276 P a g e International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 4(1): January-February 2015 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093*** Pharmaceutical Sciences ICV 5.13*** RESEARCH ARTICLE!!! FORMULATION AND EVALUATION OF METFORMIN HYDROCHLORIDE SUSTAINED RELEASE TABLETS N. Parasakthi, S. Palanichamy, T. Raja Sekharan* and P. Solairaj Department of Pharmaceutics, Sankaralingam Bhuvaneswari College of Pharmacy, Anaikuttam, KEYWORDS: Metformin, HPMC K4M, HPMC 15Cps, Sustained release tablet. For Correspondence: T. Raja Sekharan* Address: Department of Pharmaceutics, Sankaralingam Bhuvaneswari College of Pharmacy, Anaikuttam, Sivakasi-626 130, Tamil Nadu, India. Email: rajmpharm@gmail.com Sivakasi-626 130, Tamil Nadu, India. ABSTRACT Metformin hydrochloride sustained release tablets were prepared by wet granulation technique with HPMC K4M and 15Cps. The prepared granules were evaluated for its flow property with the help of the angle of repose, bulk density, tapped density, compressibility index and hausners ratio. All the formulations showed good flow properties. Then the prepared granules were compressed into tablets. The compressed tablets were evaluated for the hardness, uniformity of weight, friability, drug content and invitro dissolution studies. All the formulations showed compliance with pharmacopial standards. FTIR studies were performed to determine whether there was any interaction between drug, polymer and other excipients. But there was no interactions found. Among all the formulations F6 showed prolong release when compare to other formulations. The time intervals and the release profiles for F6 formulation complies with the limits specified in USPNF26. formulation was compared with marketed metformin sustained release tablets Obimet SR. The drug release kinetics showed hixon crowell release. All the formulations followed fickian transport mechanism. The stability test was performed for optimum formulation (F6). It was found to be stable when it was stored at 40 C±2 o C and 75%RH±5% for a period of three months. F6
277 P a g e International Standard Serial Number (ISSN): 2319-8141 INTRODUCTION: Metformin is an oral diabetes medicine that helps control blood sugar levels 1. Metformin is used alone or with other medications, including insulin, to treat type 2 diabetes (condition in which the body does not use insulin normally and, therefore, cannot control the amount of sugar in the blood). Metformin is in a class of drugs called biguanides. Metformin helps to control the amount of glucose (sugar) in your blood. It decreases the amount of glucose you absorb from your food and the amount of glucose made by your liver. Metformin also increases your body's response to insulin, a natural substance that controls the amount of glucose in the blood. Metformin is not used to treat type 1 diabetes (condition in which the body does not produce insulin and therefore cannot control the amount of sugar in the blood) 2. Sustained release dosage forms are designed to release a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects 3. The terms Sustained release, prolonged release, modified release, extended release or depot formulations are used to identify drug delivery systems that are designed to achieve or extend therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. The goal in designing sustained or controlled delivery systems is to reduce frequency of dosing or to increase the effectiveness of the drug by localization at the site of action, reducing the dose required, providing uniform drug delivery 4. Hypromellose, short for hydroxypropyl methylcellulose (HPMC), is a semisynthetic, inert, viscoelastic polymer used as an excipient and controlled-delivery component in oral medicaments, found in a variety of commercial products 5. The aim of this research work is to prepare and evaluate metformin sustained release tablets with the help of HPMC K4M and HPMC 15Cps as a polymer. Materials and Methods Metformin Hydrochloride IP was obtained as a gift sample from Wanbury Ltd, Mumbai. Hydroxy propyl methyl cellulose (HPMC) IP.K4M and 15Cps was obtained as a gift sample from Colorcon, Goa. Sodium Carboxymethyl Cellulose IP was purchased from Pioma chemicals, Mumbai. Dibasic Calcium Phosphate IP (Anhydrous) was purchased from Sudeep Pharma, Baroda. Povidone IP (K-30) was purchased from FMC-Bio polymer, Ireland Colloidal Silicon Dioxide IP (Aerosil-200) was purchased from Cabot Sanmar Ltd, Chennai. Talc IP was purchased from Udaipur Mineral, Rajasthan. Magnesium Stearate IP was purchased from Vijlak Pharma, Hyderabad. All the ingredients and chemicals used were of analytical grade.
