Solid-state NMR analysis of crystalline and amorphous Indomethacin: An experimental protocol for full resonance assignments

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 165; pp. 47 - 55
• Main Authors: Lu, Xingyu, Xu, Wei, Hanada, Masataka, Jermain, Scott V., Williams, Robert O., Su, Yongchao
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 20.02.2019
• Subjects: Indomethacin; Pharmaceutical; Resonance assignment; Solid-state NMR; Structure; Resonance assignment; Solid-state NMR; Pharmaceutical; Indomethacin; Structure
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2018.11.001

•A robust experimental protocol for assigning 1H and 13C chemical shifts in ssNMR spectra is established.•Full resonance assignments of both crystalline and amorphous indomethacin are provided.•Molecular packing information of indomethacin is obtained from chemical shift analysis. Solid-state NMR (ssNMR) analysis of pharmaceutical materials relies on accurate resonance assignments. The relatively low sensitivity and resolution from the natural abundance and solid-state nature of the active pharmaceutical ingredient (API) and particularly the disordered structure of amorphous forms result in the ambiguous identification of NMR peaks. In this study, a robust protocol for unambiguously assigning 13C and 1H chemical shifts of crystalline and amorphous APIs has been established and successfully tested on γ-polymorph indomethacin. Specifically, one-dimensional (1D) 13C-edited experiments, two-dimensional (2D) 13C-detected homo- and heteronuclear correlations, and 2D 1H-detected techniques under ultrafast magic angle spinning (MAS) provide enhanced resolution to identify overlapped 13C resonances and assign confidently the 1H chemical shifts. This experimental strategy allows us to assign particularly those carbons and protons either unassigned or ambiguous identified due to the technical challenges in previous literature. Besides, the chemical shift comparison between the crystalline and amorphous forms can potentially report the molecular packing variations.