Evaluating the Energetic Driving Force for Cocrystal Formation

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.