May 16 Vol: 6 Issue: 1 (1-1)
RESEARCH PAPER Formulation and Evaluation of Extended Release Tablets of Metformin HCl Anamika Chouhan*1, Deepak Marothia1, Khushboo Ranka1, Kamal Singh Rathore 1Department of Pharmaceutics, B.N Institute of Pharmaceutical Sciences, Udaipur-India College of Medicine and Health sciences, Department of Pharmacy, Ambo University, Ethiopia The present study was aimed to develop metformin hydrochloride extended release tablets for the treatment of noninsulin-dependent diabetes mellitus (NIDDM), particularly those with refractory obesity. Metformin HCl extended release tablets reduce the dosage frequency, enhance patient compliance and maintain the therapeutic effect of the drug throughout the day. A total of nine formulations were developed using varying proportions of hydroxy propyl methyl cellulose K1M as release retardant polymers and PVP K as binder by wet granulation method. FT-IR studies revealed that there was no interaction between drug and polymer. Before compression, the granules were evaluated for pre compression parameters. After compression, evaluation tests of tablets such as general appearance, hardness, thickness, weight variation, friability, content uniformity, in vitro release studies and stability studies were performed. Out of nine formulations, the drug release was found to be within the limit as per USP in formulation F. The stability study of formulation F revealed there was no significant change in physical and chemical properties of drug stored at 4± C/75±5% RH for three months. Key Words : extended release tablets, pre compression parameters, hardness, weight variation, friability, stability studies, content uniformity INTRODUCTION effectiveness of the drug by localization at the site of Over the past 3 years, as the expense and action, reducing the dose required or providing complications involved in marketing new drug entities uniform drug delivery4-5. have increased, with concomitant recognition of the Metformin is used in patients with type diabetes therapeutic advantages of controlled drug delivery, (non-insulin dependent diabetes). Controlling high greater attention has been focused on development blood sugar helps prevent kidney damage, blindness, of sustained or controlled release drug delivery nerve problems, loss of limbs, and sexual function systems. Usually conventional dosage form produce problems. Proper control of diabetes may also lessen wide ranging fluctuation in drug concentration in the the risk of a heart attack or stroke. The biological half blood consequent life of metformin HCl is 1.5-4.5hrs. So conventional This factors metformin HCl tablets should be administered -3 as well as factors such as repetitive dosing and times a day to maintain the therapeutic effect of the unpredictable absorption lead to sustained or drug throughout the day. Metformin HCl extended controlled drug delivery systems. The goal in release tablets reduces the dosage frequency and Designing sustained or controlled delivery systems is enhance the patient compliance. A total of nine to reduce the frequency of the dosing or to increase formulations stream and tissues undesirable toxicity and poor with efficiency1-3. www.pharmaerudition.org May 16, 6(1), 1-1 were developed using varying 1 Page
