Crystallization is extensively used in the pharmaceutical and food industries, among others, to purify chemicals intended for human consumption. Many molecules, however, can crystallize into different polymorphs depending on the precipitation conditions (e.g. solvent, degree of supersaturation). These polymorphs often exhibit different physical properties, which affects their suitability for various applications. For example, different polymorphs of a drug may have different dissolution profiles, and hence bioavaliabilites, which makes the control of the crystallization process critical in drug manufacturing.

In this work, we combine a novel method to characterize the degree of order in molecular crystals with the Finite Temperature String Method in collective variables [1] to obtain minimum free energy pathways for the nucleation of crystals from the melt and from aqueous solution. Our results shed light on the mechanisms by which molecules come together and organize into crystalline structures, which is a first step in understanding the mechanisms of polymorph selection. These results can be used to develop an improved, rational methodology for the manufacturing of drugs with a desired crystal structure.

[1] L. Maragliano, et al., J. Chem. Phys. 125, 024106 (2006)