Water activity-mediated control of crystalline phases of an active pharmaceutical ingredient

A systematic investigation of the polymorph−hydrate system for Compound I was carried out with the objective of understanding the phase relationships between the different forms as it relates to crystallization conditions. The ternary phase diagram was determined from solubility and KF measurements of the supernatant liquor for Compound I−water−ethanol mixtures. Water concentrations were converted to water activities using the NRTL-RK model as implemented in ASPEN Properties. These water activities were then used in defining phase boundaries between anhydrous and the various hydrated forms of Compound I. Since the critical water activity at the phase boundaries between anhydrous and hydrated forms in water−cosolvent systems is independent of the nature of the cosolvent it can be used to extrapolate the water concentrations defining ternary phase boundaries in any other cosolvent−water system. This was demonstrated in the cases of acetonitrile−water and dimethyl acetamide−water. Triple points (anhydrate−hy...