Polymorphic behavior of an NK1 receptor antagonist

Four anhydrous polymorphic forms (I, II, III and IV) of an NK1 receptor antagonist, Compound A, have been discovered. The pure compound can exist as either Forms I or II at room temperature and Forms III or IV at elevated temperatures. The four polymorphs were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis, X-ray powder diffraction (XRPD) and solid-state NMR spectroscopy (SSNMR). Polymorphic transformations in the solid phase were studied using DSC, hot stage XRPD, temperature-modulated SSNMR and hot stage optical microscopy. The solubilities of Forms I and II in tert-butyl acetate at different temperatures were measured and the relative stability of the two forms was established. The thermodynamic transformation temperatures between Forms I and III, as well as Forms II and IV, were estimated by DSC. Transformation from Form III to IV, which is undetectable in a normal calorimetric run, was revealed through careful thermal programming. An interesting conversion route from Form I, a more stable form at room temperature, to Form II, a less stable form at room temperature was discovered.