study to achieve desirable therapeutic profile of Aceclofenac by formulating its sustained release pellets using HPMC of various viscosity grades. Matrix pellets composed of drug and polymer as release retarding material offer the simplest approach in designing a sustained release system [9]. Multiple unit extended release dosage forms are becoming very popular dosage forms relative to single unit dosage forms because of their ability to spread uniformly in the gastrointestinal tract, thus minimizing the plasma level variability and reduced risk of local irritation [10, 11]. Pharmaceutical pellets may be defined as spherical, free-flowing granules with a relatively narrow size distribution ( μm) [12]. The ultimate dosage forms for pellets can be capsule or they may be compressed into disintegrating tablets. Interest in this area has been increasing continuously, since it offers some important pharmacological as well as technological advantages [13,14]. In the present study, Extrusion-Spheronization method was adopted for the preparation of sustained release pellets of Aceclofenac. Extrusion -Spheronization may be defined as a process in which a wet mass is extruded through a specific sieve with fixed diameter and subsequently spheronized into spherical particle called as spheroids, pellets or beads depending upon materials and process used for Extrusion Spheronization [15]. MATERIAL AND METHODS Aceclofenac was obtained as a gift sample from Flamingo Pharma Ltd (Mumbai, India). Hydroxypropyl Methylcellulose (Methocel K4M, Methocel K15M and Methocel K100M) Colorcon Asia Pvt. Ltd, (Mumbai, India ), Micro crystalline cellulose (Avicel PH101& 102) - Signet chemical corporation, (Mumbai, India) and ), Polyethylene Glycol 400 (AR grade) were purchased from Merck (Mumbai, India). All other chemicals and reagents used were of AR grade. Preliminary Studies Selection of Spheronizing Aid for Pellets The pellets of individual spheronizing aid like MCC PH101, MCC PH102 and lactose were prepared by extrusion Spheronization. The possibility of pelletization and appearance of pellets was observed as a response [16]. Selection of Binder and Binder Level Optimization Pellets of microcrystalline cellulose PH101 were prepared incorporating various binder solutions such as water, HPMC (K4M, and K15M) solution (in water). The responses of consistency of extrudate were studied and pellets were observed for their appearance and strength [17, 18]. Pellets of MCC 101 were prepared with HPMC K4M in the concentration range of 1-3%w/v. The consistency of damp mass, pellet s appearance and pellet s strength were studied. Optimization of Extrusion Spheronization Process In an attempt to formulate pellets with desired characteristics (physical appearance and sphericity), the parameters like speed of spheronization and time of spheronization were varied in the range as mentioned below. Thus, 3 2 =9 formulations were prepared as per 3 2 factorial model experimental design. Speed of spheronization (X1) = 1000, 1200, 1400 rpm Time of spheronization (X2) = 10, 15, 20 min

2 Drug- Excipients Compatibility Study Differential Scanning Calorimetry Differential scanning Calorimetry was performed using DSC (DSC 60 Shimadzu, Japan) in order to investigate potential solid state interactions between drug and excipients. Standard aluminium sample pans were used and a heating rate of 10 0 C/min was employed in the range of C. DSC thermograph of Aceclofenac with the excipients HPMC K100M, K4M and MCC was recorded on Differential Scanning Calorimeter. Table 1: Formulation compositions for different batches Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 Aceclofenac % HPMCK100 LVCR % PEG 400 % MCC PH 101 % HPMC K4M (Approximate 19 gm) (2%w/v solution in water) Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Preparation of SR Matrix Pellets Formulation The compositions for all the batches using 3 2 factorial design approach are given in Table 1. All the ingredients including drug and polymers were weighed accurately, sieved through 40 mesh sieve and mixed geometrically in a mixing bag. Powder blend was granulated with binder solution (2% HPMC K4M) and