title: Characterization and Thermodynamic Stability of Polymorphs of Di(arylamino) Aryl Compound ASP3026.
abstract: ASP3026 (N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N'-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed in Astellas Pharma Inc. as a novel and selective inhibitor of the fusion protein EML4-ALK. We investigated the thermodynamic stability of five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) in detail. To determine the most stable form at ambient temperature, powder X-ray diffraction, differential scanning calorimetry, and solubility measurements were conducted. Of the five polymorphs, A04 was the most stable and A05 was the least stable. The relationship between A04 and A03 and A04 and A01 were mutually monotropic, while that between A01 and A02 was enantiotropic. The transition temperature from A02 to A01 was estimated as 325 K. A02 was more thermodynamically stable at ambient temperature than A01. Furthermore, the method to estimate polymorphic transition temperatures using solution calorimetry was found to be effective. The systematic characterization of ASP3026 polymorphs presented in this study enables the selective crystallization of the most stable form and design of solid formulations.
authors.affiliation: Technology Process Chemistry Labs., Astellas Pharma Inc.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takeguchi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hirakura
authors.forename: Kouji
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Itsuro
authors.initials: I
authors.lastname: Shimada
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ieda
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takiyama
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors; D033362:Powder Diffraction; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D012995:Solubility; D013450:Sulfones / Q000737:chemistry*; D013816:Thermodynamics; D044366:Transition Temperature; D014227:Triazines / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: C000595153:ASP3026; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D013450:Sulfones; D014227:Triazines