Polymorphism of roxifiban

Roxifiban was found to exist in two polymorphic forms. The polymorphs were detected by X-ray powder diffraction and solid-state carbon nuclear magnetic resonance. A slight difference between the two polymorphs was also detected by isothermal microcalorimetry. However, no differences were observed by differential scanning calorimetry, infrared, or Raman spectroscopy. Solubility studies as a function of temperature in a discriminating solvent system permitted characterization of the thermodynamics of the polymorphs. The enthalpy of solution at 25degreesC was 8.1 kcal/mol and 8.9 kcal/mol for Form I and Form II, respectively, and the thermodynamic transition point was 132degreesC. The data confirm that the polymorphs are enantiotropic. Form II is the thermodynamically stable crystal form over the practical range of drug substance storage and handling and dosage form processing and storage. However, Form I has been kinetically stable after storage for more than 36 months at 25degreesC/60% relative humidity with no conversion to Form II occurring. (C) 2002 Wiley-Liss, Inc.