Computational Insights into Kinetic Hindrance Affecting Crystallization of Stable Forms of Active Pharmaceutical Ingredients

Abstract

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.

An Elusive Drug–Drug Cocrystal Prepared Using a Heteroseeding Strategy

“…A low population of the molecular conformation in solution which is the same as that in the crystal may increase the kinetic barrier for crystallization. 39 The highly flexible SOR and REG (with a degree of freedom of 138) are expected to exhibit a complex energy landscape. Although the structures of SOR and REG molecules are similar, we observed significantly different conformations of SOR and REG in their free base crystals, which lead to different crystal structures (AKENOU and QABCEE, respectively).…”

The unexpected discovery of the ninth polymorph of tolfenamic acid

“…Because of that, the white form I and the yellow form II 31,32 of TFA have been the subject of numerous studies pertaining to their stabilities as well as their nucleation and interconversion. 30,[33][34][35][36] The other polymorphs (III-VIII), in contrast, have only been reported in a few studies, and their discovery was only possible by crystallisations performed on templating agents, either in solution or by sublimation. [37][38][39] Despite the numerous studies and explorations on the polymorphism of TFA, to our surprise, we came across a new form which was readily crystallised from isopropanol (IPA) by simple fast cooling crystallisation.…”

Crystals and Crystallization in Drug Delivery Design

“…The question of which molecular or crystalline properties might be indicative of kinetic hindering of stable forms has been addressed by Yuriy A. Abramov and co-workers. Their calculations reveal that nucleation and growth limited crystallization are not the reason for the famous late-appearing stable forms of ritonavir, rotigotine, and rantitidine HCl, but rather that there is a low population of crystallographic conformations of the stable forms in solution . A recent perspective from a group of predominantly industrial authors led by Luke Schenk from Merck highlights the unfortunate reality that conventional solid-form screening and crystallization process optimization are not always successful in identifying a developable form of the candidate drug .…”