International Journal of Innovative Pharmaceutical Sciences and Research

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1 International Journal of Invative Pharmaceutical Sciences and Research FORMULATION & EVALUATION OF FILM COATED RANOLAZINE EXTENDED RELEASE TABLETS 1 Harish Adepu*, 2 S.srilatha*, 3 M.Prasanth Reddy Malla reddy institute of pharmaceutical sciences, Maisammaguda, Dhulapally, (Post via Hakimpet, secunderabad , Telangana, INDIA Abstract Ralazine is a partial fatty acid oxidase inhibitor that increases the amount of ATP produced from glucose and increases the ability of the myocardium to retain functionality despite a reduced oxygen supply. It comes under class II of Biopharmaceutical Classification System. The purpose of this study was to develop and evaluate film coated ralazine extended release tablets by wet granulation method using different polymers. Pre-formulation studies were done initially and the results were found to be within the limits. All the mentioned batches were prepared and granules were evaluated for pre-compression parameters such as loss on drying, bulk density, tapped density, hausner s ratio and compressibility index. Tablets were evaluated for weight variation, thickness, hardness, and friability, were found to be within the limits. In vitro dissolutions were performed in ph 6.8 phosphate buffer and effect of various polymers was explored. Final selection of formulation was based on similarity and difference factors which revealed that formulation (F8) containing Methocel K100M and Carbopol974P is most successful as it exhibited in vitro drug release that matched with invator product. In vitro drug release profile reveals that with combination of Methocel K100M and Carbopol974P there was increase in drug release. Scale up of optimized formulation was done. Keywords: Ralazine, Methocel K100M, Carbopol974P.Extended Release Tablet. Corresponding Author: Harish Adepu Deparment of Pharmaceutics Malla reddy institute of pharmaceutical sciences Secunderabad , Telangana, INDIA harish.adepu10@gmail.com Mobile: Available online: October Issue 2283

2 INTRODUCTION Extended-release medications have special coatings or ingredients that control how fast the drug is released from the pill into your body. This may allow you to take certain medications only once or twice a day, instead of more often. Some extended-release medications have the letters "XL" or "LA" or "XR" in their name. Extended-release /ex tend ed-re lease/ (ek-stend ed-re-lēs ) allowing a twofold or greater reduction in frequency of administration of a drug in comparison with the frequency required by a conventional dosage form. Pharmaceutical dosage forms that release the drug slower than rmal manner at predetermined rate and necessarily reduce the dosage frequency by two folds are kwn as extended release dosage forms. The term extended 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, r intentionally, reatarded by galenic manipulations. Recently extended release tablets have started gaining popularity and acceptance as a drug delivery system, mainly because they are easy to administer, has reduced dose frequency and lead to better patient compliance. An ideal drug delivery system should able to deliver an adequate amount of drug, preferably for an extended period of time, for its optimum therapeutic activity. Most drugs are inherently t long lasting in the body and require multiple daily dosing to achieve the desired blood concentration to produce therapeutic activity. To overcome such problems, controlled release and extended release delivery are receiving considerable attention from pharmaceutical industries worldwide. When a conventional dosage form is administered, the concentration of drug in the blood stream will attain a therapeutic range necessary for the action of the drug. This therapeutic range would be maintained for some time and finally the concentration drops below this range rendering the drug therapeutically inactive [1-17]. Fig.1: A hypothetical plasma concentration-time profile from conventional, multiple dosing and single doses of sustained and controlled delivery formulations. Available online: October Issue 2284

