Characterization and Thermodynamic Stability of Polymorphs of Di(arylamino) Aryl Compound ASP3026

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  • Takeguchi Kazuhiro
    Technology Process Chemistry Labs., Astellas Pharma Inc. Department of Chemical Engineering, Tokyo University of Agriculture and Technology
  • Hirakura Yutaka
    Technology Analytical Research Labs., Astellas Pharma Inc.
  • Yamazaki Kouji
    Drug Discovery Research Analysis & Pharmacokinetics Research Labs., Astellas Pharma Inc.
  • Shimada Itsuro
    Drug Discovery Research Medicinal Chemistry Research Labs., Astellas Pharma Inc.
  • Ieda Shigeru
    Astellas Pharma Tech Co., Ltd.
  • Okada Minoru
    Technology Process Chemistry Labs., Astellas Pharma Inc.
  • Takiyama Hiroshi
    Department of Chemical Engineering, Tokyo University of Agriculture and Technology

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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.

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