278 P a g e International Standard Serial Number (ISSN): 2319-8141 Preparation of Metformin Hydrochloride Granules Various formulations (F1-F6) were prepared by wet-granulation technique. The ingredients were shown in the Table no: 1. Metformin Hydrochloride, HPMC-K4M, HPMC -15cps, SCMC and Dicalcium phosphate were sifted through #40 mesh. The sifted blend was allowed to mix thoroughly in rapid mixer granulator for 15min. at slow speed. The binder solution was prepared by dissolving povidone in purified water. The prepared binder solution was added to mixed blend slowly and allowed to mix uniformly until to get granules. The resulting granules were allowed to dry in drier at 60 C until the LOD (Loss on drying) of granules was reached limit between 2-3%w/w. The dried granules were sifted through #16 mesh and the granules was pre lubricated with colloidal silicon di oxide and talc for 5 min. in RMG. The blend was finally mixed with magnesium stearate (which was sifted through # 60) for 2min. in RMG. Final blend was collected and stored for compression. Table: 1 Composition of various formulations containing Metformin Hcl Ingredients (mg) Formulation code F1 F2 F3 F4 F5 F6 Metformin Hydrochloride 500 500 500 500 500 500 HPMC-K4M 20 20 40 40 60 60 HPMC-15Cps 15 20 15 20 15 20 Sodium carboxy methyl cellulose 200 200 200 200 200 200 Dicalcium phosphate anhydrous 90 85 70 65 40 35 Povidone K-30 8 8 8 8 8 8 Purified water Qs q.s qs qs qs qs Colloidal silicon dioxide 5 5 5 5 5 5 Talc 8 8 8 8 8 8 Magnesium stearate 9 9 9 9 9 9 Evaluation of granules Prepared granules were evaluated for its flow properties. The flow properties was determined by angle of repose, compressibility index and hausner ratio. Compressibility index and hausner ratio was determined with the help of bulk density and tapped density 6.
279 P a g e International Standard Serial Number (ISSN): 2319-8141 Evaluation of tablets Then the prepared granules was compressed into tablet using 19.2 x 8.9mm plain punch on 27 stations double rotary compression machine (Cadmech India Co Pvt Ltd). Prepared tablets were evaluated for its parameters like hardness, uniformity of weight, friability test, drug content and in-vitro dissolution studies. The best formulation was evaluated for stability studies 7. FT-IR studies It was used to study the interactions between the drug and polymer. The drug and polymer must be compatible with one another to produce a stable product. Drug and polymer interactions were studied by using FTIR (Shimadzu, Japan model 8400S). The peak and patterns produced by the pure drug were compared with combination of pure drug and polymer 6. In vitro drug release studies In vitro drug release studies of Metformin HCl were carried out as per the USPNF 26 method with some modifications. Dissolution studies were performed in 900ml of distilled water using USP Type II paddle method at 75 rpm and the temperature at 37±0.5 C. The apparatus was allowed to run for 10hours. 10ml of sample was withdrawn after 1 st hour, 2 nd hour, 6 th hour and 10 th hour 8. The fresh dissolution medium was replaced every time with same quantity of dissolution medium. Collected samples were suitably diluted to 100ml with distilled water in 100 ml standard flask and analyzed at 233 nm using distilled water as blank. The percentage drug release was calculated. Best formulation was compared with marketed metformin (Obimet SR) of sustained release tablets Obimet SR (Metformin 500mg) Mechanism of drug release To know the release kinetics, the value obtained from in vitro drug release studies were plotted in various kinetic models like zero order, first order, higuchi model hixson-crowell and korsmeyer peppas 9. Zero order Zero order is cumulative amount of drug release vs time. C=K o t, Where, K o is the zero order rate constant expressed in units of concentration/time and t is the time in hours.
280 P a g e International Standard Serial Number (ISSN): 2319-8141 First order First order is log cumulative percentage drug remaining vs time. Log C=Log C o Kt/2.303, where C o is the initial concentration of drug, K is the first order constant and t is the time. Higuchi model Higuchi model is the cumulative percent drug release vs square root of time. Q=Kt 1/2, where K is the constant reflecting the design variables of the system and t is the time in hours. Hixson-Crowell model Hixson-Crowell model is the cube root percent drug remaining vs time. 3 Q o 3 Qt=K HC X t, where, Q o is the initial amount of drug in the tablet, Q t is the amount of drug release in time t, K HC is the ration constant for the Hixson-Crowell rate equation and t is the time. Korsmeyer-Peppas model Log cumulative percentage of drug release vs log time. The exponent n was calculated through the slope of straight line. M t /M =kt n Where, M t /M is the fractional solute release, K is the kinetic constant characteristic of the drug polymer system, t is the release time and n is the exponent.
