Potential and performance of anisotropic F NMR for the enantiomeric analysis of fluorinated chiral active pharmaceutical ingredients

• Published in: Analyst (London) 2024-05, Vol.149 (11), p.324-3213
• Main Authors: Gouilleux, Boris, Moussallieh, François-Marie, Lesot, Philippe
• Format: Article
• Language: English
• ISSN: 0003-2654; 1364-5528
• DOI: 10.1039/d4an00237g

Controlling the enantiomeric purity of chiral drugs is of paramount importance in pharmaceutical chemistry. Isotropic 1 H NMR spectroscopy involving chiral agents is a widely used method for discriminating enantiomers and quantifying their relative proportions. However, the relatively weak spectral separation of enantiomers ( 1 H Δ δ iso ( R , S )) in frequency units at low and moderate magnetic fields, as well as the lack of versatility of a majority of those agents with respect to different chemical functions, may limit the general use of this approach. In this article, we investigate the analytical potential of 19 F NMR in anisotropic chiral media for the enantiomeric analysis of fluorinated active pharmaceutical ingredients (API) via two residual anisotropic NMR interactions: the chemical shift anisotropy ( 19 F-RCSA) and dipolar coupling (( 19 F- 19 F)-RDC). Lyotropic chiral liquid crystals (CLC) based on poly-γ-benzyl- l -glutamate (PBLG) show an interesting versatility and adaptability to enantiodiscrimination as illustrated for two chiral drugs, Flurbiprofen® (FLU) and Efavirenz® (EFA), which have very different chemical functions. The approach has been tested on a routine 300 MHz NMR spectrometer equipped with a standard probe (5 mm BBFO probe) in a high-throughput context ( i.e. , 10 s of NMR experiments) while the performance for enantiomeric excess ( ee ) measurement is evaluated in terms of trueness and precision. The limits of detection (LOD) determined were 0.17 and 0.16 μmol ml −1 for FLU and EFA, respectively, allow working in dilute conditions even with such a short experimental duration. The enantiodiscrimination capabilities are also discussed with respect to experimental features such as CLC composition and temperature. A new analytical strategy involving 1 H-{ 19 F} 1D NMR in PBLG-based anisotropic media is explored to analyze fluorinated chiral active pharmaceutical ingredients.