Fast ¹⁹F Magic Angle Spinning NMR Crystallography for Structural Characterization of Fluorine-Containing Pharmaceutical Compounds

Abstract

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 F 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 19 F− 13 C and 19 F− 19 F dipolar-coupling-based correlation experiments for 19 F and 13 C resonance frequency assignment, which permit identification of crystallographically inequivalent sites. The efficiency of 19 F− 13 C cross-polarization and the effect of 1 H and 19 F 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.

Cell-free synthesis of amyloid fibrils with infectious properties and amenable to sub-milligram magic-angle spinning NMR analysis

“…As observed for the CF-6F-HETs sample, the experimental 19 F line width and the number of observed resonances suggest that the sample is highly homogeneous. Overall, the 1D spectral quality in the 19 F dimension of our CF synthesized samples is excellent and in the range of reported MAS NMR data obtained on small compounds [102][103][104][105] , amino acids 106 , peptides 107,108 and protein samples 100,[109][110][111][112] from the Polenova, Gronenborn and Hong laboratories at various magnetic fields and MAS frequencies. Next, to investigate the local effect of fluorine incorporation into the 13 C signals, we conducted a 2D hCH experiment on CF-2F-C-HETs.…”

Probing Molecular Packing of Drug Substances in Nanometer Domains in Pharmaceutical Formulations Using 19F Magic Angle Spinning NMR

“…During the 19 F CODEX experiment, polarization transfers among fluorine spin with the identical isotropic chemical shift but distinct anisotropic chemical shifts, which encodes information about molecular reorientations on a time scale of ≥1 ms and intermolecular distances. , When slow molecular motions are frozen, interatomic 19 F– 19 F spin diffusion becomes the dominant mechanism of spin exchange and can be utilized to quantify oligomerization, for instance, quantify protein aggregation and intermolecular distances up to 15 Å. ,− Results from a 19 F CODEX experiment proposed a trimer structure and mapped out a triangular geometry of a cell-penetrating peptide, penetratin, in trehalose-protected DMPC/DMPG bilayers, by utilizing 4- 19 F-phenylalanine labeling . Considering the relatively large gyromagnetic ratio and natural abundance, 19 F NMR has increasingly been implemented in the pharmaceutical analysis of natural abundance drugs. ,− ,,,− In recent years, 19 F spin-exchange NMR has also been applied to study fluorinated drugs. For example, Roos et al have studied sitagliptin phosphate, a medicine for treating type 2 diabetes, and comprehensively investigated interatomic 19 F distances up to 9.6 Å …”

Analysis of the Alcohol Amine Mixtures by 1D Selective COSY

“…Aforementioned three methods can solve a part of practical problems [5][6][7], but the first two methods involve sample preparation. This not only requires more time, but may also cause damage to or even lose the original sample [8,9].…”