A review of the effect of multiple conformers on crystallization from solution and strategies for crystallizing slow inter-converting conformers

• Published in: Chemical engineering science Vol. 106; pp. 275 - 292
• Main Authors: Derdour, L., Skliar, D.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 17.03.2014
• Subjects: Atropisomer; Chemical engineering; Crystal forces; Crystal growth; Crystal surfaces; Crystallization; Crystallization tendency; Crystals; Daclatasvir; Energy barrier; Intrinsic supersaturation; Nucleation; Polymorphism; Strategy; Daclatasvir; Crystal forces; Atropisomer; Intrinsic supersaturation; Energy barrier; Crystallization tendency
• ISSN: 0009-2509; 1873-4405
• DOI: 10.1016/j.ces.2013.11.025

The effect of multiple conformers in solution on nucleation, growth rate and polymorphism is reviewed and methods for crystallizing substances present as slow inter-converting conformers in solution are proposed. Review of the previous art indicated that for fast inter-converting conformers, nucleation and polymorphism are favored but no effect is expected on crystal growth rate as crystal forces are expected to modify the conformation of the integrating species onto the crystal surface. On the other hand, nucleation rates and propensity for polymorphism are expected to be lowered for systems with slow conformational inter-conversion kinetics. In addition, for such systems, the effect of crystal forces on conformational change upon crystallization is decreased which results in an impediment of crystal growth. This effect is more pronounced if the species that crystallizes is a minor conformer in solution. Strategies for crystallizing slow inter-converting conformers, including the evaluation of the propensity for nucleation of specific conformers via calculation of the intrinsic supersaturation, are presented. This latter method was used to determine crystallization conditions of a drug candidate present as slow inter-converting conformers in solution.