INTRODUCTION:

Metformin HCl is a choice of drug to treated type 2 diabetes mellitus. This belongs to bigunide class of drugs. Diabetes mellitus (or diabetes) is a chronic, lifelong condition that affects your body's ability to use the energy found in food. There are three major types of diabetes: type 1 diabetes, type 2 diabetes, and gestational diabetes. Metformin helps to control the amount of glucose (sugar) in blood. It decreases the amount of glucose absorbed from diet by suppressing glucose production of hepatic gluconeogenesis. [1]

The type 2 diabetes patient has three times more rate of gluconeogenesis compare to normal; treatment with metformin reduces this by over one-third.[2] furthermore, Metformin increases body's response to insulin, a natural substance that controls the amount of glucose in the blood.

Metformin comes as a liquid, a tablet, and an extended-release (long-acting) tablet. The regular tablet is usually taken with meals two or three times a day. The extended-release tablet is usually taken once daily with the evening meal. When used for type 2 diabetes, metformin is often prescribed in combination with other drugs. Several are available as fixed-dose combinations to reduce pill burden and making administration simpler and convenient. [3]

However, various bands of metformin tablets have been available in the market due to the advantages behind their regular usages. The clinical effectiveness exerted by tablet formulation depends on availability of drug to the body and drug must be present in the labeled amount [4]. The main objective of tablet formulation is to deliver the drug at certain and defined amount for producing therapeutic effect [5]. The formulations can have a noteworthy affect on the quality parameters such mechanical strength, dissolution study in buffer solution, content and weight uniformity etc. This also includes the physiochemical properties of the active ingredients and excipients as well as the procedures used during manufacturing of formulations [6]. Moreover, quality control parameters of tablet are useful tools for maintaining consistency in batch-to-batch manufacturing and it should be performed for every drug product. All of these parameters are closely related to each other and have effect on drug absorption, bioavailability etc. [7]. The aim of the study was to evaluate the comparative quality control parameters between the tablets of six different conventional and modified (Sustained release) formulations because standard quality parameters are essential for better quality of medicine.

EXPERIMENTAL:

Design of study

The study were design to assess comparative in-vitro quality control parameters between the commercially available conventional and modified (sustained release) tablets with different brands of metformine hydrochloride in India through the evaluation of mechanical strength, dissolution study in buffer solution, content and weight uniformity. The study was done by performing various test procedures associated to the quality of formulations.

Collection of Samples

To perform the study both conventional and modified formulations of metformin of six different brands were purchased from the drug store of Raipur, India. All the tablets of metformin were labeled to contain 500 mg of metfomin per tablet. The labeled shelf life of all of the tablets was three years from the date of manufacturing and was taken for the evaluation before two years of the labeled expiry date.

Identification of Sample

After purchasing, all the brands were coded as A1, B1, C1, D1 E1 and F1 for conventional tablets of six different manufacturers and A2, B2, C2, D2, E2 and F2 for modified (sustained release) tablets of six different manufacturers. Finally the coded samples were separated as a pair of conventional and modifies and taken for evaluation.

Procedure for evaluation

The development and manufacture of pharmaceutical formulations involved various analytical methods and tests which are important for the evaluation, following quality control tests were performed for conventional and modified formulations in the study.

Weight variation test

The weight variation test is a valid method for determining variation in the drug content [8]. The acceptable limit for the deviation of weight for tablets having average weight of 250 mg or more should not exceed 5% [9]. Twenty tablets were selected from each of the brand and weighed individually using electronic balance. Their average weights were calculated. The percent deviation for all tablet brands was calculated by using the mathematical equation [6].

Mechanical Strength

The mechanical strength of selected formulation was measured by Hardness and friability test.

Hardness Test

Hardness indicates the capability of a tablet to withstand mechanical shocks during handling in manufacturing, packaging and shipping [10]. The acceptable range of hardness or crushing strength of tablet is 4 to 7 kgf (kilogram of force) [11]. During the study, hardness of the tablet was determined using Monsanto hardness tester for both of the formulations, six tablets of each brand were taken and hardness of the tablets was determined.

Friability Test

Friability test is essential to evaluate the physical strength of tablets to withstand abrasion in packing, handling and transporting. In the study, it was determined using Roche friabilator. The value of friability was expressed in percentage (%). Ten tablets for each brand were initially weighed and transferred into chamber of the friabilator. The friabilator was operated at 25 rpm for 4 minutes (up to 100 revolutions). The tablets were weighed again and the percent (%) friability was then calculated by using following formula [6]. Generally the considerable range of weight loss of conventional compressed tablet is less than 0.5 to 1% [10].

