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

摘要

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 dissociationudconstants in water typical of biguanides: pKa1~12.40;udpKa2=2.96.udAs successful application, we report the crystaludengineering, supramolecular synthesis, crystal structureuddetermination and in vitro biological activity testing ofudtwo new PCCs of Met with the antileukemic druguddichloroacetic acid (DCA, pKa=0.9) in 1:1 (1,udMetH+∙DCA-) and 1:2 (2, MetH2ud2+∙2DCA-) ratio,respectively.