purified water to form wet mass. This wet mass was then extruded through roller extruder having 1 mm extruder screen. Extrudate was then spheronized using a Spheronizer; equipped with 4.2 mm friction plate at 1200 rpm for 20 min. as optimized earlier. (Extruder 20 and Spheronizer 250, Anish Pharma, India) Spheronized pellets were dried. These dried pellets were screened through 40 mesh and evaluated. Evaluations of Prepared Pellets Morphological Characteristics and Flow Properties of Pellets All the batches were studied with regards to the morphological features i.e. roundness, aspect ratio, pellet size, and shape using photomicrograph. The prepared pellets were evaluated for the parameters bulk density, tapped density, compressibility index (Carr s Index), angle of repose, and Hausner s ratio [19]. Particle Size Analysis Particle size of drug loaded formulations were measured by using optical microscope (Olympus CX 31, Japan) [20]. Friability Accurately weighed quantity of pellets (3 gm) were taken from final batch of pellets and placed in a friabilator and tumbled for 100 revolutions at 25 RPM. Twelve steel balls (weighing gm each) were used as an attrition agent. Subsequently, the pellets were sieved through sieve no. 20. The weight loss (%) is calculated as: % F = (Wi-Wr/Wi) 100 Where, Wi is initial weight of pellets before friability testing, and Wr is the weight of pellets retained above the sieve after friability testing. Drug Content Accurately weighed pellets equivalent 200 mg drug were crushed in a dried mortar- pestle. Powder of the pellets was dissolved in upto 100 ml phosphate buffer ph 7.4. It was stirred for 15 min and filtered. Appropriate dilutions of solution were prepared subsequently from it and were analyzed by UV-VIS spectrophotometer (UV-1700, Pharmaspec, Shimadzu Ltd, Japan) at 275 nm. In Vitro Drug Release Studies The in vitro release of the drug from pellets of all formulation batches were performed using USP apparatus Type I (Basket) Electro lab, India. The dissolution medium consisted of 900 ml of phosphate buffer ph 6.8. Dissolution was performed at 37±0.5 C, with stirring speed of 50 rpm. 5 ml of aliquot was withdrawn at time intervals of 1, 2, 4, 6, 8, 10, 12, 16, 24 Hrs. The medium was replenished with same amount of fresh dissolution media each time. The filtered samples were analyzed by UV-VIS spectrophotometer (UV-1700, Pharmaspec, Shimadzu Ltd, Japan) at 275 nm and absorbance were recorded [21]. Kinetics of Drug Release The dissolution profile of all the formulations were fitted to zero order kinetics, first order kinetics, Higuchi, Hixson-Crowell, Korsmeyer and Peppas to ascertain the kinetic modeling of drug release by using a PCP Disso Version 2.08 software, and the model with the higher correlation coefficient was considered to be the best model [22, 23]. Scanning Electron Microscope (SEM) Scanning electron microscopy was performed on pellets to assess the surface morphology like size and shape [24]. Sample was fixed on an aluminum stub with conductive double sided adhesive tape and coated with gold in an argon atmosphere (50 Pa) at 50mA for 50 s. The samples were scanned at a voltage of 5kV (Jeol-6380A, Japan electron optical laboratory) Analysis of data by Design Expert Software A 3 2 full factorial design was selected and the 2 factors i.e. concentration of HPMCK100M LVCR and PEG 400 plasticizer were evaluated at 3 levels. The statistical treatment and interpretation of data was done by Stat Ease Design Expert software. The analysis of variance (ANOVA) is represented in table. The data were also subjected to 3-D response surface methodology to study the interaction of independent variables. Optimization (Model validation) Optimization was performed using Design Expert software to obtain optimized batch. Comparison of drug release profile of desirable batches was done with the drug release profile responses predicted from the obtained model by software with results obtained by experimentation to obtain final optimized batch. The closer resemblance between observed and predicted response values indicates the validity of the generated model. RESULT AND DISCUSSION