In situ powder X‐ray diffraction investigations of solvent effects on the mechanochemical synthesis of pharmaceutical cocrystals.

Mechanochemistry is now regularly used to prepare multi-component molecular crystals for drug development and other applications. Mechanochemcial reactions enable cocrystal formation under mild conditions and in quantitative yields, while some cocrystals are only accessible through milling. However, we recently found that some solvents have a detrimental effect on the formation of cocrystals, or even lead to the decomposition of thermodynamically stable cocrystals into physical mixtures of their constituents. The mechanisms through which these reaction inhibitions and cocrystal decompositions occur remain entirely unknown, despite our recent efforts to understand them using ex situ crystallographic analyses. We therefore trust that only in situ and time-resolved X-ray powder diffraction studies of the mechanochemical cocrystallisation reactions can elucidate the unknown decomposition pathways, which may involve the formation and breakdown of intermediate crystal forms.