(320c) Crystallization From Solutions Containing Multiple Conformers: Approach of the Right Conformer

In this study, a modeling approach to determine the solubility and supersaturation of organic solids crystallized from solutions containing multiple conformations is presented. This approach, referred to as the approach of the right conformer (RC) considers that only one conformer (i.e. the RC) integrates into the crystal surface. Other conformers must transit through the RC conformer before crystallizing. This approach is likely to apply for systems with high energy barriers between conformers, which translates into a negligible effect of the crystal surface on the conformation of the solute. It is assumed that the RC to be the only species in true equilibrium with the solid at saturation. Intrinsic solubility and total solubility are introduced for non-ionizable flexible molecules and defined respectively as the concentration of the RC and the concentration of all conformers at saturation. The intrinsic supersaturation, defined as the concentration of the RC minus the intrinsic solubility is assumed to be the driving force for crystallization. Relationships of the total solubility and the ISS as function of crystallization conditions were obtained. For both substances, single crystal X-ray indicated only one conformation but in situ IR and solution NMR revealed the presence of two main conformers in solution at room temperature. In addition, rotomers' peak coalescence was reached a high temperature indicating a relatively high energy barrier between confomers. On the basis of these considerations, the approach of the RC was applied to these substances to explain their rare crystallization and solubility behaviors: Sharp decrease in crystallization duration and constant or decreasing solubility with increasing temperature. Computed total solubility was in agreement with the observed constant or decreasing solubility with temperature. In addition, the model predicts low levels of the ISS which can explain the slow crystallization observed experimentally. Finally, on the basis of the increasing ISS with temperature, an alternate crystallization method based on a single heating ramp is utilized to provide crystals with improved powder properties.