Selection of Spheronizing Aid for Pellets The plasticity of primary damp mass and surface morphology of extrudate was considered as the key points for the selection of spheronizing aid. Extrudate prepared with lactose does not show proper plasticity (good extrusion ability) and good surface appearance. MCC have better spheronizing capacity and pellet forming capacity than lactose. But, the extrudates prepared with MCC PH102 shows cracks with granular surface which does not appears in the case of MCC PH101. Pelletability and aesthetic appeal was more with MCC PH101. So ultimately MCC PH 101 was selected for the further study. 782

3 Selection of Binder for Preparation of Pellets Pellets prepared without binder (i.e. only with water) & with binders i.e. HPMC K4M, HPMC K15M (in water) were observed for their consistency and strength. Among the binders used, HPMC K4M was chosen on the basis of good consistency of the mass to be extruded and spheronized. Mass of HPMC K15M did not get spheronized due to its relatively higher viscosity. The effect of binder on extrusion and spheronization ability is shown in Table 2. Table 2: Selection of Binder Binder Concentration Response (solvent) (w/v) (Water) - No extrudability due to very low binding force HPMC K4M (water) 1-3 % Good consistency and extrudate formed HPMC K15M (water) 1-3 % Improper extrudates due to high viscosity,not spheronizable Binder Level Optimization (HPMC K4M) Binder solution of HPMC K4M was prepared in the concentration range 1-3%. Response was analyzed for consistency of the damp mass and its ability to form proper extrudates and spherical pellets with smooth surface. HPMC K4 as a binder with concentration of 1% and 1.5% failed to extrude because of its poor binding capacity. At binder concentration of 2%, it was observed that the damp mass extruded and spheronized well to provide spherical pellets due to optimum binding capacity and plasticity. At concentration of 2.5%, it was found to give good extrudate but failed to spheronize because of its high viscosity. Concentration of 3% was unable to extrude due to stickiness and high viscosity. Hence, binder concentration of 2% was selected for further study. The effect of binder concentration is shown in Table 3. Table 3: Binder Level Optimization (HPMC K4M) Binder Concentration (% w/v) Response 1% Failed to extrudates 1.5% Improper extrudates 2% Good extrudates and spheronizable 2.5% Good extrudates, unable to spheronizer 3 % Sticky extrudates Optimization of Extrusion Spheronization Process In an attempt to formulate pellets with desired characteristics (physical appearance and sphericity), the parameters speed of spheronization and time of spheronization were varied. And formulations were prepared by following 3 2 factorial design approach. From this study the optimized parameter were selected. Table 4: Optimized Parameters for Extrusion Spheronization Parameter Extrusion speed Extrusion sieve Spheronization plate Spheronization speed Spheronization time Drug - Excipients Compatibility Study Value 45 rpm 1 mm 4.2 mm 1200 rpm 20 min The possible interactions between Aceclofenac and excipients and polymers were studied. There was no considerable change in DSC endothermic values on comparison of pure Aceclofenac s with Aceclofenac added excipients and polymers. The peak value was obtained at C which complied with that of pure drug. There is no major shifting in this peak value. The presence of other excipients might have suppressed the peak height. Hence, it is concluded that there is no interaction of Aceclofenac with the excipients used i.e. they are compatible. The DSC thermogram is shown in figure 1. Flow Properties of Pellets and Morphological Characteristics The flow properties of all factorial batches are shown in Table 5. Angle of repose values ranges from 19.39±1.45 to 31.29±1.67. The value of bulk density and tapped density ranges from 0.65±0.07 to 0.87±0.031 (gm/cm 3 ) and 0.74±0.009 to 0.95±0.05 (gm/cm 3 ) respectively. The value of Carr s index below 15% indicates a powder which usually gives rise to excellent flow characteristics whereas that above 25% indicates poor flow ability. Hausner