proportions of hydroxy propyl methyl cellulose K1M keeping the conical flask on rotary shaker at rpm. and PVP K as release retardant polymers by wet A portion of drug dissolved in distilled water, alcohol, granulation method6-11. acetone, methylene dichloride, chloroform and Materials and Methods Metformin hydrochloride was obtained from Smruthi Organics, Mumbai. Microcrystalline Cellulose was procured from Patel Industries, Ahmedabad. PVP K was obtained from Nanhang Industries, Quzhou, Zhejiang, China. HPMC K1M was obtained from Coloron Asia Pvt Ltd., Mumbai. Magnesium Stearate was procured from Donglian Aromatic Chemicals Development Co. Ltd. (China). Isopropyl Alcohol was obtained from Exxon Mobile Chemical Company (USA) and Colloidal Silicon Dioxide was procured from Signet Chemical, Mumbai. Precompression Parameters General appearance: Drug was observed for its color, odor and taste and obtained results are described in table Identification of drug: Identification of metformin HCl was carried out by Infra Red Absorption Spectrophotometer. Selection of solvent: The phosphate buffer ph 6.8 was selected as dissolution media because it represents the ph of gastrointestinal fluid and it is recommended for metformin HCl tablets by USFDA. Solubility studies: The solubility of drug in various solvent was determined by using shake flask method. Excess amount of drug that can be dissolved was added to 5 ml conical flask containing 1 ml of dissolution phosphate buffer ph 6.8 was filtered through membrane filter (.45μm) and concentration of drug in the filtrate was determined at 33nm by UV Spectrophotometer. Melting point: Melting point of the drug sample was determined by using melting point apparatus. The reported and observed melting point is shown in Table. Bulk density: The bulk density of the ingredients was evaluated using a graduate cylinder. Tapped density: It is the ratio of total mass of powder to the tapped volume of powder. The tapped volume was measured by tapping the powder to constant volume. It is expressed in gram/ml. Compressibility and Hauser s ratio: Compressibility and Hauser s ratio were determined by using formula. Angle of repose This is the maximum angle possible between the surface of a pile of powder and the horizontal plane. Sufficient quantities of Metformin HCl granules were passed through a funnel from a particular height onto a flat surface until it formed a pile, which touched the tip of the funnel. The height and radius of the pile were measured. The angle of repose was calculated using the formulatan θ = h/r θ = tan-1 (h/r) media. The shaking process was carried for 4 hrs by www.pharmaerudition.org May 16, 6(1), 1-1 Page
UV Spectroscopy: metformin HCl pure drug was weighed accurately and Determination of λmax: shifted through 4# mesh. Then PVP K-3 was Accurately weighed 1 mg of drug was dissolved in dissolved completely in sufficient quantity of water 1 ml of phosphate buffer ph 6.8 in 1 ml and IPA. volumetric flask. This solution was labeled as Stock-1. Wet granulation was done in Rapid Mixing Granulator From the Stock-1, 1 ml of solution was withdrawn (RMG). In the rapid mixing granulator, metformin HCl and diluted up to 1 ml in 1 ml volumetric flask pure drug, the PVP K-3 solution was added with and labeled as Stock-. From Stock-, 1mL of slow speed of rapid mixing granulator. Then the rapid solution was withdrawn and diluted up to 1 ml in mixing granulator operated at high speed. Then again 1mL volumetric flask. The spectrum of this solution sufficient water was added if necessary. Then lastly was run in -4 nm range in UV spectrometer. for two minutes the rapid mixing granulator operated The spectrum peak point in graph of absorbance of on slow speed to form granules. metformin HCl versus wavelength was shown in In drying, the granules were dried in air dryer without figure and it shows the absorbance maxima 3nm in giving temperature for min. Then these semidried phosphate buffer ph 6.8. granules subjected for final drying in FBD at inlet Standard calibration curve: The main Stock solution was prepared by dissolving 1 mg of drug in 1 ml of phosphate buffer ph 6.8 in 1 ml volumetric flasks. This solution was labeled as Stock -1. From