Metformin Hydrochloride

The most popular solid dosage forms are being tablets and capsules; one important drawback of these dosage form for some patients, is the difficulty to swallow. Drinking water plays an important role in swallowing of oral dosage forms. For these reasons tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention. Mouth dissolving tablets are not only indicated for people who have swallowing difficulties, but also are ideal for active people. The concept of formulating Mouth dissolving tablets containing Metformin Hydrochloride offer a suitable and practical approach in serving the desired objective of faster disintegration and dissolution characteristic with increase bioavailability.

The aim of this study was to Design and Process Validate Bi-layer Tablet of Metformin Hydrochloride (MTH) and Gliclazide (GZ) effective for the treatment of Non-Insulin Dependent Diabetes Mellitus (NIDDM). For formulation of bi-layer tablet, initially both layer optimized individually. MTH and Gliclazide were formulated as sustained release layers (L1 and L2) by using various Hydrophilic polymers such as Methocel CR, HPMC K100, HPMC 15Cps and Methocel K100 LV. The effect of concentration of hydrophilic matrix (Methocel CR, HPMC 15Cps), binder (Polyvinyl Pyrollidone [PVP K90/PVP K30] on MTH and GZ drug release rate from matrix system was studied. The dissolution study of sustained release layer showed that an increasing amount of Methocel CR and HPMC or PVP K30/90 results in reduced drug release. Optimized batch of both drug formulations were used for formulation of bi-layer tablet. The rational for formulation of bi-layer tablet of these two drugs in combination was from class second generation sulphonylureas and biguanides was suitable for the treatment of NIDDM. Bi-layer tablet was suitable for preventing direct contact of these two drugs and maximize the efficacy of combination of two drugs for treatment of NIDDM.

Two sensitive and reproducible methods are described for the quantitative determination of Glipizide and Metformin Hydrochloride in presence of its degradation products. The first method was based on high performance liquid chromatographic (LC) separation of the drug from its degradation products on the reversed phase, Cosmosil® column [C18 (5 mm, 4.6 x 150 mm, i.d.)] at ambient temperature using a buffer consisting of 10 mM potassium dihydrogen phosphate (pH adjusted to 2.5 with diluted o- phosphoric acid) and acetonitrile 50: 50 v/v as optimized mobile phase in a gradient program. The flow rate was 0.7 ml min-1 and quantitation was achieved UV determination at 225 nm based on peak area with linear calibration curves at concentration range 10-25 µg ml-1 and 20-50 µg ml-1 respectively. The second method was based on   high performance thin-layer chromatographic (HPTLC) separation followed by densitometric measurement of spots at 216 nm. The separation were carried out on Merck HPTLC aluminium sheets of silica gel 60 F 254 using Toluene: Methanol: Ethyl acetate: Formic acid in the ratio of (3:6:3:0.2, v/v/v/v), as mobile phase. This system was found to give compact spots for Glipizide and Metformin hydrochloride after double development (retention factor, RF 0.08 ± 0.02 and RF 0.74 ± 0.02 respectively). The second order polynomial regression analysis data was used forth regression line in the range of 200-1400 ng spot-1 and 200-1400 ng spot-1 respectively. Both the method has been successively applied to pharmaceutical formulation. No chromatographic interference from the tablet exicipients was found. Both the methods were validated in terms of precision, robustness, recovery, limits of detection and quantitation.

The aim of this investigation was to develop and optimize Metformin Hydrochloride matrix tablets for sustained release application. The sustained release matrix tablet of Metformin Hydrochloride was prepared by wet granulation technique using Tamarind pulp polysaccharide. The polysaccharides obtained after extracted from natural source and evaluated for their colour, viscosity and pH. The prepared tablet was evaluated for their hardness, friability, drug content, In vitro dissolution, swelling studies. In vitro drug release profiles of Metformin Hydrochloride Tablet using Tamarind pulp polysaccharide formulation release of drug from the Tablet exhibited a sustained & controlled pattern over an extended time period. .The tablet formulation TF-1 was found to release the drug of about 95% after 12 hrs, The tablet formulation TF-5 was found to release the drug of about 70% after 12 hrs, thus concluded to have sustained drug release for longer period of time in sustained and controlled pattern when compared to other tablet formulations. Using Higuchi’s Model and the Korsmeyer equation, the drug release mechanism from the sustained release tablets was found to be Anomalous (non-Fickian) diffusion. Compatibility study confirmed that interactions do not exist between the drug and polymer.

  A simple, fast, and precise reverse phase, gradient HPLC method was developed for the separation and quantification of metformin hydrochloride and its related compounds Cyanoguanidine impurity, Melamine impurity, 1- methylbiguanidine impurity, Monoguanylmelamine impurity, N,N Dimethylmelamine impurity in tablet formulations. Liquid chromatography with using Partisil SCX, 250 X 4.6 mm, 10µm and mobile phase is 17 gms of ammonium Dihydrogen phosphate in 1000 ml water and adjust the pH to 3.0 with phosphoric acid and degassed under sonication. The flow rate was 1.0 ml/min and the effluent was monitored at 218 nm. This new method was validated in accordance with USP requirements for new methods for assay determination, which include accuracy, precision, linearity, range and robustness. The current method demonstrates good linearity over the range of 0.01µg/mL to 10µg/mL for Impurity A and metformin HCl. Remaining all impurities with concentration from 0.02 µg/mL to 15 µg/mL for six levels. The accuracy is carried out with concentrations ranging from 50% to 200% of Target concentration the Mean % recovery for each impurity at each level should be between 85.0 % and 115.0.The precision of this method reflected by relative standard deviation of replicates all metformin Related Substances is NMT 10%. Validation of the same method was also performed according to USP requirements for quantitative determination of impurities which include robustness and limit of quantification (LOQ) and Limit of detection LOD. No significant variation in RRT of Metformin and its substances at flow rate (0.8 to 1.2mL/min.), at pH (2.8 to 3.2), column temperature (23°C to 27°C), hence the method is robust. Key words: Metformin Hydrochloride, Metformin related substances, HPLC, method validation.