The curious case of (caffeine).(benzoic acid): how heteronuclear seeding allowed the formation of an elusive cocrystal

Abstract

Cocrystals are modular multicomponent solids with exceptional utility in synthetic chemistry and materials science. A variety of methods exist for the preparation of cocrystals yet, some promising cocrystal phases have proven to be intractable synthetic targets. We describe a strategy for the synthesis of the pharmaceutically relevant (caffeine).(benzoic acid) cocrystal (1), which persistently failed to form using a broad range of established techniques. State-of-the-art crystal structure prediction methods were employed to assess the possible existence of a thermodynamically stable form of 1, and to identify appropriate heteronuclear seeds for corystallization. Once introduced, the designed heteronuclear seeds facilitated the formation of 1 and, significantly, continued to act as long-lasting laboratory .contaminants., which encouraged cocrystal formation even when present at such low levels as to evade detection. The seeding technique described thus enables the synthesis of cocrystals regarded as unobtainable under desired conditions, and potentially signifies a new direction in the field of materials research.

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

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