Fluorinated Biradicals for ¹⁹F Magic-Angle Spinning Dynamic Nuclear Polarization-Enhanced NMR Spectroscopy

Dynamic nuclear polarization (DNP)-enhanced solid-state NMR is a powerful technique for structural studies of low-concentration systems, including active pharmaceutical ingredients (APIs) in complex formulations and cellular environments. When combined with ¹⁹F NMR, it offers a highly selective approach to detect fluorine atoms, which are common in APIs, yet typically absent from excipients. However, the broader adoption of ¹⁹F DNP has been limited by hardware constraints and the lack of optimized polarizing agents. In this study, we introduce fluorinated analogs of the benchmark biradicals TEKPol and bCTbK, specifically designed to enhance direct ¹⁹F DNP performance. These radicals were tested on two model-fluorinated drugs across multiple formulations. Compared to their protonated counterparts, the fluorinated biradicals consistently yield superior enhancements, achieving up to 330-fold signal amplification in solution and 53-fold in a commercial tablet, along with significantly reduced polarization build-up times. These results demonstrate that fluorinated radicals can substantially improve sensitivity and acquisition speed in ¹⁹F DNP NMR, enabling robust detection of APIs even in challenging matrices. This work paves the way for broader use of ¹⁹F DNP in pharmaceutical analysis, particularly in settings where probe limitations preclude indirect polarization transfer via protons.