Real-Time In Situ Powder X-ray Diffraction Monitoring of Mechanochemical Synthesis of Pharmaceutical Cocrystals

摘要

Mechanosynthesis has attracted the attention of chemists and materials scientists interested in new synthetic opportunities offered by a fully or nearly solvent-free reaction environment. Recent advances in mechanochemistry resulted from the realization that supramolecular concepts, such as molecular recognition and self-assembly, templating, and (organo)catalysis can be used to enhance and control mechanosynthesis. Furthermore, techniques such as liquid-assisted grinding (LAG, also solvent-drop grinding, kneading) were recently developed which offered a general means to optimize mechanochemistry for quantitative and/or enan-tioselective synthesis. However, mechanisms of milling reactions often remain speculative and poorly understood. A persistent obstacle in this sense has been the inability to directly monitor reactions and phase changes, thereby dictating that mechanistic studies had to be performed in a stepwise fashion, that is, by stopping the milling at designated times for analysis of the reaction mixture. Such invasive analysis is not suitable for fast reactions or for short-lived or air-sensitive intermediates. A mechanochemical process conducted in a stepwise manner can yield a different result from an uninterrupted one. While temperature, pressure, and acoustic measurements have been used to follow milling reactions, such measurements are limited to specific systems.