Volume 1 Issue 1 Page 82

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1 DESIGN AND IN VITRO EVALUTION OF SUSTAINED RELEASE FILM COATED TABLETS OF VERAPAMIL HYDROCHLORIDE BS Venkateswarlu*, B Jaykar, Pasupathi A, R Margret Chandira, Palanisamy P Vinayaka mission s college of pharmacy, Vinayaka missions university, Salem, Tamil Nadu * Corresponding author: palanisamy2907@gmail.com ABSTRACT An attempt was made to formulate the sustained release tablet of verapamil hydrochloride by using the wet granulation method for the treatment of hypertension. In the present formulation the tablets releases the loading dose by immediate drug release and maintenance dose up to 15 hours by extended release. The drug excipient compatability study was carried out with HPLC method and there was no interaction found. Immediate release fraction was formulated by using croscarmellose sodium as a disintegrating agent and extended release fraction was formulated by using Hypromellose E4 as a rate controlling polymer. The granules were evaluated for pre and post compressional character which showed satisfactory results. In vitro dissolution study was carried out for 15 hrs using USP dissolution apparatus type II with 0.1 N HCl and 7.4 ph phosphate buffer as dissolution medium. From the dissolution profile, F2 & F3 values were calculated which were within the specification. Stability study was carried out for the optimized formulation at 40 C/75% RH for 1 month, the result showed that there was no significant change in physical and chemical parameter of the tablet. Key words: Verapamil Hydrochloride, Sustained release tablet, Hypromellose E4. 1. INTRDUCTION Verapamil Hydrochloride is a calcium channel blocker and class IV antiarrhythmic agent used in the supraventricular arrhythmias, and in the management of angina pectoris, hypertension and myocardial infarction. Hypertension, commonly referred to as high blood pressure, is a medical condition where the pressure is chronically elevated is one of the commonly found diseases, affecting most of the populations in the world. So, for treating hypertension effectively is main criterion of study. For treating hypertension, commonly used drugs include ACE inhibitors, alpha blockers, beta blockers, calcium channel blockers, diuretics and combination of any of these categories in immediate action required. The objective of this study is to develop immediate and sustained release formulation of Verapamil hydrochloride coated Tablets. 2. MATERIALS AND METHODS 2.1. Materials: Verapamil HCL was procured by Cadila pharmaceutical Limited, Ahmedabad, Lactose monohydrate, Microcrystalline cellulose 102, Hypromellose (Methocel E4 Premium), Hypromellose (Methocel E5LV Premium) and PVPK-30 was gifted by Feicheng Rutai Fine Chemicals Co Ltd, Mannitol SD-102 was gifted by Arihant trading Co. Ltd, Sodium alginate, Magnesium Stearate, Crosscarmellose sodium (ac-di-sol), Opadry Blue OY and Talc was gifted by Relience cellulose Pvt Ltd, Purified Water was gifted by Loba Chemie Pvt Ltd Formulation of Verapamil SR Tablet: a) Co mixed ingredients verapamil hyochloride and mannitol SD 200 geometrically and sifted through 40 mesh b) Co mixed other granulation ingredients in a polybag c) Mixed steps a and b in RMG (Rapid Mixer and Granulator) for dry mixing for 10 minutes. d) Binder was dissolved in water to get clear binder solution. e) Binder solution was added to the dry mixed ingredients in RMG with both mixing and chopper blades on initially at high speeds and finally at low speed for 5 minutes. f) Dried the granules in FBD (fluidized bed drier) at 60 o c for 30 min and then milled through 2.0 mm screen in multimill and passed oversized through sieve 20 mesh g) Dried the bulk of step (f), for another 15 min h) Sifted Magnesium Stearate through 40 mesh i) Lubricated the bulk of step (g) with bulk of step (h). Compressed the lubricated blend of step (i) by using x 6.50 mm, capsule shaped punches with bisecting line on upper punch and plain 3. EVALUATION TESTS 3.1. Evaluation of tablet: These include the diameter, size, shape, thickness, weight, hardness, disintegration and dissolution characters. The diameters and shape depends on the die and punches selected for the compression of tablets Dissolution Test: The objectives in the development of in vitro dissolution tests are to show that the release of the drug from the dosage form is as close as possible to 100 % and the rate of drug release is uniform from batch to batch. Drug Verapamil is a water insoluble API. 7.4 ph phosphate buffer is taken as dissolution media. Following method was adopted to check dissolution profile. Volume 1 Issue 1 Page 82

