Introduction :
Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or (alpha)-glucosidase inhibitors.

It is a white to off-white crystalline compound with a molecular formula of C4H12ClN5 (monohydrochloride) and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. Metformin HCl has poor compressibility, and high water solubility (1 in 2). The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Among biguanides useful as diabetic therapeutic agents, metformin has proven particularly successful. Metformin is an anti-diabetic agent that acts by reducing glucose production by the liver and by decreasing intestinal absorption of glucose. It is also believed to improve the insulin sensitivity of tissues elsewhere in the body (increases peripheral glucose uptake and utilization). Metformin improves glucose tolerance in impaired glucose tolerant (IGT) subjects and NIDDM subjects, lowering both basal and postprandial plasma glucose.

Metformin does not produce hypoglycemia in either diabetic or non-diabetic subjects. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response can decrease. Metformin also has a favorable effect on serum lipids, which are often abnormal in NIDDM patients.

There is a continuously growing interest in the pharmaceutical industry for ER oral drug delivery systems. There is also a high interest for design of dosage formulations that allow high drug loading, particularly for actives with high water solubility. Metformin HCl is an anti-diabetic agent which is prescribed for the treatment of non-insulin dependent diabetes mellitus. The primary benefit of extended release preparations of metformin HCl compared to an immediate release formulation is that a more uniform maintenance of blood plasma active concentration is achieved. Thus, potentially avoiding undesirable peaks and troughs associated with multiple immediate release preparations.

Experimental Methods

77%w/w metformin HCl, 0.5%w/w silicon dioxide colloidal (Aerosil 200) and 0.5% magnesium stearate, and Methocel K15 Premium (Hypromellose), were used as matrix formers at 22 %w/w. Metfomin HCl and Methocel K 15 Premium were passed through a mesh 20 sieve, then blended in a Collete IMH mixer for 10 minutes. Add purified water, and granulated the mixture until granule was formed. Dry the gtranule using Fluid Bed Dryer until the moisture Content <1%.

Manufacturing and Tablet Parameters
Carr's Index 21 %
Pre-compr.force (kN) 1.9 ± 0.1 N/A
Main compr.force (kN) 15.5 ± 0.8 N/A
Ejection force (N) 312 ± 45 N/A
Tablet w eight (mg) 1300 ± 10
Tablet w eight variation (%) 0.55 %
Tablet break. force (kp) 17 ± 1 kp
Tablet friability (% ) 0.25 %

Metformin HCl Dissolution Profiles
% Drug Release1 Hour3 Hours6 Hours10 Hours
Inovator XR 1000mg39.33%66.36%87.67%96.37%

The mechanism of drug release in these formulations is mainly governed by diffusion and as the drug is so highly soluble, polymer viscosity grade did not significantly affect the diffusion rate

The application of hypromellose (HPMC) in ER tablets is widely studied. When in contact with aqueous solvent, HPMC hydrates rapidly and forms a gel barrier layer around the tablet. The rate of drug release from HPMC matrices is dependent on numerous factors such as type of polymer, drug, polymer/drug ratio, particle size of drug and polymer, and the type and amount of fillers used in the formulation.