Protonation-deprotonation and structural dynamics of antidiabetic drug metformin

Since the late 1950s, metformin is the worldwide first-line pharmacologic treatment for type 2 diabetes. Beyond the fact that the mode of action of this drug has always been very difficult to elucidate, little is known about its physicochemical properties in aqueous solution. Herein, we focus on the protonation-deprotonation features of metformin by using jointly Raman scattering and theoretical calculations. Vibrational markers evidence the fact that within a wide pH interval extended at either side of the physiological one, i.e. ∼7 ± 4, metformin is mainly monoprotonated. Although the biprotonated form appears as major population at very low pH values (<1.5), Raman markers of neutral species do not dominate even at very high pH values (>13), presumably because of the extreme basicity of metformin as described by recent NMR measurements. Density functional theory calculations using both explicit and implicit hydration models, have led to presume a possible coexistence of two possible monoprotonated forms in aqueous environment. In conclusion, the biophysical features of this molecule and the amount used in clinical practice might certainly explain the pleiotropic actions toward several targets where metformin could be a permanent cationic partner, a proton donor/acceptor, as well as a good candidate for stabilizing the so-called π→π interactions.