title: Polymorphic behavior of an NK1 receptor antagonist.
abstract: 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.
authors.affiliation: Analytical Research Department, Merck Research Laboratories, R818-B112, P.O. Box 2000, Rahway, NJ 07065, USA. yaling_wang@merck.com
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: R M
authors.initials: RM
authors.lastname: Wenslow
authors.forename: J A
authors.initials: JA
authors.lastname: McCauley
authors.forename: L S
authors.initials: LS
authors.lastname: Crocker
mesh_terms: D002152:Calorimetry, Differential Scanning; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D009025:Morpholines / Q000737:chemistry*; D064729:Neurokinin-1 Receptor Antagonists; D012995:Solubility; D013696:Temperature; D013818:Thermogravimetry; D014230:Triazoles / Q000737:chemistry*
chemical_list: C440622:1-(5-((2-((1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-3-(4-fluorophenyl)morpholin-4-yl)methyl)-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D014230:Triazoles