Catalytic Effect of Solvent Vapors on the Spontaneous Formation of Caffeine–Malonic Acid Cocrystal

Caffeine (a model pharmaceutical mimic) and malonic acid (a common excipient partner) are known to form a molecular cocrystal spontaneously over about 1 week when their powders are mixed at ambient conditions. We report the dramatic catalytic acceleration of this reaction when the mixture of powders is exposed to vapors of common laboratory solvents. Acetone and methanol vapors show rate enhancements over 1000-fold, effecting quantitative conversion in less than 5 min. The reaction progress was tracked ex situ by powder X-ray diffraction, and products were verified by ¹³C solid-state NMR. Our data show no evidence of an intermediate phase. Gravimetric experiments show that solvent vapor uptake is not stoichiometric and is reversible. This rare example of gas phase catalysis of supramolecular transformations has important implications for a deeper mechanistic understanding of diffusion-controlled solid–solid reactions.