281 P a g e International Standard Serial Number (ISSN): 2319-8141 By using korsmeyer model, the mechanism of drug release was determined. If n = < 0.45, it is fickian diffusion and if n= 0.45 0.89, it is non-fickian diffusion transport. An exponent value of 0.89 is indicative of Case-II Transport or typical zero-order release Stability study F6 formulation was packed in Alu-PVC Blister and kept at 40 C±2 o C and 75%RH±5%. F6 formulation was analyzed for drug content and in-vitro dissolution studies in the intervals of 1, 2 and 3 months. The real time stability studies were carried out at 30 C±2 o C and 65%RH±5% for in-vitro dissolution studies. RESULTS AND DISCUSSION Evaluation of Metformin HCl granules: The prepared granules were evaluated for its flow property. Angle repose was found to be 32.45±0.20 to 34.43±0.19. It showed good flow property of the granules. Compressibility index and hausner s ratio was determined with the help of bulk density and tapped density. Compressibility index was in the range of 11.76±0.180 to 15.01±0.130 and hausner s ratio was in the range of 1.13±0.004 to 1.18±0.020. This also indicates that the granules are good in its flow properties. Table: 2 Evaluation of Metformin HCl granules Angle Of Bulk Density Tapped Density Compressibility Hausner s Formulations Repose (θ) (g/cm 3 ) (g/cm 3 ) Index (%) Ratio F1 33.02±0.35 0.45±0.006 0.51±0.020 11.76±0. 180 1.13±0.004 F2 32.45±0.20 0.39±0.002 0.45±0.002 13.33±0.020 1.15±0.002 F3 34.43±0.19 0.43±0.003 0.51±0.010 15.01±0.130 1.18±0.020 F4 32.33±0.15 0.47±0.007 0.55±0.002 14.54±0.110 1.17±0.010 F5 33.46±0.20 0.38±0.004 0.45±0.002 13.03±0.040 1.18±0.020 F6 32.98±0.34 0.51±0.003 0.58±0.003 12.76±0.070 1.13±0.020 Evaluation of Metformin HCl tablets The prepared tablets were evaluated for different parameters. The hardness of the tablet was found to be between 9.14±0.0894 to 9.22±0.1483. The uniformity of weight of the tablets was found to be 842.35±6.3102 to 843.75±5.9194. This indicates that the tablets were within the acceptable deviations of ±5%. Friability test for all the formulations was within the range of 0.1936±0.0965 to 0.3324±0.0827. The friability should be within the 1% deviation. All the
282 P a g e International Standard Serial Number (ISSN): 2319-8141 formulations were within the acceptable deviation. The drug content for all the formulations were found to be in the range of 98.11±1.03 to 99.93±1.11. The IR study confirmed that there are no interactions between the drug, polymers and other excipients used in this formulation. Table: 3 Evaluation of Metformin HCl tablets Formulation Hardness Uniformity of Friability Drug code (kg/cm 2 ) weight (mg) (%) Content (%) F1 9.22±0.1483 842.35±6.3102 0.3324±0.0827 99.93±1.11 F2 9.14±0.0894 841.65±6.4911 0.3011±0.0771 98.11±1.03 F3 9.20±0.1000 842.45±6.0217 0.2810±0.0655 99.20±0.43 F4 9.16±0.1517 842.80±6.6696 0.2650±0.0412 98.71±0.01 F5 9.14±0.1140 842.40±6.3528 0.2452±0.0888 99.56±0.25 F6 9.20±0.0707 843.75±5.9194 0.1936±0.0965 99.68±0.17 Invitro release study In-vitro release studies of Metformin HCl were performed as per the methods and time intervals specified in USP NF 26. Six formulations of Metformin HCl tablets were prepared with varying proportions of polymers HPMC-K4M and HPMC 15cps and dissolution studies were carried out. The percentage drug release was gradually increased with increase in time intervals. 100% drug was released for F1 and F2 formulations before 10 th hour. The drug release was 98.44±0.31%, 95.34±0.10%, 91.46±0.12%, and 90.61±0.06% respectively in 10 th hour for F3 to F6 formulations. The results are shown in figure-1. The release rate was high in initial periods but the release rate may become slower as time goes on. However the release profiles of drugs from formulations F1 to F5 were not found to be as per the specifications and time intervals quoted in USP NF26. The standard limits of drug release in the prescribed time as per USP NF26 is 1 hour: 20-40%; 2 hours: 35-55%, 6 hours: 65-85% and in 10 hours not less than 85%. F6 formulation showed the drug of 38.78%, 49.72%, 78.23% and 90.60% in first hour, 2 nd hour, 6 th hour and 10 th hour respectively. The time intervals and the release profiles of Metformin HCl complied with the limits specified in USP NF26. F6 formulation was also compile with marketed metformin sustained release tablet Obimet SR. Comparison graph was shown in figure-2.