2 Table 1: Formulation table of Verapamil Hydrochloride SR Tablet S. No Ingredients F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 1 Verapamil hyochloride Mannitol SD Croscarmellose sodium (Ac-di Sol) PVP K30 (Povidone K 30) Lactose monohydrate Sodium Alginate (Protanal LF 120M) Microcrystalline Cellulose (Avicel PH101) Hypromellose (Methocel E4M Premium) Hypromellose (Methocel E5 LV) Premium) Purified water - - QS QS QS QS QS QS QS QS 11 Magnesium Stearate Talc Total Table 2 Dissolution method for drug USP Apparatus Type II (Paddle) Speed 50 rpm Medium Phosphate Buffer ph 7.4, 900 ml Sampling times 3,6,9,12,15 Hr Analysis By UV method 278 nm 3.3. Drug release kinetic analysis by using different release model of active molecule: Several theories and kinetic models were described the drug release characteristics of immediate release and modified release dosage forms, by using dissolution data and quantitative interpretation of values obtained in dissolution assay if facilitated by the usage of the generic equation dosage form that mathematically translates the dissolution curve in function of some parameters related with pharmaceutical dosage form Stability Study: Tablets of the final batch were packed in High-Density Polyethylene Containers (HDPE, 60CC) and were subjected to accelerated stability studies (400±20C/75±5%RH 1, 2 & 3 Months). The effects of temperature and humidity with time on the physical and chemical characteristics of the tablet were evaluated for assessing the stability of the prepared formulation. After each time period, the samples were tested for appearance, dissolution, assay and impurities. 4. RESULT AND DISCUSSION 4.1. Solubility: Solubility of the drugs is determined in 5 different media which is given below, Table 3. Solubility of active molecule Table No: 4 Particle size distribution of active molecule Media Solubility (mg/ml) Particle size µm Water distribution 0.1N HCl D (v, 0.1) Phosphate Buffer D (v, 0.5) Acetate Buffer D (v, 0.9) Phosphate Buffer l 4.2. Particle size determination: For many active substances, particle size has an impact on powder flow, content uniformity and drug dissolution. In order to assure consistent product quality, the particle size of the active molecule has been characterized Density and flow properties: From the above data it was concluded that the drug had poor compressibility and poor flow ability. So, during development BD and Flow ability will be improved for better granulometry parameters (Table 5). Table No: 5 Density and flow properties of active molecule Sr. Density (gm/ml) Flow properties No. Bulk Tapped Carr s index Hausner s Ratio I.R. Spectra of active molecule: Spectrum of Verapamil Hydrochloride in phosphate buffer ph 6.8 Volume 1 Issue 1 Page 83

3 %DRUG DISSOLVED Fig No:1 I.R. Spectra of active molecule Fig No:2 FTIR Interpretation of IR graphs The figure shows the IR spectrum of Verapamil Hydrochloride; from the peaks the following functional groups are found. Between 3030 and 2860 cm -1 : A broad complex absorption due to superimposing C-H stretching vibrations of the methyl and methylene groups cm -1 : A band due to C-H stretching vibration of the methoxy groups. Between 2800 and 2300 cm -1 : A broad complex absorption due to N-H stretching vibration of the protonated amine cm -1 : A sharp weak band due to C=N stretching vibration of the saturated alkyl nitrile. 