Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: Mechanochemistry vs slow evaporation from solution

The reliability of solvent drop grinding (SDG), also referred to as liquid assisted grinding, wet cogrinding, or mechanochemistry, to facilitate cocrystal formation is addressed with a series of model cocrystals and pharmaceutical cocrystals. The synthesis and single crystal structures of 17 new cocrystals that are sustained by COOH⋯N_arom and OH⋯N _arom, supramolecular heterosynthons are presented. These cocrystals were prepared by both slow evaporation from solution and SDG. We also investigated whether or not SDG could be used to prepare previously reported carbamazepine (CBZ) pharmaceutical cocrystals. The following eight cocrystal formers were investigated in this context: 4,4′-bipyridine, 4-aminobenzoic acid/H₂O, 2,6-pyridinedicarboxylic acid, benzoquinone, terephthalaldehyde, saccharin, nicotinamide, and aspirin. Our results reveal that all of the cocrystals that were grown from solution and characterized by single crystal X-ray crystallography can also be prepared by SDG. SDG therefore appears to be a cost-effective, green, and reliable method for discovery of new cocrystals as well as for preparation of existing cocrystals.