Challenging the Ostwald rule of Stages in Mechanochemical Cocrystallisation

October, 2020


Mechanochemistry provides an extremely efficient, green, but still poorly understood route to synthesize and screen for a variety of new materials, including polymorphs of organic solids. In our most recent work, published in Chemical Science we present a hitherto unexplored effect of the milling assembly, i.e. milling jars and balls, on the reaction outcome of mechanochemical cocrystallisation. Previous work on mechanochemical reactions has established that introducing grinding additives, such as liquid or polymer additives can be used very efficiently to direct the reaction outcome, leading to extensive studies how the amount and nature of grinding additive affect reaction products and polymorphism. Focusing on a model pharmaceutical cocrystal of nicotinamide and adipic acid we demonstrate that changes to the choice of milling media (i.e. number and material of milling balls) and/or the choice of milling assembly (i.e. jar material) can be used to direct polymorphism of mechanochemical cocrystallisation, enabling the selective synthesis, and even reversible and repeatable interconversion of polymorphs – an unprecedent observation. While real-time mechanistic studies of mechanochemical transformations have so far suggested that reactions follow a path described by Ostwald's rule of stages, i.e. from metastable to increasingly more stable product structures, the herein presented systematic study presents an exception to that rule, revealing that modification of energy input in the mechanochemical system, combined with a small energy difference between polymorphs, permits the selective synthesis of either the more stable room temperature form, or the new metastable high-temperature form, of the target cocrystal. Our work is an important contribution to a better fundamental understanding of mechanochemical reaction, and also provides a new tool to screen novel materials in the future.

The work was carried out by scientists from McGill University in Montreal, the Max Planck Institute for Solid State Research in Stuttgart, the University of Warsaw, and DESY.

Luzia Germann

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