The percent friability was measured by using formula.

% Friability = W1-W2 /W1×100

Where, W1= Weight of tablet before test

W2= Weight of tablet after test

Drug Content

Twenty tablets were weighed and grind in a mortar with pestle to get fine powder. Powder equivalent to the mass of one tablet was dissolved in distilled water and filtered through a whatman filter paper. The filtrate was diluted with distilled water and measures the absorbance of the resulting solution at 232nm in UV-Visible spectrophotometer [9]. The content of Metformin HCl. was calculated using equation obtained from standard curve. (Y = 0.071x - 0.053., R² = 0.995)

Dissolution Test

Dissolution test is carried out to determine drug release pattern during a specific period of time [12]. Dissolution test was performed using Dissolution Tester – USP (Electrolab, TDT-08L Plus) for only conventional tablet. 900 ml of phosphate buffer, pH 6.8 was used as dissolution medium [9]. The process was done at a speed of 50 rpm by maintaining temperature at 37±1ºC in each test. 1.0 ml of sample was withdrawn from the dissolution apparatus at a regular time intervals of 10 minutes, 20 mi8nute and 45 minutes. Further dilute up to 10 ml with water and measured the absorbance of the resulting solution at 233 nm for metformin by using UV spectrophotometer.

Data processing and analysis

Data processing and analysis after the completion of all test procedures data for all the individual tablets were recorded and separated on different sheets according to the manufacturer. Finally data were analyzed by using the above mentioned mathematical formula and MS-Excel®, 2007.

RESULT AND DISCUSSION:

During the study, at first the weight variation which is the key to controlling crushing strength and friability of tablet was assessed [13]. The unofficial test stated that all the samples of conventional formulation were coded as A1, B1, C1, D1, E1,F1 and samples of modified formulations were coded A2, B2, C2, D2, E2, F2 have passed the weight variation uniformity test as specified in the Indian/British Pharmacopoeia (not exceed 5% deviation) [9]. Weight variation uniformity between two groups of conventional and modified tablets was almost with in limit 5% shown in table 1. Mechanical strength is the second most important physical feature for assessing tablet [13]. In the study, it was found that A1, B1, C1 D1, E1 and F1 brands of conventional and A2, B2, C2, D2, E2 and F2 brands of modified group passed the test of tablet crushing strength or hardness. The conventional brands had acceptable crushing strength of between 6.0 kgf to 6.40 kgf. On the other hand, the modified tablet brands had a crushing strength of between 3.8 kgf to 5.6 kgf shown in table 1. All the brands showed satisfactory crushing strength.

In the friability test, all brands showed impressive friability values. The friability values for conventional tablet brands were ranged from 0.40 to 1 % whereas the modified tablet brands showed 0.1 to 0.9% of friability. In all formulations the percent (%) friability was less than or near to 1% which ensures that all the tablets of each brand of both formulations were mechanically stable [10]. The results were shown in table 1.

Drug content was studied as important quality control parameters which determine the uniformity of the content of the different brands of formulations. All the conventional brands showed 96.6 to 103% and modified brands showed 96 to 103% of drug contents. All the brands showed satisfactory results which were shown in table 1.

Dissolution was another studied important quality control parameters directly related to the absorption and bioavailability of drug [14]. This study was performed with only conventional formulation and which revealed that drug release rate was better in all conventional brands. After 45 minutes, the release rate of tablet of conventional brands of metformin was 96 to 103% and the results shown in table 2.

Table 1: Evaluation of different quality control parameters of conventional and modified Metformin HCl tablets.

Sample (Tablet brands)	Weight variation (%)	Hardness (kgf)	Friability (%)	Drug content (%)
A1 Conventional	2.05	6 ± 0.42	0.45	101
B1 Conventional	1.6	6 ± 0.58	1	96.6
C1 Conventional	0.8	6.4 ± 0.76	0.8	103
D1 Conventional	0.4	6.29 ± 0.60	0.4	97
E1 Conventional	2.24	5.1 ± 0.72	7.24	98.9
F1 Conventional	0.48	6.32 ± 0.41	0.48	98
A2 Sustained Release	1.9	5.2 ± 1	5.9	103
B2 Sustained Release	1	4.2 ± 0.70	1	99
C2 Sustained Release	1	4.7 ± 0.80	1	96
D2 Sustained Release	0.4	3.8 ± 0.60	0.4	98
E2 Sustained Release	0.1	4.6 ± 0.75	0.1	96.6
F2 Sustained Release	0.9	5.6 ± 0.80	0.9	97.9

Table 2: Evaluation of dissolution profile of conventional Metformin HCl. tablets.

