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.

Direct compression of a tablet formulation is preferred in the industry over wet granulation, due to its simplicity, fewer steps, lower cost and faster development time.

Experimental Methods
50%w/w metformin HCl, 0.5%w/w silicon dioxide colloidal (Aerosil 200) and 0.5% magnesium stearate, and Methocel K100M CR (Hypromellose), were used as matrix formers at 30 %w/w, Microcrystalline cellulose PH102 was used as a water-insoluble filler at 19 %w/w. Metfomin HCl, Methocel K 100 CR, MCC and silicon Dioxide Colloidal were passed through a mesh 20 sieve. All ingredients with the exception of magnesium stearate were blended in a Turbula mixer for 10 minutes. Then magnesium stearate was added and the formulation was mixed for an additional 3 minutes.

Tablets with a target weight of 1000mg and target breaking force of 20 kp were manufactured using an instrumented Manesty rotary tablet press. Tablet ejection forces, weights, breaking force and friability values were determined.

Drug release profiles were determined using USP compliant dissolution bath, Apparatus II (paddle method) with sinkers. The dissolution media was 1000ml of purified water (37±1°C) with a paddle speed of 100rpm. A dual beam spectrophotometer, fitted
with 0.1mm cells, was used for detection of metformin HCl at a wavelength of 218nm.

Results and Discussions
All formulations under investigation here had good powder flow indicated by low value of Carr’s index and resulting in low tablet weight variation. Ejection forces for all tablets were relatively low indicating sufficient lubrication of powder blends. Tablet breaking force values of approximately 20-21 kp and low friability (0.1%) were produced.

Manufacturing and Tablet Parameters
Carr's Index 18 %
Pre-compr.force (kN) 1.9 ± 0.1 N/A
Main compr.force (kN) 19.6 ± 1.3 N/A
Ejection force (N) 312 ± 45 N/A
Tablet weight (mg) 1021 ± 5
Tablet weight variation (%) 0.74 %
Tablet break. force (kp) 20.8 ± 1.5 kp
Tablet friability (% ) 0.1 %

Metformin HCl Dissolution Profiles
% Drug Release1 Hour2 Hours3 Hours6 Hours10 Hours
Experiment28.64%40.48%54.28% 71.55%96.37%
Glucophage XR 500mg25.99%38.47%50.19%72.4%92.6%

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.