Metformin (MET),
commonly marketed as a hydrochloride salt (MET-HCl)
for better pharmacokinetic profile over the free base, would release
a high concentration of chloride ions and cause adverse gastrointestinal
effects. The preparation of chloride-free MET salts could potentially
circumvent this issue. In this study, seven carboxylic acids (formic
acid, acetic acid, malonic acid, succinic acid, fumaric acid, cinnamic
acid, and acetylsalicylic acid) were used for preparing MET carboxylate
salts. When compared with MET-HCl, all MET salts/salt hydrates show
lower dissolution rates in pH 6.8 phosphate buffer. However, the cinnamic
acid and acetylsalicylic acid show significantly higher dissolution
rates in the forms of MET salt/salt hydrate. In the permeability test,
the permeability of the MET in all of the salts was not improved.
However, the permeability of cinnamic acid in the MET cinnamate is
reduced, and the permeability of acetylsalicylic acid in the MET acetylsalicylate
is increased. Meanwhile, at a higher crystallization temperature,
the acetone solvent and a hydrolyzed product of acetylsalicylic acid
react with MET respectively, leading to two unexpected 1,3,5-triazine
derivatives. The results of
in vitro
bioactivity
assays indicate that one of the triazine molecules promote glucose
consumption more effectively than MET-HCl, and had relatively weak
lactate production ability at low concentration. This glucose metabolism
regulating compound may serve as a novel lead antihyperglycemic agent
for further optimization.