Understanding the role of solvent in regulating the crystal habit

Abstract

The crystal habit is one of the most important properties for active pharmaceutical ingredients (APIs), which can significantly affect their downstream processing. In this study, to better understand the role of solvent in crystal habit evolution, the crystal interface–solvent interactions and their effect on the crystal habit were investigated using cefradine as a model compound. Molecular dynamics simulation was applied to calculate the interactions between the solute (cefradine) and solvent (organic/water mixture) molecules occurring at the crystal/solution interface. It turned out that the interactions between the solvent and (101) face are diminished in the mixed solvent of methanol, ethanol and acetonitrile, thereby lowering the solvation barrier to crystal growth. In contrast, for the solvent of DMA, DMF and DMSO, the solute–solvent interaction is stronger at the (011) and (01-1) faces, which lowers the adsorption rate of solute molecules onto these faces and consequently inhibits the crystal growth along the a-axis. The developed knowledge based on the crystal interface–solvent interactions can form a basis for further optimization of the crystal habit of cefradine.