Profound Effect of the Milling Assembly on Polymorphism in Mechanochemical Cocrystallization
Mechanochemistry provides a highly efficient, but still poorly understood route to synthesize and screen for polymorphs of organic solids. We present a hitherto unexplored approach to control the mechanism and outcome of mechanochemical cocrystallization through changes to the milling assembly, <i>i.e. </i>milling jar and balls. Whereas polymorph control of mechanochemical cocrystallization is typically discussed in terms of liquid additives, real-time synchrotron X-ray diffraction studies reveal a direct impact of the choice of milling media on the rate of formation and interconversion of cocrystal polymorphs. This effect enabled the discovery of a new polymorph of a cocrystal of nicotinamide and adipic acid, whose formation and conversion to the previously known, enantiotropically-related form, was readily controlled by milling in jars made of different materials.