Perils of Polymorphism: Size Matters

Abstract

S ince the discoveryo fp olymorphismi n1 832, the ability of molecularc rystals to adopt different crystalf orms 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,afavorite subject of Jack Dunitz, who is honored in this special issue, has opened aw indow 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, changingp olymorphs tabilities, providing insights into nucleation, enabling discovery of new polymorphs, and even suggesting ar oute to disappearing polymorphs, brought to our attention by Dunitz and Bernstein twenty yearsa go.

A Prolific Solvate Former, Galunisertib, under the Pressure of Crystal Structure Prediction, Produces Ten Diverse Polymorphs

“…McCrone postulated many years ago that the number of polymorphic forms found is generally proportional to the effort expended in finding them . Still, seeing ten true polymorphs of any molecule is rare, even for those which have been intensively screened. , A substantially greater effort had gone into finding different polymorphs of GAL than, for example, ROY, where as many as 7 of 11 polymorphs have crystallized concomitantly from the same liquid. ,, Yet, we did not resort to exotic techniques, such as heteronucleation onto isostructural templates , or polymers, crystallization from complex mixtures, , or nucleation under confinement , to produce ten different polymorphs. All of the neat forms of GAL , with the notable exception of form X, were produced by conventional methods adapted to the formation of multiple solvates.…”

Crystallisation in printed droplets: understanding crystallisation of d-mannitol polymorphs

“…This could be possible as crystallisation in the confinement of nanopores can result in a change in the stability ranking of polymorphs. 9,51,52 Nonetheless, we do not believe that this is the case here. Another explanation would be that the β form requires homogeneous nucleation, which would be in the absence of surface or foreign particles.…”

Control and prediction of the organic solid state: a challenge to theory and experiment

“…The relative stability of polymorphs can depend on the size of the crystal [ 72 ] and solvent at nanoscale sizes where the proportion of surface to bulk molecules is not negligible. This can help explain why confinement in nano-pores or droplets can affect the polymorph formed [ 73 ]. However, the observation of metastable polymorphs in tiny droplets can just reflect the inhibition of the transformation or lack of replenishment of the supersaturation [ 74 ].…”