Mohammad A. Akbar et al.

/ Journal of Pharmacy Research 2011,4(10),3436-3438

Research Article ISSN: 0974-6943

Available online through www.jpronline.info

In vitro Dissolution Studies of Different Brands of Sustained Release Metformin Hydrochloride Matrix Solid Dosage Forms Available in the Pharmaceutical Market of Bangladesh
Mohammad A. Akbar *1, Mahbub Mawla2,Mohammad A. Khan 3, Tanvirul Hye 1, Muhammad Asaduzzaman 1, Md. A. Muhit1 and Sheikh Z. Raihan 1 1 Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh. 2 Quality Control Officer, Beximco Pharmaceuticals Ltd, Tongi-1711, Gazipur, Bangladesh. 3 Department of Community Medicine, National Institute of Preventive and Social Medicine, Dhaka-1212, Bangladesh

Received on: 19-06-2011; Revised on: 08-07-2011; Accepted on:01-10-2011 ABSTRACT

This study was designed to investigate the in vitro dissolution profile of ten brands of Metformin hydrochloride sustained release matrix tablet that are commercially available in the pharmaceutical market in Bangladesh in order to evaluate the quality standard of the available marketed product. The study was carried out on the ten brands of Metformin hydrochloride matrix tablets using dissolution test-1 method apparatus -2 (paddle) at 100 rpm in 1000 ml simulated intestinal medium (pH 6.8 0.1) for 10 hours time period according to the guideline of United States Pharmacopeia (USP). In this study, all the brands except two brands (Code: MH-5 and MH-8) complied with the USP in vitro dissolution specification of 85% drug release at 10th hour in simulated intestinal medium. Drug release of 81.6 % and 79.7 % were showed by the brand code of MH-5 and MH-6 respectively within the specified time period which did not meet the terms of the USP guideline. To reveal the release kinetics of sustained release tablets of Metformin hydrochloride, release profiles were analyzed for zero order, first order and Higuchi equation and found that first order and Higuchi model showed high linearity with correlation coefficient (r2) value of 0.98 or more. In conclusion, our results indicated that all the brands of Metformin hydrochloride sustained release matrix tablets included in this study apart from MH-5, MH-8 showed high dissolution profile and hence good bioavailability. Key words: Metformin hydrochloride, Sustained release matrix tablet, Release kinetics, In vitro dissolution study.

INTRODUCTION
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a biguanide class oral anti-hyperglycemic (anti-diabetic) agent. It is used as monotherapy as an adjunct to diet and exercise for the management of non-insulin dependent diabetes mellitus (NIDDM) type-2 diabetes, in patients whose hyperglycemia cannot be controlled by diet alone.[1] A traditional oral multiple release formulation releases the drug with undesirable peaks and troughs. These drawbacks can be overcome by designing a suitable sustained release Metformin hydrochloride preparation. Recently several studies have been carried out to investigate the pharmacokinetic and pharmacodynamic advantages of oral sustained release products of Metformin hydrochloride.[2-5] The primary benefit of a sustained release dosage form, compared to a conventional dosage form is the uniform drug plasma concentration, and therefore uniform therapeutic effect. The process of in vitro dissolution played a vital role in liberating a drug from the tablet matrix and marking whether it is available for subsequent gastrointestinal absorption. The in vitro dissolution of the drug from the tablet matrix depends on many factors, which include not only the physiochemical properties of drug, but also the nature of formulation and the process of manufacturing. [6] Hence in vitro dissolution analysis of pharmaceutical dosage form has emerged as a very important parameter that ensured product quality as well as for differentiating among formulations of the same therapeutic agent.[7] For sustained release tablets the role of in vitro dissolution becomes still more crucial as an additional coating step involve in manufacturing process. [8] In vitro dissolution study is an important tool in the evaluation of the best formulation and also in understanding the possible risks related to specific gastrointestinal environment, dose dumping, and food effects on bioavailability and interaction with other drugs. [9] Today dissolution studies are the most frequently used tools in the development, characterization and utilization processes of controlled release formulations. [10]