3 MATERIALS Ralazine received gift sample from MSN Laboratories Pvt. Ltd., Compritol obtained from DOMO Friesland Campina Domo B.V. Microcrystalline cellulose - (Avicel 102), (Avicel 101), Povidone k30, Stearic acid purchaged from F M C Biopolymer. Meglumine from Speaciality minerals Lifford. Methocelk100M gift sample from Dow chemical company. Ethocel7fps from Colorcon Asia pvt ltd. Carbopal 974 p from Lubrizol advance materials. Colloidal silicon dioxide, Magnesium stearate obtained from Synpro pvt ltd. Isopropyl alcohol from Ranbaxy. Opadry yellow obtained from Colorcon Asia Pvt Ltd. METHODS PREPARATION OF FILM COATED RANOLAZINE EXTENDED RELEASE TABLETS: INTRA-GRANULATION: Step 1: Sifting Ralazine is sifted through # 40 sieve and mixed thoroughly in a poly bag. Microcrystalline cellulose (Avicel- 101),Methocel K100M and Compritol passed through # 40 sieve and collected in poly bag. Step 2: Granulation: Dry mixing: Transferred the sifted material from step-1 into the rapid mixer granulator and mixed for 15 minutes by setting impeller at slow rpm and chopper set to off. Binder solution preparation: Binder solution was prepared by dissolving povidone k30 in purified water. Wet granulation: Binder solution was added slowly to the step-2a dry mix by setting impeller at slow rpm and chopper set to on. Impeller speed 200 rpm Chopper speed 1000 rpm Wet screening: After completion of addition of binder solution, wet granulate was raked and kneaded till to get wet granulate with desired consistency is reached. Drying : Unload the wet granulate into fluid bed dryer bowl and dry the wet granulate in fluid bed dryer at an inlet temperature of C till the desired LOD of % w/w was achieved. Available online: October Issue 2285

4 Dry screening: Sifted the dried granules through # 20 sieve and collected the oversized granules separately. Milled the oversized granules using 2.5 mm screen at medium speed with knives forward and passed through # 20 sieve. EXTRA-GRANULATION: Step 3: Pre blending and final blending Sifting: MethocelK100M was sifted through # 40 sieve and geometrically mixed in a polybag and collected in a polybag. Pre blending: Load the dried, sized granules in step.2f & 3a in to the octagonal blender and blended for 20 minutes. Lubrication: Magnesium stearate & Aerosil was sifted through # 60 sieve, added to the step-3b blend and mixed for 5 minutes. Table 1: Preparation of Ralazine Film Coated Tablets (Mg/Tab) Ingredients F1 F2 F3 F4 F5 F6 F7 F8 INTRAGRANULAR Dry mix Ralazine Mcc PH Compritol Carbopol Methocel K100M Meglumine Stearic acid Wet granulation Povidone Stearic acid Methocel E P.H 2 o Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S EXTRA GRANULAR Pre lubrication Methocel K100M Lubrication Aerosil Magnesium stearate Weight of the tablet COATING Ethocel 7 fps Opadry yellow Water Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Weight of the coated tablet Available online: October Issue 2286

5 RESULT & DISCUSSION Standard curve of Ralazine in 0.1N HCl at λmax 272nm The standard graph of Ralazine was plotted in 0.1N HCL, linearity was obtained between concentrations g/ml in 0.1N HCL and R 2 value in 0.1N HCL was Table 2: Standard curve of Ralazine in Fig. 2: Standard Graph of Ralazine 0.1N HCL at λmax 272nm in 0.1 HCL Concentration (µg/ml) Absorbance (nm) Slope R Table 3: Standard curve of Ralazine in Fig. 3: Standard Graph of Ralazine 6.8 Phosphate Buffer at λmax 272nm in 6.8 Phosphate Buffer Concentration (µg/ml) Absorbance (nm) s Slope R Available online: October Issue 2287

6 Table 4: Drug-excipient compatibility studies S.No API and excipients initial 40 º ±2 C, 75±5% RH 7 days 14 days 1 Ralazine + Avicel Ralazine+Methocel k100m 3 Ralazine+Magnesium stearate 4 Ralazine+Meglumine White or offwhite powder 5 Ralazine+Carbopol 974P 6 Ralazine+Povidone k30 7 Ralazine+Final tablet blend 30 days Fig.4: FTIR of Ralazine Fig.5: FTIR of drug+mg.stearate Fig.6: FTIR of drug+stearic acid Fig.7: FTIR of drug+meglumine Available online: October Issue 2288

7 EVALUATION OF TABLET BLEND Fig.8: FTIR of drug+carbopol The pre-compression blend of matrix tablets were characterized with respect to angle of repose, bulk density, tapped density, Carr s index and Hausner s ratio and the results of the precompression blend were shown in table 22.Angle of repose was less than 28 and Carr s index values were less than 15 and Hausner s ratio values were less than 1.25 for the pre-compression blend of all the batches indicating good flow properties. S. No Batch No. Table 5: Evaluation of pre compression parameters angle of repose(θ) 8 F ± ± ± ±0.01 Mean ± S.D, n=6 ; C.I- Compressibility index EVALUATION OF TABLETS Bulk density (g/ml) Tapped density (g/ml) The prepared extended tablets were tested with respect to weight variation, hardness, thickness, and friability. The hardness of the tablets and friability values in the range of 13 to 14.50kg/cm 2 and 0.23% indicating that the tablets were compact and hard. The thickness of the tablets in the range of 8.18 to 8.58 mm. weight variation in the range of 1350mg. All the tablets of different batches complied with the official requirements for weight variation, hardness and friability. Available online: October Issue 2289 C.I Hausner s ratio 1 F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ±0.05

