Facts and Factors in the Formation and Stability of Binary Crystals

Despite significant ongoing experimental and computational efforts, factors involved in the choice between homomolecular and heteromolecular recognition remain elusive. Here, a large-database study of cohesive energy and intermolecular noncovalent interactions (NCI) in cocrystals from the Cambridge Structural Database has been undertaken. Centrosymmetric space groups (especially P (1) over bar) are largely more frequent than unary crystals, while the frequency of chiral space groups is halved. Overall close-packing is observed, but the relative sizes of the two coformers can vary widely. 86% of extant cocrystals are hydrogen-bonded, all of which include bonding between the two coformers. Carbonyl oxygens and aromatic nitrogens are the most consistent acceptors, while the donor activity decreases according to COOH > NH >> ROH series, so that COOH center dot center dot center dot N (aromatic) is the favorite H-bond. pi center dot center dot center dot pi stacking is another recurring interaction. The lattice energy of the binary crystal is nearly always more stabilizing than the sum of the lattice energies of pure coformers. When sublattices are considered, the AB one is mostly more stabilizing than the AA + BB sum; moreover, in most cases the AB heteropair also ranks first in energy. Finally, it has been demonstrated that cocrystallization mainly involves the evolution to stronger hydrogen bonds than those found in the coformer crystals, implying that heterorecognition provides a thermodynamic drive to cocrystal formation. Existing cocrystals are a collection of successful attempts at cocrystallization, and conversely their common properties may provide valid suggestions along the path to success.