In Bangladesh, there are number of pharmaceutical companies that are manufacturing and marketing sustained release Metformin hydrochloride matrix tablet. This paper deals with the comparative in vitro dissolution or in vitro bioavailability characteristic of sustained release matrix tablets of most commonly available brands of Metformin hydrochloride in Bangladesh in order to evaluate the quality standard of the products. MATERIALS AND METHODS Chemicals References standard of Metformin hydrochloride powder BP (Wanbury, India), reagent, sodium hydroxide (Merk, Germany) and monobasic potassium phosphate (Merk, Germany) were collected from Beximco pharmaceuticals Limitel, Bangladesh. Equipments Shimadzu cu-1700 UV-visible Spectrophotometer (Kyoto, Japan), Metler Toledo MP-200 pH meter (UK), Erweka DT-700 Dissolution tester (Germany), Sartorius CPA 225D electronic balance (Germany) were used in this experiment. Drug samples used in this study Ten (10) brands of metformin hydrochloride sustained release matrix tablet were purchased from various medicine shops. They were randomly marked as MH-1, MH-2, MH-3, MH-4, MH-5, MH-6, MH-7, MH-8, MH-9, and MH-10. The samples were properly checked for their manufacturing license number, batch number, and date of manufacture and expiry dates before purchasing. The labeled active ingredient was 500 mg of metformin hydrochloride and all were packaged in strip or in blister packing. The samples were collected in such a way that the production date not more than four months ago from the time of purchase. The strip or blister packs stored at 252C for four weeks before the dissolution study, in order to evaluate any organoleptic changes. Dissolution study The dissolution tests were carried out using the type-2 apparatus (paddle), at 100 rpm (rotation per minute) in 1000 ml in simulated intestinal medium for 10 hours at temperature 37 0.5oC ( test method -1), according to US pharmacopeia (USP) guidelines[11] . For in vitro dissolution study simulated intestinal medium (pH 6.8 0.1) was required. Preparation of simulated intestinal medium (buffer pH 6.8 0.1) 6.8 g monobasic potassium phosphate was dissolved in 1000 ml water and pH was adjusted by adding 0.2 N sodium hydroxide Solution. For system, equilibration paddles were rotated for 15 minutes. One tablet chosen randomly from each

*Corresponding author.
Mohammad Ahsanul Akbar Lecturer, Department of Clinical Pharmacy and Pharmacology, University of Dhaka, Dhaka-1000, Bangladesh Graduate Student and Teaching Assistant Department of Pharmaceutics, University of Florida, USA Tel: +8801754375551 E-mail:ahsanulpharma@yahoo.com, makbar@ufl.edu

Journal of Pharmacy Research Vol.4.Issue 10. October 2011

3436-3438

Mohammad A. Akbar et al. / Journal of Pharmacy Research 2011,4(10),3436-3438

Log of % remaining drug

Table 1: multiple coefficients (r2) of different brands (marked as MH1 to MH-10) sustained release metformin hydrochloride matrix tablets
Code MH-1 MH-2 MH-3 MH-4 MH-5 MH-6 MH-7 MH-8 MH-9 MH-10 Multiple coefficient of determination (r2) Zero order First order Higuchi 0.8624 0.8516 0.8409 0.8696 0.8771 0.816 0.8299 0.8769 0.8047 0.8093 0.9904 0.9882 0.9868 0.9905 0.9876 0.9837 0.9836 0.9821 0.9788 0.9838 0.9914 0.9883 0.9849 0.9933 0.9934 0.9755 0.981 0.9922 0.9708 0.9728

2.5 2 1.5 1 0.5 0

MH = Metformin hydrochloride

6 Time ( hour )

10

12

100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 Time ( hour ) 8 10 12

% release of drug

MH-1 MH-6
MH = Metformin hydrochloride

MH-2
MH-7

MH-3 MH-8

MH-4 MH-9

MH-5 MH-10

Figure 2: First order release kinetics profiles of different brands (marked as MH-1 to MH-10) sustained release metformin hydrochloride matrix tablets
100 90 % of drug release 80 70 60 50 40 30 20 10 0 0 2 4 6 SQRT 8 10 12

MH-1 MH-6
MH = Metformin hydrochloride

MH-2 MH-7

MH-3 MH-8

MH-4 MH-9

MH-5 MH-10

Figure 1: Zero order release kinetics profile of different brands (marked as MH-1 to MH-10) sustained release metformin hydrochloride matrix tablets of the tablets was put into the paddle suspended in the dissolution medium. 10 ml of the sample was withdrawn at 1st hour and 3 rd hour time intervals and the same volume of preheated (37 0.50C) fresh dissolution medium was replaced to keep the volume constant. The samples withdrawn were filtered through whatman 42 filter paper, diluted, and analyzed at 232 nm, by UV-visible spectrophotometer (UV-1700). Analysis of released data To analyze the in vitro release data, various kinetic models were used to describe the release kinetics. The release data obtained were treated according to zeroorder (cumulative amount of drug release versus time), first-order (log cumulative percentage of drug remaining versus time), and Higuchi (cumulative percentage of release versus square root of time) equation model. The zero order rate equation described the system where the drug release rate was independent of its concentration. [12] The first order equation described the release pattern where release rate was concentration dependent.[13] Higuchi release kinetics describes the release of drugs from insoluble matrix as a square root of time dependent process. RESULTS AND DISCUSSION Most of the commercially available brands of the Metformin hydrochloride sustained release matrix tablet in Bangladesh met the official USP specification and few of them failed which might have some formulation or any other problems. The study also emphasized the need of constant surveillance on marketed drug product by the government, manufacturers, and independent research groups to ensure supply and availability of quality medicines for the patients in Bangladesh. Commercially available ten brands (Code: MH-1, MH -2, MH -3, MH -4, MH -5, MH -6, MH -7 and MH -8, MH -9, MH -10) of metformin hydrochloride sustained release matrix tablets were studied for their in vitro dissolution behavior in simulated intestinal medium (pH 6.8 0.1) for 10 hours time period using USP reference dissolution apparatus and release kinetics of the matrix tablets are shown in the figures 1, 2 and 3. All of the ten brands of Metformin hydrochloride sustained release matrix tablets were investigated to find out whether they complied with the USP in vitro dissolution specification of 85% drug release within 10 hours in simulated intestinal medium (pH 6.8 0.1) or not. After comprehensive in vitro dissolution studies, it was found that all but two of the ten brands (code: MH -1, MH -