s Ratio (H) is an indirect index of ease of powder flow. The flow properties of the batch F3 and F5 was found to be excellent. The comparative studies of photomicrograph of all batches are as shown below in Figure 2. DSC mw Thermal Analysis Result Temp C DSC mw Thermal Analysis Result Temp C File Name: Drug+Excipient.tad Detector: DSC60 Acquisition Date 13/01/17 Acquisition Time 13:35:36 Sample Name: Drug+Excipient Sample Weight: 5.850[mg] Annotation: Start End Peak Onset Endset Heat Height xc xc xc xc xc xmj xj/g xmw Drug+Excipient.tad Temp Drug+Excipient.tad DSC File Name: Drug.tad Detector: DSC60 Acquisition Date 13/01/17 Acquisition Time 13:15:34 Sample Name: Drug Sample Weight: 7.650[mg] Annotation: Start End Peak Onset Endset Heat Height xc xc xc xc xc xmj xj/g xmw Drug.tad Temp Drug.tad DSC [Temp Program] Start Temp Temp Rate Hold Temp Hold Time [C/min ] [ C ] [ min ] [Temp Program] Start Temp Temp Rate Hold Temp Hold Time [C/min ] [ C ] [ min ] Time [min] Time [min] Fig. 1: DSC thermogram of Aceclofenac and Aceclofenac with formulation excipients 783

4 [ [ Khan et al. Table 5: Flow Property of Pellets Flow property Angle of Repose (θ) Bulk density (gm/cm 3 ) Tapped density (gm/cm 3 ) Carr s Index (%) Hausner s Ratio F ± ± ± ± ±0.02 F ± ± ± ± ±0.02 F ± ± ± ± ±0.03 F ± ± ± ± ±0.06 F ± ± ± ± ±0.04 F ± ± ± ± ±0.02 F ± ± ± ± ±0.07 F ± ± ± ± ±0.04 F9 28.2± ± ±0.05 5± ±0.02 All values expressed as mean± SD, n=3. Fig. 2: Photo micrograph of all batches Aspect ratio and roundness are the important parameters for the characterization of pellets. Aspect ratio nearer to 1 and roundness nearer to 100% shows spherical pellets. On the basis of aspect ratio and roundness, batches F3, F4, F5, showed good results with respect to HPMC K100 LVCR and plasticizer ratio. Batch F3 showed minimum aspect ratio i.e and maximum roundness i.e %. The morphological characteristics of all factorial batches are shown in Table 6. The Photomicrographic study also confirmed that batch F3 has more spherical and uniform pellets with smooth surface compared to other batches. Table 6: Morphological Characteristics of Pellets Batches Shape Aspect ratio Roundness (%) F1 Cylindrical /Rod F2 Cylindrical + Dumbbell F3 Sphere F4 Oval + Sphere F5 Oval + Sphere F6 Dumbbell + Oval F7 Dumbbell +Ellipsoid F8 Cylindrical + Dumbbell F9 Ellipsoid + Dumbbell Particle size analysis On the basis of aspect ratio and roundness, batches F3, F4 and F5 has shown good results with respect to HPMC K100 LVCR and plasticizer ratio, Particle size was determined by optical microscopy for drug loaded matrix pellets. Average particle size was found in the range mm to mm. Average roundness of the pellets was found to be in the range to which is shown in Table 7. Amongst all batches, batch F3 showed larger particle size mm and highest roundness %. Hence, it is concluded that the pellets of batch F3 are more spherical relative to other. Particle size analysis parameters of pellets are shown in Table 7. Table 7: Particle Size Analysis of Batches (F3, F4, F5) Batch Length Width Area Asp.Ratio Roundness Shape Sphere volume F F F

5 Friability The friability of the pellets tested with steel balls was found below 0.2%, and thus the pellets have desirable hardness and are of a good quality with respect to friability. Friability (%) of all the factorial batches is shown in Table 8. Drug content The drug loaded pellets of Aceclofenac prepared with the optimized formula exhibits drug loading capacity in range of 92.52±0.15% ±0.05%. Batch F3 showed maximum drug content i.e %. Drug content of all the factorial batches are shown in Table 8. Table 8: Friability (%) and Content Uniformity Batch (%)Friability Drug content% F1 0.18± ±0.12 F2 0.15± ±0.02 F3 0.14± ±0.05 F4 0.15± ±0.15 F5 0.13± ±0.05 F6 0.18± ±0.13 F7 0.13± ±0.05 F8 0.14± ±0.02 F9 0.15± ±0.04 All values expressed as mean± SD, n=3. In-Vitro Drug Release Study In-vitro drug release study of all the formulation batches (F1-F9) were performed in triplicate using USP apparatus Type-I (Basket). The batches F4, F5, F6, F7, F8 and F9 shows drug release 68.25±0.28 %, 75.15±0.20%, 75.41±0.49%, 69.52±0.08%, 74.04±35% and 