Ikeda Yukihiro, Ishihara Yoko, Moriwaki Toshiya, Kato Eiji, Terada Katsuhide
Discovery Research Center, Takeda Pharmaceutical Company, Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 2010 Jan;58(1):76-81. doi: 10.1248/cpb.58.76.
A novel analytical method for the determination of pharmaceutical polymorphs was developed using terahertz spectroscopy. It was found out that each polymorph of a substance showed a specific terahertz absorption spectrum. In particular, analysis of the second derivative spectrum was enormously beneficial in the discrimination of closely related polymorphs that were difficult to discern by powder X-ray diffractometry. Crystal forms that were obtained by crystallization from various solvents and stored under various conditions were specifically characterized by the second derivative of each terahertz spectrum. Fractional polymorphic transformation for substances stored under stressed conditions was also identified by terahertz spectroscopy during solid-state stability test, but could not be detected by powder X-ray diffractometry. Since polymorphs could be characterized clearly by terahertz spectroscopy, further physicochemical studies could be conducted in a timely manner. The development form of compound examined was determined by the results of comprehensive physicochemical studies that included thermodynamic relationships, as well as chemical and physicochemical stability. In conclusion, terahertz spectroscopy, which has unique power in the elucidation of molecular interaction within a crystal lattice, can play more important role in physicochemical research. Terahertz spectroscopy has a great potential as a tool for polymorphic determination, particularly since the second derivative of the terahertz spectrum possesses high sensitivity for pharmaceutical polymorphs.
利用太赫兹光谱技术开发了一种测定药物多晶型物的新型分析方法。研究发现，一种物质的每种多晶型物都呈现出特定的太赫兹吸收光谱。特别是，对二阶导数光谱的分析在区分粉末X射线衍射法难以分辨的密切相关的多晶型物方面非常有益。通过从各种溶剂中结晶并在各种条件下储存而获得的晶体形式，通过每种太赫兹光谱的二阶导数进行了具体表征。在固态稳定性测试期间，通过太赫兹光谱法也鉴定了在应激条件下储存的物质的部分多晶型转变，但粉末X射线衍射法无法检测到。由于太赫兹光谱法可以清楚地表征多晶型物，因此可以及时进行进一步的物理化学研究。所研究化合物的晶型由包括热力学关系以及化学和物理化学稳定性在内的综合物理化学研究结果确定。总之，太赫兹光谱在阐明晶格内分子相互作用方面具有独特的能力，在物理化学研究中可以发挥更重要的作用。太赫兹光谱作为一种多晶型测定工具具有巨大潜力，特别是因为太赫兹光谱的二阶导数对药物多晶型物具有高灵敏度。
