Evaluating the Energetic Driving Force for Cocrystal Formation

[Image: see text] We present a periodic density functional theory study of the stability of 350 organic cocrystals relative to their pure single-component structures, the largest study of cocrystals yet performed with high-level computational methods. Our calculations demonstrate that cocrystals are on average 8 kJ mol(–1) more stable than their constituent single-component structures and are very rarely (<5% of cases) less stable; cocrystallization is almost always a thermodynamically favorable process. We consider the variation in stability between different categories of systems—hydrogen-bonded, halogen-bonded, and weakly bound cocrystals—finding that, contrary to chemical intuition, the presence of hydrogen or halogen bond interactions is not necessarily a good predictor of stability. Finally, we investigate the correlation of the relative stability with simple chemical descriptors: changes in packing efficiency and hydrogen bond strength. We find some broad qualitative agreement with chemical intuition—more densely packed cocrystals with stronger hydrogen bonding tend to be more stable—but the relationship is weak, suggesting that such simple descriptors do not capture the complex balance of interactions driving cocrystallization. Our conclusions suggest that while cocrystallization is often a thermodynamically favorable process, it remains difficult to formulate general rules to guide synthesis, highlighting the continued importance of high-level computation in predicting and rationalizing such systems.