New Multicomponent Crystals of Antidiabetic Drug, Metformin: Mechanochemistry, Structural Studies, Biological Activity and Topological Analysis

Three multicomponent crystals of metformin were investigated to elucidate factors governing crystal architecture. Structures were determined by X-ray diffraction and analyzed using the Atoms-in-Molecules (AIM) approach, focusing on critical points and electron density topology. Three types of crystals were obtained: salt, cocrystal salt solvate and mixed salt with both organic and inorganic anions. Protonation of nitrogen atoms in metformin alters bond lengths and electron density, while strong intramolecular hydrogen bonds in hydrogenmaleate anions stabilize the structures and define the preferred anion geometry. Comparison with monoprotonated metformin revealed similar topological features despite differing protonation states. Mechanochemical synthesis via liquid-assisted grinding (LAG) enabled selective formation of specific crystalline forms, with the solvent type and acid polymorph influencing product distribution. These results highlight the critical roles of protonation, hydrogen bonding, and synthetic methodology in designing and controlling multicomponent metformin crystal structures.