the Stock -1, 1 ml of solution was withdrawn and diluted up to 1 ml in 1 ml volumetric flask. This solution was labeled as Stock-. From the Stock-; 1mL, ml, 3mL up to 1 ml of solutions were withdrawn and diluted up to 1mL in 1mL volumetric flask with same media. The absorbance of each solution was measured at 3 nm using phosphate buffer ph 6.8 as a blank in UV spectrometer. The absorbance versus concentration curve was plotted. temperature of 4 C and again after air dried without heating, granules were further dried by same process to obtained dried granules. Then these granules passed through 16 # mesh. In polymerisation step the polymers HPMC K 1CR was accurately weighed and shifted through 4 # mesh, the lubricating agent magnesium stearate weighed accurately and shifted through 4 # mesh. In final Mixing step, in double cone blender firstly dried granules of metformin HCl was mixed with polymer for 5 min. Then lubricating agent magnesium stearate was mixed in to first mixture for min. Finally these granules are ready for compression. Then these granules are compressed by using punch size of length 1.mm and.5(d-tooling) maintaining Manufacturing Procedure humidity below 5%RH. Different metformin HCl Different metformin HCl formulations were prepared formulations were prepared by wet granulations by Wet granulations technique (F-1 to F-). Firstly technique (F-1 to F-). www.pharmaerudition.org May 16, 6(1), 1-1 3 Page
Table1: Different Formulations of Metformin HCl S.No. Ingredients F1 F F3 F4 F5 F6 F7 F8 F 1. Metformin HCl. HPMC K1M 175 175 15 1 5 45 5 3. MCC 185 18 157 145 135 155 15 11 13 4. PVP K 3 3 7 7 7 7 7 7 5. IPA:Water(1:1) 6. Magnesium Stearate 1 8 7. Aerosil 1 7 Evaluation of Tablets: tablets were selected and hardness of the tablets Appearance: was measured. The general appearance and elegance of tablet was Friability: identified visually, which include tablet size, shape, Friability was determined by Roché friabilator. The presence or absence of an odor, surface texture etc. friabilator was operated at 5 rpm for four minutes Weight variation: To study weight variation, tablets of each formulation were weighed using an electronic balance, average weights was calculated, individual tablet weights were compared with the average (1 revolutions) then remove any loose dust from them and weigh them accurately. A maximum loss of weight not greater than 1. percent is acceptable for most tablets (Table). The percent friability was calculated using equation % F = 1- weight and the maximum percent difference allowed is 5%. Thickness: Where, % F = friability in percentage W = Initial weight of tablet The results of thickness for formulated tablets were determined using calibrated Vernier callipers and results are shown in Table. Tablet thickness was almost uniform in all the tablets and values were controlled within a ±.5% variation of standard value. 1 W = weight of tablets after revolution Assay: Twenty tablets were weighed and powdered. A quantity of powder containing about.1gm of metformin hydrochloride was weighed. The weighed quantity was shaken with 7mL of water for 15min. Hardness: This was diluted to 1mL with water and filtered. The hardness of the tablets was determined using 1mL of the solution was diluted to 1mL and 1 ml hardness tester. It was expressed in kg/cm.ten of the solution was diluted to 1mL. The absorbance www.pharmaerudition.org May 16, 6(1), 1-1 4 Page