72.01±0.28% respectively in 16 hr, which can release the drug upto 24 hr but are unable to meet the criteria of 80% drug in release 16 hr probably due to more weight gain of HPMC K100MLVCR. F1 batch sustained the drug release only upto 78.97±0.56% in 16hr. The batches F2 and F3 showed drug release upto 82.2±0.12% and 85.38±0.016% in 16 hr, which meets the criteria of 80% drug release in 16 hr probably due to low weight gain of HPMC K100MLVC. Only the batches F2 and F3 showed desirable release profile suitable for sustained release systems. Batch F3 showed highest drug release as compared to the F2 batch in 24 hr i.e ±0.19%, although both batches contains the same concentration of HPMC K100MLVCR which may be due to the high concentration of PEG 400 in F3 batch. The PEG 400 increases the drug release on increasing it s level from 1% to 3%. This increase in drug release may probably be due to PEG 400 as it is hydrophilic and a solubility enhancing agent. The results of cumulative drug release (%) of all the formulation batches are shown in Table 9 and Table 10. The graphical representations of the dissolution profile of all factorial batches are shown in Figure 3, 4 and 5. Kinetics of drug release To describe the kinetics of the drug release from the matrix pellets, release data was evaluated by model-dependent (curve fitting) method using PCP Disso v3 software and the model with the highest correlation coefficient amongst them was considered to be the best model. The results shows that the factorial batches F1, F2 and F8 follows Korsmeyer Pappas order kinetics while the batches F3, F4, F5, F6, F7, F9 follows Matrix order kinetics. The observations are summarized in Table 11. Table 9: Cumulative Drug Release (%) of F1 to F5 Time[Hr] F1 F2 F3 F4 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±1.47 All values are expressed as mean± SD, n=3. Table 10: Cumulative Drug Release (%) of F6 to F9 Time[Hr] F6 F7 F8 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±1.97 All values are expressed as mean± SD, n=3. 785

6 Fig. 3: Cumulative drug release of formulation batches F1-F3 Fig. 4: Cumulative drug release of formulation batches F4-F6 Fig. 5: Cumulative drug release of formulation batches F7-F9 Table 11: Drug Release Kinetics of All the Factorial Batches Batch r 2 n K Code Zero order First order Matrix Korsmeyer peppas Hixon crowell F F F F F F F F F Scanning Electron Microscopy The scanning electron microscopic (SEM ) evaluation is important for determining the surface morphology, size, shape. Surface of pellets as shown in SEM photograph was smooth and spherocity was also good and size of pellets was found to be 968 μm to 1003 μm and ratio of length to width (Aspect ratio) is 1.03 which indicates pellets are spherical in shape. 786

7 [[ Q 2 [ Khan et al. Fig. 6: SEM analysis of optimized F3 batch ANOVA Study Evaluation and interpretation of research findings are of utmost importance and the p-value serves a valuable purpose in these findings. Table 12 and 13 shows ANOVA for the dependent variables Q2 and Q24 respectively. The coefficients of X1 and X2 were found to be significant at p<0.05 Hence, it confirms the significant effect of both the variables on the selected responses. Overall both the variables caused significant changes in the responses. ANOVA and Multiple regression analysis were done using Stat-Ease Design Expert software. Response surface plot The Linear and Quadratic models obtained from the regression analysis was used to build a 3-D graphs in which the responses were represented by Sloped surface as a function of independent variables. The relationship between the response and independent variables can be directly visualized from the response surface plots. The response surface plots were generated using Design Expert software presented in Fig 7 and 8 to observe the effects of independent variables on the response studied such as Q2 and Q24 respectively. Table12: Analysis of Variance for Q2 Source Sum of Squares Degrees of Freedom Mean Square F Value P Value Model Significant/Non significant Model A-HPMC K100MLVCR Significant B-PEG Residual Cor Total Table 131: Analysis of Variance for Q24 Source Sum of Squares Degrees of Freedom Mean Square F Value P Value Model Significant/Non significant Model A-HPMC K100MLVCR B-PEG AB Significant A^ B^ Residual Cor Total Design-Expert Software Factor Coding: Actual Q2 Design points above predicted value Design points below predicted value X1 = A: HPMC K100MLVCR X2 = B: PEG B: PEG A: HPMC K100MLVCR Fig. 7: Response Surface Plot for Q2 787

