Hydrogen-bonded cocrystals of the drug metformin: from molecular interactions analysis to supramolecular synthesis and characterization of Met-bis(DCA), a pharmaceutical cocrystal with enhanced anti-leukemic activity

Metformin (met) being a drug of first choice for oral therapy of type 2 diabetes, its anticancer activity is the subject of active research. Met can exist in three resonance-stabilized forms, i.e. as neutral molecule (Met), monoprotonated (MetH+) or diprotonated (MetH22+) cation, with dissociation constants in water typical of biguanides: pKa1~12.40; pKa2=2.96. As successful application, we report the crystal engineering, supramolecular synthesis, crystal structure determination and in vitro biological activity testing of two new PCCs of Met with the antileukemic drug dichloroacetic acid (DCA, pKa=0.9) in 1:1 (1, MetH+∙DCA-) and 1:2 (2, MetH2 2+∙2DCA-) ratio,respectively.