Study of the solvent-dependent crystal shape of theophylline using constant chemical potential molecular dynamics simulations

Abstract

The crystal habit of an organic crystalline material impacts its properties, processing, and performance, especially in pharmaceuticals. In solution crystallization, solvents play a crucial role in modulating the crystal habits by interacting with the different growing facets – either enhancing or inhibiting the growth of specific facets. Thus, an in-depth understanding of the role of the solvent in crystal shape selection is of paramount importance for the design and growth of crystals. In this work, we used constant chemical potential molecular dynamics (CμMD) to simulate the growth of theophylline crystals in solvents with decreasing polarity, i.e. water, isopropyl alcohol, and dimethylformamide. Our results indicate that as the polarity of the solvent increases, theophylline crystallizes into rod-shaped crystals; the aspect ratio is modulated by the relative growth of the (001) and (010) facets. Furthermore, solvent profile analyses revealed that the desolvation of the crystal facets plays a major role in the growth process.