Three-Dimensional NMR Spectroscopy of Fluorinated Pharmaceutical Solids under Ultrafast Magic Angle Spinning

High-resolution solid-state analysis of multicomponent molecular systems, e.g., pharmaceutical formulations, is a great challenge. Solid-state nuclear magnetic resonance (ssNMR) spectroscopy plays a critical role in the characterization of solid dosage forms due to its capabilities of chemical identification, quantification, and structural elucidation at a molecular level. However, the low NMR sensitivity as well as the high spectral complexity and low drug loading of multicomponent products hinder an in-depth investigation of the active pharmaceutical ingredient (API) at the natural isotopic abundance. Herein, we developed two new three-dimensional (3D) ssNMR methods, including ¹H-¹⁹F-¹H and ¹⁹F-¹⁹F-¹H correlations and successfully applied them to characterize a fluorinated drug molecule, aprepitant, and its commercial nanoparticulate formulation EMEND (Merck & Co, Inc., Kenilworth, NJ, USA). These ¹H-detection methods utilize the significantly enhanced sensitivity and resolution of ¹H and ¹⁹F afforded by 60 kHz ultrafast magic angle spinning (MAS) and enable the analysis of milligram samples. The 3D techniques simultaneously provide homonuclear ¹H-¹H and ¹⁹F-¹⁹F, and heteronuclear ¹H-¹⁹F correlations of the crystalline aprepitant without interferences from other pharmaceutical components in the drug product. Moreover, our results demonstrate that ¹⁹F is a highly sensitive spin for probing molecular details of fluorinated drug substances in solid formulations, due to its high isotopic abundance, large gyromagnetic ratio, and absence of signal interference from pharmaceutical excipients, as well as for characterizing structural properties of a broad range of fluorine-containing materials.