283 P a g e International Standard Serial Number (ISSN): 2319-8141 Figure: 1 Comparison of invitro drug release study of Metformin HCl sustained release formulations F-1 to F-6 Figure: 2 Comparative Dissolution Study of Metformin HCl with Marketed sample The invitro release datas were plotted in different kinetics model. The release rate kinetic data for all the formulations was shown in table-4. According to zero order, the formulations showed a high linearity with correlation co-efficient values (r 2 ) for zero order was found to be between 0.9552±0.0106 to 0.9995±0.0004, for first order it was 0.9331±0.0060 to 0.9994±0.0006. Diffusion is related to transport of drug from the matrix tablets into the dissolution medium depends upon the concentration. This is explained by Higuchi s equation. For higuchi 0.9881±0.0007 to 0.9995±0.0003, for hixon crowell 0.9817±0.0017 to 0.9984±0.0012 and for
284 P a g e International Standard Serial Number (ISSN): 2319-8141 korsmeyers-peppas 0.9811±0.0084 to 0.9969±0.0029. It showed that the drug release follows hixon crowell. By using korsmeyer model, the mechanism of drug release was determined. If n = < 0.45, it is fickian diffusion. The results of all the formulations showed that the n values are between 0.2265±0.0083 to 0.3774±0.0014. It proved that all formulations followed fickian transport mechanism. Table: 4 Release kinetics of Metformin sustained release tablet formulations Correlation Co-efficient (r 2 ) value Korsmeyers - Peppas Formulation Hixon Correlation Code Zero First Higuchi Slope (n) crowell Co-efficient value (r 2 ) value 0.9986± 0.9938± 0.9955± 0.9957± 0.9811± 0.2265± F1 0.0019 0.0025 0.0035 0.0018 0.0084 0.0083 0.9995± 0.9944± 0.9922± 0.9976± 0.9834± 0.2274± F2 0.0004 0.0025 0.0047 0.0025 0.0085 0.0036 0.9854± 0.9331± 0.9995± 0.9817± 0.9932± 0.2391± F3 0.0029 0.0060 0.0003 0.0017 0.0033 0.0046 0.9602± 0.9879± 0.9943± 0.9984± 0.9969± 0.3008± F4 0.0016 0.0031 0.0010 0.0012 0.0029 0.0037 0.9575± 0.9987± 0.9881± 0.9927± 0.9876± 0.3186± F5 0.0021 0.0001 0.0007 0.0010 0.0004 0.0108 0.9552± 0.9994± 0.9914± 0.9940± 0.9968± 0.3774± F6 0.0106 0.0006 0.0040 0.0042 0.0008 0.0014 The stability study for F-6 formulation was carried at 40 o C /75%RH for a period of three months. Drug content and invitro release studies were performed for first, second and third month and the value was compared with initial value. With the comparison value F6 formulation was found to be stable for the period of three months at 40 o C /75%RH. CONCLUSION: From this present research it was concluded that the prepared granules having good flow properties. The values of tablets evaluations were within the prescribed limits. The drug release was prolonged as the polymer concentration was increased.
285 P a g e International Standard Serial Number (ISSN): 2319-8141 ACKNOWLEDGEMENT: The authors are thankful to the Correspondent, Mr. S. Sriram Ashok, Sankaralingam Bhuvaneswari College of Pharmacy, Sivakasi for providing the facilities to carry out this work. REFERENCES: 1 http://www.drugs.com/metformin.html 2 http://www.nlm.nih.gov/medlineplus/druginfo/meds/a696005.html 3 http://en.wikipedia.org/wiki/sustained_release_dosage_forms 4 Navin Dixit, Sheo Dutt Maurya, Bhanu P.S.Sagar, (2013), Sustained Release Drug Delivery System. Indian Journal of Research in Pharmacy and Biotechnology, 1(3), 305-310 5 http://en.wikipedia.org/wiki/hypromellose 6 Raja Sekharan T, Palanichamy S, Shanmuganathan S, Tamilvanan S and Thanga Thirupath A, (2009), Formulation and Evaluation of Theophylline Controlled Release Matrix Tablets using Guar gum. Ars Pharm, 50(4), 205-214. 7 T. Raja sekharan, S. Palanichamy, S. Shanmuganathan, A. Karthikeyan, S. R. Senthilkumar, A. Thanga thirupathi, (2009), Formulation and Evaluation of Theophylline Controlled Release Matrix Tablets using Xanthan gum. Der Pharmacia Lettre, 1 (2), 93-101. 8 The United State of Pharmacopoeia 24/NF26. Asian Edition, (1995), The Official Compedia of United States of Pharmacopoeial Convection Inc. Rockville. 9 T. Raja Sekharan, S. Palanichamy, S. Tamilvanan, S. Shanmuganathan and Thanga Thirupathi, (2011), Formulation and Evaluation of Hydroxypropyl Methylcellulose-based Controlled Release Matrix Tablets for Theophylline. Indian J. Pharm. Sci., 73 (4), 451-456.