Evaluating the energetic driving force for co-crystal formation

Abstract

We present a periodic density functional theory (DFT) study of the stability of 350 organic co-crystals relative to their pure single-component structures, the largest study of co-crystals yet performed with high-level computational methods. Our calculations demonstrate that co-crystals are on average 8 kJ/mol more stable than their constituent single-component structures, and are very rarely (<5% of cases) less stable; co-crystallization 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 co-crystals -- 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 co-crystals 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 co-crystallization. Our conclusions suggest that while co-crystallization 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.

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Identifiers

ORCID for Christopher Robert Taylor: orcid.org/0000-0001-9465-5742

ORCID for Graeme M. Day: orcid.org/0000-0001-8396-2771

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