A Spectroscopic and Diffractometric Study of Polymorphism in Ethyl 3‑{3-[((2<i>R</i>)‑3-{[2-(2,3-dihydro‑1<i>H</i>‑inden-2-yl)-1,1-dimethylethyl]amino}-2-hydroxypropyl)oxy]-4,5-difluorophenyl}propanoate Hydrochloride

Two polymorphic forms of ethyl 3-{3-[((2R)-3-{[2-(2,3-dihydro-1H-inden-2-yl)-1,1-dimethylethyl]­amino}-2-hydroxypropyl)­oxy]-4,5-difluorophenyl} propanoate hydrochloride, an investigational pharmaceutical compound, are characterized using spectroscopic and diffractometric techniques. These polymorphic forms exhibit very similar spectra and diffraction patterns and present challenges for analytical and physical characterization techniques. Capillary powder X-ray diffraction (PXRD) patterns for the two forms show minor but distinct differences. A single crystal X-ray diffraction structure for one of the forms was obtained. The unit cell of the other form was obtained by PXRD indexing. Detailed solid-state nuclear magnetic resonance (SSNMR) studies observing the 1H, 13C, 15N, 19F, and 35Cl nuclei are performed to characterize the subtle structural differences between the two forms. Molecular spectroscopic methods including infrared, Raman, UV–visible, and fluorescence spectroscopy are also applied. The combined results, particularly the results obtained from X-ray diffraction analysis, 13C, 15N, and 35Cl SSNMR, and fluorescence spectroscopy, are consistent with the more thermodynamically stable form having a structure that is an extended, perturbed superstructure of the less stable form.本研究采用光谱学与衍射表征技术，对作为在研药物化合物的盐酸3-{3-[((2R)-3-{[2-(2,3-二氢-1H-茚-2-基)-1,1-二甲基乙基]氨基}-2-羟基丙氧基]-4,5-二氟苯基}丙酸乙酯的两种晶型进行了表征。这两种晶型的光谱与衍射图谱极为相似，给分析表征与物理性质鉴定技术带来了挑战。两种晶型的毛细管粉末X射线衍射（Capillary powder X-ray diffraction, PXRD）图谱仅存在细微但明确的差异。其中一种晶型的单晶X射线衍射结构已被解析获得，另一种晶型的晶胞参数则通过PXRD指标化方法得到。针对1H、13C、15N、19F及35Cl原子核开展了细致的固态核磁共振（Solid-state Nuclear Magnetic Resonance, SSNMR）研究，以表征两种晶型之间细微的结构差异。同时还采用了红外、拉曼、紫外-可见及荧光光谱等分子光谱学表征方法。综合各项表征结果，尤其是X射线衍射分析、13C、15N及35Cl固态核磁共振，以及荧光光谱所得的结果，证实热力学稳定性更强的晶型其结构为稳定性较弱晶型的延展型扰动超结构。