1607, 1591 and 1518 cm -1 : Bands due to skeletal stretching vibrations of the benzene ring cm -1 : A strong band due to C-O stretching vibrations of the aromatic ethers Drug-excipients compatibility Study: No change appeared in the powder mixer at above all conditions indicate that there are no incompatibilities present between drug and excipients (Table 6) Table No: 6 Drug-excipients compatibility Study Sample Ratio Observation of total impurity 25ºCº±2 C / 60%RH± 5 % RH 40ºC±2 C/ 75%RH± 5 % RH Drug + lactose monohydrate 1:1 one month Two month Drug + Mannitol SD 200 1:1 one month Two month Drug + PVP K-30 1: 0.5 one month Two month Drug + Magnesium Sterate 1: 0.25 one month Two month Drug + Microcrystalline Cellulose 1:1 one month Two month Drug + sodium alginate 1:0.5 one month Two month Drug + Hypermellose E4 1:0.5 one month Two month Drug + Hypermellose E5 1:0.5 one month Two month Drug + Talc 1: 0.25 one month Two month 4.6. Granule analysis: Granule analysis data such as bulk density, tapped density, carr s index (C I), Hausner s ratio (H R) as per table: 7 Table No: 7 Granulometry analysis Parameter F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 B. D. (gm / ml) T. D. (gm / ml) C. I. (%) H. R Angle of repose LOD % Fig No: 3 In-vitro INNOVATER dissolution VS TRIAL profile F4 TO F9 of F4-F INNOVATOR TRIAL F4 TRIAL F5 TRIAL F6 TRIAL F7 TRIAL F8 TRIAL F TIMES IN HOURS Volume 1 Issue 1 Page 84

4 4.7. In-Vitro dissolution study: In-vitro dissolution study of trial batches F4 to F9 was taken and these batches having different concentration with different grade of Hypromellose in F4 and F9, the different concentration of Hypromellose were used. In F4 trial we got 101 % Cumulative Drug Release within 9 hrs and F/05 trial we got 97.8 % Cumulative Drug Release in between 9 to 12 hrs. So this grade cannot be used for extend the dissolution up to 18 hrs and next batch plan with high viscosity grade. In B.No F/08 and F/09, different concentrations of Microcrystalline Cellulose and Sodium Alginate (Protanal LF 120M) were used. In F/08 trial we got up to 80.4% cumulative drug release in 18 Hrs and in F/09 trial we got 76.8 % cumulative drug release in 18 hrs. These batches show very slow drug release compare to target drug release. So this grade was not suitable for further development. In F6 and F7, different concentrations of Sodium Alginate (Protanal LF 120M) and Hypromellose were used. In F6, % drug release was 99.4% in 15 hrs and in F7 trial; % drug release was 98.5% in18 hrs so these F6 and F7 batches were nearly comparable with target drug release so these grade can be used for further development. This may be due to structural reorganization of Hypromellose E5 polymer. Increase in concentration of Hypromellose E5 may result in increase in the tortuosity or gel strength of the polymer. But initial dissolution need to be improved. Assay value of all these batches is acceptable Drug release kinetic analysis by using different release model: To know the mechanism of drug release from these formulations, the data were treated according to first-order (log cumulative percentage of drug remaining vs time), Higuchi s (cumulative percentage of drug released vs square root of time), and Korsmeyer Peppa s (log cumulative percentage of drug released vs log time) equations along with zero order (cumulative amount of drug released vs time) pattern. (Table 8) Table No: 8.Data analysis by using different model of F/10 Model Zero order First order Higuchi Korsemeyer-Peppas Linearity (R 2 ) Slope (n) Intercept (c) The R 2 value from plot of zero order and first order shown that the formulation follows first order release pattern. The in vitro release profiles of drug from the formulation could be best expressed by Higuchi s equation, as the plots showed high linearity (R 2 = ). To confirm the diffusion mechanism, the data were fit into Korsmeyer-Peppas s equation. The formulations F/12 showed good linearity (R 2 =1), with slope (n) value equal to 0.5, indicating that mechanism of drug release follows non Fickian diffusion. This n value, however, appears to indicate a coupling of diffusion and erosion mechanisms so called anomalous diffusion. The relative complexity of this formulation and its components may indicate that the drug release is controlled by more than one process Stabiity studies: Stability studies were conducted for one month and results were noted in the Table SUMMARY AND CONCLUSION Results of preformulation studies of the active drug indicate