8 Batch No. IN VITRO DISSOLUTION STUDIES Table 6: Evaluation of post compression parameters: Average weight (mg) Thickness (mm) Table 7: Dissolution profile of All Formulation % Drug Released Hardness (kg/cm 2 ) Friability (%) F1 1350± ± ± ±0.05 F2 1350± ± ± ±0.06 F3 1350± ± ± ±0.05 F4 1350± ± ± ±0.03 F5 1350± ± ± ±0.08 F6 1350± ± ± ±0.05 F7 1350± ± ± ±0.06 F8 1350± ± ± ±0.05 Ranexa 1350 mg 8.4± ±0.03 < 1% Time(in hrs) F1 F2 F3 F4 F5 F6 F7 F8 invator Fig. 9: Comparitive in vitro drug release profile of Ralazine F1-F5 with Invator Available online: October Issue 2290

9 Data of in-vitro release: The data were fit into different equations and kinetic models to explain the release kinetics of ralazine from the tablet.the data were processed for regression analysis using ms-excel statistical functions. To kw the mechanism of drug release from these formulations,the data were treated according several mathematical models, namely Zero order(cumulative amount of drug release vs time), First order(log cumulative % of drug remained vs time), Higuchi (cumulative % of drug release vs square root of time)and Korsmeyer-Peppas(log cumulative % of drug release vs log time) in order to determine the release patterns and to get an idea of in vivo release mechanism of Ralazine.The in-vitro kinetic data for formulations was shown below: Table 8: R 2 values for release kinetics of Ralazine formulations Formulations Zero order First order Higuchi Peppas n value F F F F F F F F Invator When the optimised formulation F8 subjected to First Order, Zero Order, Higuchi models.drug release data was best explained by First order order equation, as the plots showed the highest linearity (r 2 =0984 ), which follows first order release. Table 9 : Comparision of cumulative Percentage drug release of Optimised product with marketed product % DRUG RELEASE Time(in Marketed hrs) F8 product Fig. 9 : Comparision of cumulative Percentage drug release of Optimised product with marketed product Available online: October Issue 2291

10 The in-vitro drug dissolution studies were conducted for marketed product and optimised formulation.the marketed product was released 99% drug release in 24 hours where as the optimised formulation F8 released 99.5% drug release in 24 hours in this way the optimised formulation is better than the marketed formulation. Table 10: Simiarity factor analysis MARKETED TEST Time (in hrs) R t T t R-T R-T SUM f2=93.73 f1=1.457 Similarity factor of optimized formulation with marketed formulation (Ranexa-XR) was found to be SUMMARY The present study was mainly based upon the Formulation Development and in vitro Evaluation of Ralazine extended release tablets 1000 mg (Antianginal) by Wet Granulation Technique. Various formulations of Ralazine tablets were prepared by using different proportion & combination of Excipients. Tablet blends were prepared and micromeritic studies were carried out for those blends. Pre compressional parameters such as angle of repose, bulk density, tapped density, compressibility index for physical mixtures of extended release layer formulations (F1 F8) were evaluated and results were reported. From the results obtained by UV, the calibrati on curve was constructed having regression value of Compatibility studies were performed and it was observed that all the ingredients used were compatible with the drug. Formulation (F8) was formulated by including 90mg of Carbopol974P, 40mg of methocelk100m. The results showed 99.5% drug release was found in 24hrs. Dissolution studies were performed for the optimized formulation (F-8) at different time intervals. All the parameters were found to be satisfactory. Dissolution studies were performed and it was found that formulation F8 have shown best results and comparable with the invator found to be similar. So, formulation (F8) was taken as optimized formulation. Available online: October Issue 2292