MH-1 MH-6

MH-2 MH-7

MH-3 MH-8

MH-4 MH-9

MH-5 MH-10

MH = Metformin hydrochloride

Figure 3: Higuchi release kinetics profile of different brands (marked as MH1- to MH-10) sustained release metformin hydrochloride matrix tablet 2, MH -3, MH -4, MH -6, MH -7, MH -9, and MH -10) fulfill the USP in vitro dissolution specification of 85% drug release at 10th hour (Figure 1). The two brands coded MH-5 and MH-8 were failed to fulfill the USP in vitro dissolution specification of 85% drug release at 10th hour. The amount of drug present in each tablet was determined by spectroscopic method. The dissolution data (from the values of 1st , 3 rd and 10th hour) according to USP specification of all batches were best fitted to first order and Higuchi models. The model that best fitted the release data was evaluated by multiple coefficients (r2) mentioned in table 4. For all ten brands, first order and Higuchi release kinetics were predominant than the zero order release kinetics. From these release kinetics, it might be revealed that the drug release of those brand followed concentration dependent and diffusion controlled release method from the matrix of tablet. ACKNOWLEDMENTS The authors like to thanks Beximco Pharmaceutical Limited, Bangladesh for providing standard metformin hydrochloride and use of dissolution apparatus, UV-visible Spectrophotometer and other necessary instruments. REFERENCES:
1. 2. 3. Bourne DWA. Pharmacokinetics. In: Banker GS, Rhodes CT. Modern Pharmaceutics. 4th ed. New York: Marcel Dekker Inc; 2002. p. 67-92. McEvoy GK, Snow EK, AHFS Drug Information, 45, American Society of HealthSystem Pharmacists, Bethesda, Maryland, 2003, 3016. Colo GD I, Zambit0 Y., Baggiani A., Carelli V., Serafini MF, A site-specific controlled-release system for Metformin, J Pharm Pharmacol, 57, 2005, 565-571.

Journal of Pharmacy Research Vol.4.Issue 10. October 2011

3436-3438

Mohammad A. Akbar et al. / Journal of Pharmacy Research 2011,4(10),3436-3438

4. 5. 6. 7. 8. Hu DL, Liu Y., Tang X., Zhang Q., Preparation and in vitro/in vivo evaluation of sustained-release Metformin hydrochloride pellets, Eur J Pharm Biopharm Amsterdam, 64, 2006, 185-92. Balasubramaniam J., Rao VU, Vasudha M., Babu J., Rajinikanth PS, Sodium alginate microspheres of Metformin HCl: Formulation and in vitro evaluation, Curr Drug Deliv, 4, 2007, 249-256. Basak SC, Rahman J., Ramalingam M., Design and in vitro testing of a floatable gastroretentive tablet of Metformin hydrochloride, Pharmazie Eschborn, 62, 2007, 145-148. Augsburger LL, Shangraw RF, Giannini RP, Shah VP, Prasad VK, Brown D, Thiazides VIII: Dissolution Survey of marketed Hydrochlorothiazide tablets, J Pharm Sci, 72(8), 1983, 876-881. Ayres JW, Huang H, Albert K, Effect of polymer in sustained release matrix tablet, J Pharm Sci, 73, 1984, 1629. 9. 10. 11. 12. 13. Lordi NG. Sustained Release Dosage Forms. In: Lachman L, Lieberman HA and Kanig JL (Eds): The Theory and Practice of Industrial Pharmacy, 3, Varghese Publishing House, Bombay, 1992, 430-456. Sungthongjeen S, Pitaksuteepong T, Somsiri A, Sriamornsak P. Studies on pectins as potential hydrogel matrices for controlled-release drug delivery. Drug Dev Ind Pharm, 25(12), 1999, 1271-1276. Longer MA. Robinson JR. Sustained Release Drug Delivery System, Remington JP, Remingtons Pharmaceutical Science, 18th, Mack Pub. Co, Easton Pennsylvania, 1990, 1676-1690. US Pharmacopoiea (USP) guidelines. USP 32, NF27, Vol: 3. 2009. p. 2907-2908 Hadjiioannou TP, Christian GD, Koupparis MA, Macheras PE. Quantitative Calculations in Pharmaceutical Practice and Research, Edition, John Wiley & Sons VCH Publishers Inc, New York, 1993, 345-348.

Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.4.Issue 10. October 2011

3436-3438