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−hydrate−solvent) were estimated in these two cosolvent−water systems. Two representative crystallizations in these
crystallization solvents produced a hemihydrate in 15% acetonitrile−water, and the tetrahydrate in 15% dimethyl acetamide−water, both of which were predicted by the phase
diagrams in these systems. The importance of this work lies in
obviating the need for phase equilibria measurements in every
cosolvent−water system used in crystallization processes. Additionally the crystal structure of hemihydrate was solved by
single-crystal X-ray diffraction, and the binding mode of water
in the lattice elucidates the thermal and hygroscopicity behavior
of this form. In addition the crystal structure unambiguously
identified the hemihydrate and enabled the design on an
appropriate crystallization process incorporating aw as a major
variable.