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

Abstract

Two polymorphic forms of 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, 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