Fast F-19 Magic Angle Spinning Nmr Crystallography For Structural Characterization Of Fluorine-Containing Pharmaceutical Compounds

Fluorine-containing compounds comprise 20 to 30 percent of all commercial drugs, and the proportion of fluorinated pharmaceuticals is rapidly growing. While magic angle spinning (MAS) NMR spectroscopy is a popular technique for analysis of solid pharmaceutical compounds, fluorine has been underutilized as a structural probe so far. Here, we report a fast (40-60 kHz) MAS (19 ) NMR approach for structural characterization of fluorine-containing crystalline pharmaceutical compounds at natural abundance, using the antimalarial fluorine-containing drug mefloquine as an example. We demonstrate the utility of 2D F-19-C-13 and F-19-F-19 dipolar-coupling-based correlation experiments for F-19 and C-13 resonance frequency assignment, which permit identification of crystallographically inequivalent sites. The efficiency of (FC)-F-19-C-13 cross-polarization and the effect of H-1 and F-19 decoupling on spectral resolution and sensitivity were evaluated in a broad range of experimental conditions. We further demonstrate a protocol for measuring accurate interfluorine distances based on 1D DANTE-RFDR experiments combined with multispin numerical simulations.