Analysis of a new hydrochloride salt of the common pharmaceutical metformin

Metformin is a common active pharmaceutical ingredient and is usually administered orally in the solid form as a stable monohydrochloride salt. Herein, we discuss the crystal structure of a recently discovered dihydrochloride metformin salt, which reveals that protonation of the secondary amine in the divalent metformin cation disrupts both the extensive electron delocalisation and N-H···N hydrogen bonding found in the known α- and β-polymorphs of the metformin hydrochloride salt; this leads to charge-assisted N-H+ ···Cl- hydrogen bonds dominating the solid form, forming a three-dimensional network. Analysis shows that metformin dihydrochloride can be distinguished from the metformin hydrochloride polymorphs by infrared spectroscopy and powder X-ray diffraction. Computational calculations suggest that metformin dihydrochloride has a lower lattice enthalpy than the known metformin hydrochloride phases, indicating a high solubility and lower stability consistent with experimental measurements.