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

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.