of the resulting solution was observed at 3nm. Solubility: Dissolution studies: Solubility of drug determined in different media is In vitro dissolution study was carried out for different obtained and given in Table : formulation of metformin HCl in phosphate buffer ph Table: Solubility determination of metformin HCl 6.8 and analyzed at 3 nm by UV spectrophotometer and plotted graph as shown in Figure 6.6 and 6.7. Drug release studies were conducted using USP- dissolution apparatus-, paddle type at a rotational speed of 5 rpm at 37±.5 ºC. The dissolution media used were ml of ph 6.8 phosphate buffer solutions for 1h. Sink condition was maintained for the whole experiment. Samples (1 ml) were withdrawn at regular intervals and the same volume Solubility Sr. No. Solvent Solubility profile 1 Distilled Water. Freely soluble ph 6.8.15 Freely soluble 3 Ethanol.1 Slightly soluble (gm/ml) Melting point determination: Melting point of metformin HCl was performed by open capillary method and the melting point was found to be -4oCand given in above Table 3 Table3: Melting point determination of pre warmed (37±.5 ºC) fresh dissolution medium Reported Melting Point Observed Melting Point was replaced to maintain the volume constant. The -6 C -4 C samples withdrawn were filtered through a.45 μ Identification of Pure Drug: membrane filter and the drug content in each sample was analyzed after suitable dilution with a UV spectrophotometer (Shimadzu UV-17) at 33 nm. The dissolution test was performed in triplicate. Drug dissolved at specified time periods was plotted as cumulative percent release versus time (h) curve. Stability studies: The best formulation of Metformin hydrochloride extended release tablets was subjected to stability Fig.1: FTIR spectrum of pure drug Table 4: Identification of drug was carried out by FTIR. Peak (cm-1) Functional group 14.3 CN Stretching 1455. NH Deformation 37 CH Deformation release. 3374 NH Stretching Results 638.3 NH Deformation 31 NH studies by storing at 4C± C /75±5% RH for 3 months. At every month interval, the tablets were visually examined for any physical change and evaluated for the drug content and in vitro drug Preformulation Parameters: www.pharmaerudition.org May 16, 6(1), 1-1 Calibration curve of drug: 814.6 CH Stretching An absorption maximum was found at 33nm. 5 Page
properties of the powder. This was further supported by lower compressibility index values. Generally, compressibility index values upto15% results in good to excellent flow properties. Fig.: Spectrum of drug in phosphate buffer ph6.8 Drug Excipient compatibility study: A) Physical compatibility: Given in Table 7 B) Drug- excipient compatibility studies by FTIR: 1. Compatibility study of drug with MCC Standard curve of drug: Table 5: Standard curve of the drug in phosphate buffer ph 6.8 S.No. 1 3 4 5 Concentration 4 6 8 1 Absorbance.68.54.71.1 1.78. Compatibility study of drug with PVP K 3. Compatibility study of drug with all excipient Fig.3: Calibration curve of metformin HCl in phosphate buffer ph 6.8 Result of Linearity test shows that the absorbance of the drug in phosphate buffer ph 6.8 at 3 nm is linear (R²=.6) with concentration range of 1 µg/ ml to 1 µg/ml. 4. Compatibility study of drug with Aerosil Density and flow properties Table 6: Observation of density and flow properties for Metformin HCl S.No. Parameters 1 Bulk density(gm/cm³) Tapped density(gm/cm³) 3 Compressibility index (%) 4 Hausner s Ratio 5 Angle of repose Drug.4.6 3.5 1.47 4.7 The results of angle of repose (<3) indicate fair flow www.pharmaerudition.org May 16, 6(1), 1-1 Fig.4.1-4.4: Drug- excipient compatibility studies by FTIR in different excipients 6 Page
