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.

机械化学（Mechanochemistry）如今已被常规用于制备药物开发及其他应用所需的多组分分子晶体。机械化学反应可在温和条件下实现共晶（cocrystal）的合成，且能获得定量产率；部分共晶仅能通过球磨（milling）手段获得。然而我们近期发现，部分溶剂会对共晶的形成产生不利影响，甚至会使热力学稳定的共晶分解为其组分的物理混合物。尽管我们已借助非原位晶体学分析（ex situ crystallographic analyses）尝试解析相关机制，但此类反应抑制与共晶分解的具体作用路径仍完全未知。我们因此认为，唯有针对机械化学共晶结晶反应开展原位且时间分辨X射线粉末衍射（X-ray powder diffraction）研究，方能阐明目前尚不明确的分解路径，此类路径可能涉及中间晶型的形成与拆解。