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

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.