Computational Insights Into Kinetic Hindrance Affecting Crystallization Of Stable Forms Of Active Pharmaceutical Ingredients

A computational investigation of the potential source of kinetic hindrance for the late appearance of pharmaceutically relevant stable forms of ritonavir, rotigotine, ranitidine hydrochloride, and pharmaceutical compound A was performed along the crystallization coordinates of the relative rates of conformational interconversion, crystal nucleation, and growth. Conformational distribution, classical nucleation, and growth morphology theories were utilized, respectively, to compare the results with those of polymorphic systems, famotidine, nimodipine, paracetamol, indomethacin, tolfenamic acid, and mebendazole for which kinetic hindrance of the stable forms was not reported. The results did not support a potential mechanism of kinetic hindering of the stable polymorphic form due to nucleation and growth limited crystallization. However, a low population of crystallographic conformations of the stable forms in solution allowed us to distinguish the behavior of the late appearing stable systems from other polymorphic systems. To account for the low crystallographic conformer population as the potential source for kinetic hindrance, we suggest that self-association of the monomeric active pharmaceutical ingredients molecules precedes over nucleation in solution. As an implication to crystal structure prediction studies, it is suggested to complement the analysis of the lattice energy landscape of conformational polymorphs by the prediction of crystallographic conformers distribution in the gas phase and in solvents of potential interest.