that, it has poor flow property and compressibility property, and it was overcome by diluents and excipient compatibility evaluation was carried out, the result indicated that drugs, excipients, and polymers were compatible with each other. Optimized proportion of Hypromellose was decided based on trial and error methods and depending upon the dissolution profile. F10 batch was optimized by employing Hypromellose to check the reproducibility and matching the dissolution profile with the targeted drug release. In Wet granulation, Hypromellose E4 was used as a Controlled Release agent. In batches F04 to F09, different grades and different concentration of Hypromellose were used. The results of these batches conclude that Hypromellose E4 shown fast release compares to targeted release, Hypromellose E5 used as a Binder. In F10, the initial drug release was improved with increased in concentration of Sodium alginate and increased in concentration of Hypromellose E5. In batch F10, obtained with the increase the concentration of Sodium alginate and Hypromellose E5. In F10 obtained with the increase the concentration of SLS and dissolution profile of F10 showed that Percentage cumulative drug release identical with targeted and it were fulfill the criteria and significantly retard the release up to15 hours When compare with the innovator profile. So the batch F10 was considered as the optimized batches for once a day tablet formulation. The F11 was the coated formulation of F10, with opadry blue as coating agent; Coating was carried out till it increased the 2 percentage of weight. The stability study were carried out as per in ICH guideline for the period of one month. The results indicated that the coated formulation (F11) was stable as in period of one. It concluded that the hypromellose e5 could be used as a controlled release excipient in the solid dosage form. Volume 1 Issue 1 Page 85

5 Table: 10 First month Stability Data of sustained release film coated Tablet at 40 C ± 2 C / 75% RH ± 5 % RH Parameters Initial 1 Months Description Blue, oblong, biconvex filmcoated tablets with bisection line on one side. Blue, oblong, biconvex filmcoated tablets with bisection line on one side. Assay % % Related Substance (%) (Total Impurities) Dissolution Medium: 1) 750 ml of 0.1 N HCL 2) 7.4 ph Phosphate Buffer, paddle,50 rpm Thickness (mm) Hardness (Kp) Friability 100 Revolutions Revolutions From the above stability data at 40 C ± 2 C / 75% RH ± 5 % RH, it reveals that the product is stable at 40 C/ 75%RH for 1 months. 6. ACKNOWLEDGEMENTS Authors are thankful to Prof. (Dr.) B.Jayakar, Principal, Vinayaka Missions College of Pharmacy, Salem, Tamil Nadu, India, for providing all the facilities for this research work. REFERENCES 3 hr =80.1% 6 hr = 74.8% 9 hr = 85.3% 12 hr = 91.2% 15 hr = 99.5% Aulton ME, The Science of dosage form design, Churchill living stone, 2002, 2 nd edition, BellamiWT, P-Glycoprotein and multi drug Resistance, Drug Bank.Com, 36, 1996, Fanner DE, Buck JR and Banker GS, Journal of Pharmaceutical Sciences, 1970, Franz R, Doonan G, Measuring the surface temperature of tablet beds using infrared thermometry, Pharm Technol, 7, 1983, Lachman L, Liberman H and Kanig J, The Theory and Practice of Industrial Pharmacy, Third Edition, 1990, , 298, 335, 372, 711, 714. Leon lachman, The theory and practice of industrial pharmacy, 3 rd edition, 1987, hr = 80.1% 6 hr = 74.3% 9 hr = 85.4% 12 hr = 90.8 % 15 hr = 99.7% Libermen H, Lachman L, Pharmaceutical Dosage Forms Tablets, Vol. I to III, Marcel Dekker Inc, N.Y, 2003, Obara S, Mc Ginity J, Influence of processing variables on the properties of free films prepared from aqueous polymeric dispersions by a spray technique, Int J Pharm, 126, 1995, Obara S, Mc Ginity J, Influence of processing variables on the properties of free films prepared from aqueous polymeric dispersions by a spray technique, Int J Pharm, 126, 1995, Raymond C Rowe, H Kibbe, Handbook of pharmaceutical excipients, 4 th edition, publisher- science and practice, Royal pharmaceutical society of great britain, London, 67, 2003, Yie W Chain, Novel drug delivery systems, 2 nd ed. Madison Avenue (NY), 56, 1992, Volume 1 Issue 1 Page 86