Table7: Result of physical compatibility of Metformin HCl Drug+Excipients Ratio Drug Microcrystalline cellulose 1 1:1 Observations on appearance Initial (Color) At 4 C± C 75%RH±5% for 1 Month HPMC K 1M 1:1 PVP K 1:1 Magnesium Stearate 1:1 Aerosil 1:1 Drug+MCC+PVPK+ HPMC K 1M +Aerosil+Magnesium stearate Proportional Mixture Drug+MCC+PVPK+ HPMC K 1M +Aerosil+ Magnesium stearate + Coating Material Proportional Mixture Evaluation of Pre-compression In the below Table 8 characteristics of the granules from F-1 to F- is given. From the values of angle of repose, Hauser s ratio and Carr s Index it can conclude that granules have good flow properties Table8: Pre-compression parameters Tablet Weight(mg) Thickness Hardness (Kg/cm) 6±.8 7±.5 F1 F F3 F4 F5 F6 F7 F8 5.63±.5 5.85±.5 Friability (%).±.1.1±.5 8±.8 7±.5 8±.11 8±. 7±.5 6±. % Assay 8.3±. 11.1±.1 6.15±.5 5.7±.1 5.63±.1 6.±.7 6.5±. 5.5±.7.1±.4.15±.3.5±.1.8±.5.±..18±..4±.54 8.1±.1 7.4±.15.+.55 1.5+.1 7.8+.5 Evaluation of Post-compression Parameters Table : Post-compression parameters S. Formulation Code Bulk density No. (g/cm3) 1 3 4 5 6 7 8 F1 F F3 F4 F5 F6 F7 F8 F Tapped density (g/cm3) Angle of Repose (º).55.63.5.64.56.57.5.6.61 36.5.74 3.41 33.6 5.3 7.3 6.87 8.1.1.45.54.4.56.45.44.5.51.53 www.pharmaerudition.org May 16, 6(1), 1-1 Carr s Index (%). 14.8 16.5 16.66. 18. 11.86 16.4 16.5 Hauser s Ratio (HR) 1. 1.16 1. 1.14 1.18 1.17 1.13 1. 1.3 7 Page
Discussion The thickness of the tablets was found to be in the mg weight tablets. In friability test the maximum range of 5.63±.5 to 6.15±.mm. The results weight loss should be not more than 1%. The results showed that the thickness of all formulated tablets is revealed that the tablets passed the friability test. found to be uniform. The hardness of all tablet In vitro dissolution profile: formulations was found to be in the range of 6±.8 Medium: ph 6.8 phosphate buffer to 8±.8 kg/cm. It indicates all the tablets have Apparatus: Apparatus (Paddle) adequate mechanical strength. The accepted Speed: 5 rpm percentage deviation was ±5% for more than 34 Temperature: 37±.5 C Table1: % Cumulative drug release data from batch F1-F5 Time in min % Cumulative drug released F1 F F3 15.7 3.5 3 5.4 6 4.3 6 11 1 7.8 1 1.8 13.1 18 3.45 5.46 4 4.31 33 6. 3 47 45 3.45 36 58 57 45 4 64 6 55.76 48 7 71 63 54 74 74 7 6 7 8 76 66 78 83.85 7.5 7 8 88 86 F4 3 6 1 18 3 3 4 53 5.5 64 6 7.63 78.4 84 F5 5 8 13 6 33 4.84 48.8 56 6 6 76 8 Discussion: The trial batches F1 to F5 were formulated using PVP Trial F3 was compressed with an increase in the K as binder with water and IPA. binder concentration. In this trial no capping was Trial F1 was compressed using SC punch, which observed. Broken edges were also disappeared showed the problem of capping in the tablets, and during coating. But dissolution profile was not as per also during coating of the tablets, the coating was required so, further trials were taken. not uniform and the movement of the tablets during Trial F4 and F5 were compressed with less binder pan coating was not good and also the edges broke concentration. In this trial capping was not observed during the rotation. with suitable dissolution profile but very less as Trial F was compressed after increasing the compared to the reference product. So, further trials concentration of binder. But in this trial also capping were taken by increasing concentration of polymer. was observed. www.pharmaerudition.org May 16, 6(1), 1-1 8 Page
Table11: % Cumulative drug release data from batch F6-F: Time in min F6 15.88 3 4.8 6 8 1 1 18 1.66 4 5 3 31 36 4 4 51 48 6 54 6 6 75 66 7 7 8 % Cumulative drug released F7 F8.75 4.11 4.77 7 8 11 13 1 1 7.64 35 37 4 45 4 54 56 6.48 63 66.4 73 75.88 8 84 8 F 3.88 6.1 14.3 1.33 6 37.57 46.53 56.41 64 73.5 81 1.7 8.86 Release kinetics: Different kinetic equations (zeroorder, first-order, Korsemeyer-Peppas Higuchi s model) equation were and applied to interpret the release rate of the drug from drug delivery systems. Following graphs were obtained: Fig.6: Cumulative plots for Higuchi model for F1-F Fig.5: Cumulative plots for zero order model for F1-F www.pharmaerudition.org May 16, 6(1), 1-1 Page
