Solid State Investigation and Characterization of a Nepadutant Precursor: Polymorphic and Pseudopolymorphic Forms of MEN11282

Abstract

MEN11282 (1) is a precursor of nepadutant (MEN11420), a potent and selective antagonist at the human tachykinin NK-2 receptor (hNK-2), that has been evaluated in clinical trials for different therapeutic indications. Three crystalline forms of 1 were identified and characterized by both single crystal and powder X-ray diffraction (SCXRD and XRPD): a monohydrate (1·H2O, SCXRD) and two different anhydrous forms, namely, 1_α and 1_β (XRPD). Because of the relevance that the solid form of a substance of pharmaceutical interest plays during the manufacturing process, variable temperature powder X-ray diffraction (VT-XRPD) in conjunction with differential scanning calorimetry were used to investigate the behavior of the different solid forms of 1. The rationale for the dehydration and hydration process involving 1·H2O and 1_α and the stability of 1_β toward water uptake is provided based on their crystal packings.