Sample (Tablet brands)	(%) Drug release after 10 min	(%) Drug release after 20 min	(%) Drug release after 45 min
A1 Conventional	32%	61%	102.1%
B1 Conventional	28%	49%	98%
C1 Conventional	30%	63%	100.5%
D1 Conventional	28%	52%	98.2%
E1 Conventional	35%	68%	103%
F1 Conventional	24%	49%	96.3%

CONCLUSION:

Metformin is a well established and proven oral Anti-diabetic drug in the biguanide class for the treatment of type-2 diabetes mellitus. The current pharma market of India is flooded with various conventional and modified preparations. With other combination and single formulation, metformine is also now widely used for the management of diabetis in the country. Therapeutic response of any formulation depends on its quality parameters. From the study it was identified that mechanical strength, hardness and dissolution profile during the test procedure of both conventional and modified tablet brands complied the specification. It should be strictly considered that an ideal tablet will have sufficient hardness to maintain its mechanical stability but not more. Because harder tablet can delay disintegration time or alter dissolution profile. Finally, as quality control parameters are related to one another from initial step to pharmacological action of the drug, a high-quality tablet either single or in combination should meet all the standard quality parameter for getting its desired therapeutic response.

REFERENCES

1. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002; 137(1):25–33. doi:10.7326/0003-4819-137-1-200207020-00009.

2. Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S, Schumann W, Petersen K, Landau B, Shulman G. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49(12):2063–9.

3. Bailey CJ, Day C. Fixed-dose single tablet antidiabetic combinations. Diabetes Obes Metab. June 2009;11(6):527–33.

4. Jabeen, S., Ali, A., Hassan, F., Fatima, N. Studies on the effects of cyclodextrin polymer as a tableting aid on some selected analgesics. Pakistan Journal of Pharmacology. 2006; 23(1): 67-71.

5. Islam, S.M.A., Islam, S., Shahriar, M., Dewan , I. Comparative in vitro dissolution study of aceclofenac marketed tablets in two different dissolution media by validated analytical method. Journal of Applied Pharmaceutical Science. 2011;1(9): 87-92.

6. Kalakuntla, R., Veerlapati, U., Chepuri, M., Raparla, R. Effect of various super disintegrants on hardness, disintegration and dissolution of drug from dosage form. J. Adv. Sci. Res. 2010; 1(1): 15-19.

7. Jain, N., Mandal, S., Banweer, J., Jain, S. Effect of superdisintegrants on formulation of taste masked fast disintegrating ciprofloxacin tablets. International Current Pharmaceutical Journal; 2012;1(4): 62-67.

8. Reddy, K.R, Mutalik, S., and Reddy, S. “ once-daily sustained-release matrix tablets of nicorandil: Formulation and invitro evaluation”, AAps pharma sci. Tech. 2003; 4:1-9.

9. Indian Pharmacopeia, Fourth edition in 1996, P-470. British Pharmacopoeia. (2005): Volume. 4, Appendix XII H A273, Table: 2.9.5-1.

10. Banker, G.S. and Anderson, N.R. Tablets. In Lachman, L. and Lieberman, H.A, The theory and practice of industrial pharmacy CBS Publishers and Distributors Pvt. Ltd., India . 2009; 229-345.

11. Patel, R. P., Patel, M. H. Prajapati, B. G., and Baria, A. H. “Formulation and evaluation of sustained release matrix tablet of Tizanidine Hydrochloride by direct compression technique”, e – Journal of Science and Technology (e-JST), pp. 69-81.

12. Kishore, B.H., Venkareswararao, T., Sankar, K.R., Rao, B.S. Studies on dissolution rate of paracetamol tablets by using different polymers. Journal of Global Trends in Pharmaceutical Sciences. 2011; 2(1): 1-10.

13. Tousey, M.D. Tablet pro: A tablet making training resource for tablet making professionals. Techceuticals. 2011; 4(1):1-15.

14. Pabla, D., Akhlaghi, F., Zia, H. A comparative pH dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry. European Journal of Pharmaceutics and Biopharmaceutics. 2009; 72: 105–110.

Received on 10.06.2015 Modified on 28.06.2015

Asian J. Research Chem. 8(7): July- 2015; Page 441-444

DOI: 10.5958/0974-4150.2015.00070.X