Fig.7: Cumulative plots for first order model for F1-F Fig.8: Cumulative plots for Korsemeyer-Peppas model for F1-F Fig.: In vitro release profile for F after different time period Table1: In vitro release kinetic data for F1 to F Formulation Zero-order kinetics First-order kinetics data data Regression Regression coefficient (r) coefficient (r) F1.55.4 F.83.75 F3.4.78 F4.86.58 F5..4 F6.1.54 F7.4.13 F8.6.83 F.5.731 Higuchi matrix kinetic data Regression coefficient (r).58.54.6.51..41.1.37.3 Korsemeyer Peppas data Regression coefficient (r).88.5.8.5.4.86.1.1.78 Stability Data: Batch F was put on stability as below mentioned condition Table13: Stability Study: Pack Condition Batch No. Appearance Test Parameters Drug Content (%) Alu Alu Blister 4 C/75%RH F Specification 5-15 Initial 1.58 www.pharmaerudition.org May 16, 6(1), 1-1 1 month 1.7 Month.8 3 Month.71 1 P a g e
Table14: First, Second and Third months stability data of tablets at the condition 4 C/ 75±5% RH Time 15 3 6 1 18 4 3 36 4 48 54 6 66 7 Initial Release 1 month 3.88 6.1 14.3 1.33 6 37.57 46.53 56.41 64 73.5 81 1.7 8.86 months 4.1 6.4 1.67 14.87 1.5 6.78 38.1 47.14 6.5 65.87 74.6 81.4.3 8. 3 months 4.8 7. 11 15.1.1 6.3 38.1 47.8 6.5 65.4 75.1 8.6 3.4 4.86 7 1 16 4.57 8.14 4.1 51 6 6 84 1 7.86.87 From the above stability data at 4 C/ 75±5% RH, it. Handbook of pharmaceutical excipient, nd Edition reveals that the product is stable in above conditions 3. Prescribing Information for Metformin HCl. for three months. Available from: http://www.drugs.com CONCLUSION 4. Prescribing Information for Metformin HCl. The present study concludes that combination of Available from: http://www.rxlist.com hydroxy propyl methyl cellulose and binder PVP K 5. Roy, H, Brahma, CK, Nandi, S, and Parida, KR. can be utilized for designing and development of (13) Formulation and Design of Sustained controlled release solid dosage form. The best Release Matrix Tablets of Metformin Hydrochloride: formulation F has shown a drug release NLT 6-8 Influence % in 18hr was in accordance with the USP Polymers. International Journal of Applied and Basic dissolution criteria for extended release metformin Medical Resarch, 3(1), 55-63. HCl formulation. In the present research, extended 6. Garg, C and Saluja, V. (13) Once-daily release tablet formulations of metformin HCl were Sustained-Release Matrix Tablets of Metformin successfully Hydrochloride based on An prepared for a once daily administration. REFERENCES of Hypromellose and Polyacrylate Enteric Polymer and Chitosan. J Pharm Education Resarch, 4(1), -7. 7. Rathore KS, Uma U, Formulation and Evaluation of Sustained Release Matrix Tablets of Metformin 1. United States Pharmacopoeia 3 NF 5 (7) The Official Compendia of Standards, published by United States Pharmacopoeial Convention, Inc. Hydrochloride, The Pharmaceutical and Chemical Journal, Sept. 14, 1():5-13. 8. Falguni M. Patel, Ara N. Patel and KS Rathore, Rockville. www.pharmaerudition.org May 16, 6(1), 1-1 11 P a g e
Release of metformin hydrochloride from Kumar, N. (1) Sustained Release Matrix Type ispaghula - sodium alginate beads adhered cock Drug Delivery System: A Review. World Journal of intestinal mucosa, IJCPR, 11, 3( 3), p.5-55. Pharmacy and Pharmaceutical Sciences, 1(3), 34-. Shaik, MR, Korsapati, M, and Panati, D. 6. Polymers in Controlled Drug Delivery Systems. 11. Modi, SA, Gaikwad, PD, Bankar, VH, and Pawar, International Journal of Pharma Sciences, 1, S. (11) Sustained Release Drug Delivery System: 11-116. A Review. International Journal of Pharma. 1. Kumar, V, Prajapati, SK, Soni, GC, Singh, M and Research and Development, (1), 147-16. Source of Support: Nil, Conflict of Interest:None www.pharmaerudition.org May 16, 6(1), 1-1 1 P a g e