11 CONCLUSION From the above experimental result, it can be concluded that film coated ralazine extended release tablets can be prepared by wet granulation method using different polymers in varying combinations. Tablet blends were prepared and micromeritic studies were carried out for those blends and found to be within the limits. Compatability studies were carried out and found that drugs and excipients are compatible with each other.post compression parameters were carried out found to be within the limits. Also dissolution data of all formulations reveals that as combination of methocelk100m, carbopol974p increases the percentage drug release was found to be increased Formulation (F8) containing combination of methocelk100m, carbopol974p shows that the 99.5% drug release was found in24hrs and found similar with that of invator.. On comparing R 2 with invator, formulation (F8) shows similar results with invator,hence formulation F8 Vere considered as best formulation with good f2 values ie.,respectively. So, formulation (F8) was taken as optimized formulation. REFERENCES 1. Rang H.P;M.M.Dale;J.M.Ritter; R.J.Flower. The Heart. In: Pharmacology. 5 th Edition;Informa Health care,usa,2008;volume 1; page number: Rawlins EA. Bentley s Text Book of Pharmaceutics. 8 th ed. ELBS. 3. Shargel L, Kanfer I. Generic Drug Product Development of solid oral dosage forms. Winley Inter Science 2010: S.P Vyas & R.K.Khar. controlled drug delivery concepts and advances. In: Targeted & Controlled Drug Delivery System.1 st Edition; India Binding House,Noida ; Page Number : Ranexa (Ralazine) extended-release tablet. weblog. (accessed on 2010 Dec 9). 6. B.Mayuri, Madhu.E.Nicholas, SY Manjunath. Subal Debnath. Formulation and evaluation of Ralazine extended release tablets. J. Chem. Pharm. Res., 2010, 2(5): Huang Y B, Tsai Y H, Yang W C, Chang J S, Wu P C, Takayama K. Once daily Propralol extended-release tablet dosage form: formulation desogn and in vitro/in vi investigation Eur J Pharm Biopharm.2004:58: Available online: October Issue 2293

12 8. P.DwarakanadhaReddy,D.Swarnalatha,B.HanumanKishore.Dinakar,V.Chaithanya,K.S hivakumar, Janardhan, Vishnu Venamma, Mahindra Reddy, M.Puroshotaman.Formulation and evaluation of extended release etodolac tablets.jitps 2010, Vol.1 (7), Jagdish Bidada, Indrajeet Gonjari, Akshay Bhusari, Chandrakant Raut, Amar Dhule. Development of extended release matrix tablets of Ralazine containing polyacrylic and ethylcellulose polymers. J. Chem. Pharm. Res., 2011: 3 (4) Vanaja kumari, P Venkateswar reddy and M Sudhakar. Formulation and evaluation of ralazine sustained release matrix tablets. Int J Pharm 2012; 2(1): Mofizur Rahman.Md, Mithilesh Kumar Jha, Md. Qamrul Ahsan and Taslima Begum. Effect of various grades of hydroxy propyl methylcellulose matrix systems as oral sustained release drug delivery systems for ralazine. J. Chem. Pharm. Res., 2010, 2(5) Mohammad NU, Ahmed I, Roni MA, Islam MR, et al. In vitro Release Kinetics Study of Ralazine from Swellable Hydrophilic Matrix. Dhaka-1000, Bangladesh Dhaka Univ. J Pharm Sci 2009 June;8(1): R.C.Patel et al.,method development of ralazine by hplc. International Journal of Pharmaceutical and Applied Sciences/1 (2)/ G. Frommeyer et al., This editorial refers to Further insights into the underlying electrophysiological mechanisms for reduction of atrial fibrillation by ralazine in an experimental model of chronic heart failure published in the European journal of heart failure/2012,12 issue on pages Bharat.M.Reddy et al., gives evidence about ralazine's therapeutic effect on diastolic heart failure, glycemic control, and atrial fibrillation and other arrhythmias;published in texas heart institute journal v.37 / H. Doddayya et al.,(2011) 14 refers about in vitro release oh Ethyl cellulose and gum rosin published in IJPBA, May - Jun, 2011, Vol. 2, Issue, 3 ; Received 17 Apr 2011; Revised 05 May 2011; Accepted 16 Jun Sastry, Srikonda, Nyshadham, Janaki. International Publication Number WO 2006/ A July 13. Available online: October Issue 2294