Conformational Selectivity and Evolution Affected by the Desolvation Process

Abstract

The inconsistency between solution chemistry and the crystal structure indicates the potential conformational evolution and rearrangement during the nucleation process. However, the mechanism of how the conformation is selected to form the corresponding polymorph is still not clear due to the complicated crystallization environment. In this work, conformation and polymorph selectivity of three anhydrous forms of gabapentin were investigated. Quantum chemical computation was used to analyze gabapentin conformations in the solution state and explore their transformation pathway. Besides, visual molecular dynamics was adopted to calculate the structural difference of the conformers in solution and crystal states, which was closely related to conformational selectivity. Moreover, the effects of solvent types and the supersaturation on solute–solvent interactions were investigated by Fourier transform infrared spectra and molecular dynamics simulations. Combined with the outcome of rapid cooling experiments, it was found that the solute–solvent interaction may affect the difficulty of desolvation so as to affect the conformational selectivity before nucleation. A special evaporation experiment was designed to obtain the unstable polymorph of gabapentin. Finally, the possible mechanism of selective polymorph crystallization was proposed and analyzed.