Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).Some evidence indicates that liver concentrations of metformin in humans may be two to three times higher than plasma concentrations, due to portal vein absorption and first-pass uptake by the liver in oral administration. Chemistry
Metformin hydrochloride (1,1-dimethylbiguanide hydrochloride) is freely soluble in water, slightly soluble in ethanol, but almost insoluble in acetone, ether, or chloroform. The pKa of metformin is 12.4. The usual synthesis of metformin, originally described in 1922, involves the one-pot reaction of dimethylamine hydrochloride and 2-cyanoguanidine over heat. According to the procedure described in the 1975 Aron patent, and the Pharmaceutical Manufacturing Encyclopedia, equimolar amounts of dimethylamine and 2-cyanoguanidine are dissolved in toluene with cooling to make a concentrated solution, and an equimolar amount of hydrogen chloride is slowly added. The mixture begins to boil on its own, and after cooling, metformin hydrochloride precipitates with a 96% yield. Derivatives
A new derivative HL156A, also known as IM156, is potential new drug for medical use. History
The biguanide class of antidiabetic medications, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac or goats rue (Galega officinalis), a plant used in folk medicine for several centuries.
In other areas of the world, there is also Obimet, Gluformin, Dianben, Diabex, Diaformin, Metsol, Siofor, Metfogamma and Glifor. There are several formulations of Metformin available to the market, and all but the liquid form have generic equivalents. Metformin IR (immediate release) is available in 500-, 850-, and 1000-mg tablets, while Metformin XR (extended release) is available in 500-, 750-, and 1000-mg strengths (also sold as Fortamet, Glumetza, and Glucophage XR in the US). The use of an extended release formulation is to counteract common gastrointestinal adverse effects, as well as to increase compliance by reducing pill burden and therefore can improve adherence, at the expense of the pills larger size. Also available is liquid metformin (sold only as Riomet in the US), where 5 mL of solution contains the same amount of drug as a 500-mg tablet. The use of a liquid form can be beneficial in helping those with physical or psychological swallowing problems take the medication, or to potentially reduce the number of steps needed to take the medication. Combination with other medications
When used for type 2 diabetes, metformin is often prescribed in combination with other medications. Several are available as fixed-dose combinations, with the potential to reduce pill burden, decrease cost, and simplify administration. Thiazolidinediones (glitazones)
Rosiglitazone
A combination of metformin and rosiglitazone was released in 2002, and sold as Avandamet by GlaxoSmithKline, or as a generic medication. Formulations are  500/1, 500/2, 500/4, 1000/2, and 1000 mg/4 mg of metformin/rosiglitazone.