文摘
A systematic investigation of the polymorph-hydrate systemfor Compound I was carried out with the objective of understanding the phase relationships between the different formsas it relates to crystallization conditions. The ternary phasediagram was determined from solubility and KF measurementsof the supernatant liquor for Compound I-water-ethanolmixtures. Water concentrations were converted to water activities using the NRTL-RK model as implemented in ASPENProperties. These water activities were then used in definingphase boundaries between anhydrous and the various hydratedforms of Compound I. Since the critical water activity at thephase boundaries between anhydrous and hydrated forms inwater-cosolvent systems is independent of the nature of thecosolvent it can be used to extrapolate the water concentrationsdefining ternary phase boundaries in any other cosolvent-watersystem. 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 thesecrystallization solvents produced a hemihydrate in 15% acetonitrile-water, and the tetrahydrate in 15% dimethyl acetamide-water, both of which were predicted by the phasediagrams in these systems. The importance of this work lies inobviating the need for phase equilibria measurements in everycosolvent-water system used in crystallization processes. Additionally the crystal structure of hemihydrate was solved bysingle-crystal X-ray diffraction, and the binding mode of waterin the lattice elucidates the thermal and hygroscopicity behaviorof this form. In addition the crystal structure unambiguouslyidentified the hemihydrate and enabled the design on anappropriate crystallization process incorporating aw as a majorvariable.