8 [ Q 2 4 Khan et al. Design-Expert Software Factor Coding: Actual Q24 Design points above predicted value Design points below predicted value X1 = A: HPMC K100MLVCR X2 = B: PEG B: PEG A: HPMC K100MLVCR Fig. 8: Response Surface Plot for Q24 Optimization (Model validation) The formulation OF3 was prepared for the model validation. The Q2 and Q24 were evaluated and found within the limits. The Solutions for the numerical optimization of Extrusion Spheronization process are given in Table 14. The values of responses predicted from the obtained model are shown in Table 15 along with the results obtained by experimentation. The closer resemblance between observed and predicted response values indicates the validity of the generated model. Table 14: Solutions for Numerical Optimization of Dissolution Study S. HPMC K100M PEG 400 Q2 (%) Q24 (%) Desirability No. LVCR (%) (%) Selected Table 15: Comparison of Predicted and Experimental Values Responses OF3 Predicted Experimental Q2 (%) Q16 (%) Q24 (%) CONCLUSION A sustained released matrix pellets of Aceclofenac was formulated. The prepared pellets were optimized for parameters like Flow Properties, Morphological characteristics, Particle Size Analysis, Drug Content and Drug Released. The formulation having composition as HPMC K100M LVCR 11 % and PEG % was selected as optimised. The evaluated parameters of optimised batch were found to be within the limits. Drug release of optimized batch (F3) at 2 hr was found to be less than 30 % (25.43 %) and at 24 hr more than 80 %( 98.32%). The results showed that combination of HPMC K100M LVCR as hydrophilic matrix polymer and PEG 400 as potential plasticizer is effective and useful for sustaining the Aceclofenac release and Extrusion-Spheronization technique was promising approach for the preparation of a sustained release Aceclofenac pellets which can be also used on large scale. ACKNOWLEDGEMENT The authors are grateful to Flamingo Pharmaceutical Ltd. (Mumbai, India) for kind gift sample of Aceclofenac. Further, we extend our thanks to Colorcon Asia Pvt. Ltd, (Mumbai, India) Signet chemical corporation, (Mumbai, India) and Merck (Mumbai, India) and AICTE for financial assistance. REFERENCES 1. Fujimoto S, Miyazaki M, Endoh F, Takahashi O. Shrestha, RD. Formulation and In Vitro evaluation of sustained release tablet of aceclofenac. Int J Pharm. 1985; 55, Gupta PK, Hung CT, Perrier DG. Aceclofenac: A potent Nonsteroidal anti-inflammatory Drug. Int J Pharm 1986; 33, Schwope AD, Wise DL, Howes JF. Formulation and In Vitro evaluation of sustained release microspheres of aceclofenac. Int J Pharm Life Sci. 1968; 17, Saraf S, Sing D, Garg G, Aceclofenac: A Potent Non-Steroidal Anti-Inflammatory Drug. Pharma Info Net. 2006; 4, British Pharmacopoeia. The Stationary Office, MHRA,British Pharmacopoeial Commission Office,Vol 1, London, Kuksal A, Tiwary A K, Jain N K, Jain S. Formulation and in vitro, in vivo evaluation of extended release matrix tablet of zidovudine: influence of Combination of hydrophilic and hydrophobic Matrix Formers.AAPS. PharmSciTech. 2006; 1, Khan GM, Zhu JB. Controlled release co precipitates of ibuprofen and carbopol preparation, characterization and in vitro release. Bio Int Sciences, 2001; 1, Lopes C, Manuel S, Lobo J, Costa P, Pinto J. Directly compressed mini matrix tablets containing ibuprofen-preparation and evaluation of sustained release. Drug Develop Ind Pharm. 2006; 32, Watanabe Y, Takayamaa K, Hisashi E. Effect of Hydroxypropyl methylcellulose on the release profiles and bioavailability of poorly water-soluble drug from Tablets prepared using macrogol and HPMC. Int. J. pharm. 2000; 202, Bodmeier R. Tableting of coated pellets. Eur J Pharm Biopharm. 1997; 43,

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