Perils of Polymorphism: Size Matters

Since the discovery of polymorphism in 1832, the ability of molecular crystals to adopt different crystal forms has intrigued and frustrated the scientific community. Control of this property has been limited by poor understanding of nucleation pathways and the absence of methods that can intercept crystallization at its earliest stages. Nonetheless, polymorphism, a favorite subject of Jack Dunitz, who is honored in this special issue, has opened a window into the forces that govern molecular organization in the solid state, while enabling discovery of new crystal forms with improved properties. This review illustrates the growth of crystals in nanoscale reactors with sizes comparable with those for nucleation, where thermodynamics and kinetics intersect, changing polymorph stabilities, providing insights into nucleation, enabling discovery of new polymorphs, and even suggesting a route to disappearing polymorphs, brought to our attention by Dunitz and Bernstein twenty years ago.