1H–19F cross-polarization magic angle spinning dynamic nuclear polarization NMR investigation of advanced pharmaceutical formulations

A new 3.2 mm ¹H-¹⁹F-X magic angle spinning dynamic nuclear polarization NMR (MAS DNP-NMR) probe was developed with a unique coil design with separate radiofrequency channels for ¹H excitation and ¹³C or ¹⁹F detection to enable acquisition of ¹H-¹⁹F cross-polarization (CP) MAS experiments, direct-detected ¹⁹F spectra with proton decoupling, and acquisition on ¹³C with simultaneous double decoupling on the ¹H and 19F channels as well as ¹H-¹⁹F-¹³C double-CP experiments under low temperature MAS DNP conditions. We use these sequences to study AZD2811, which is an active pharmaceutical ingredient (API), in its pure dry state as well as in its corresponding drug delivery formulation consisting of drug-loaded polymeric nanoparticles (PNPs). Included in this study are also small interfering RNAs (siRNAs) for therapeutic targeting of peptidyl-prolyl cis-trans isomerase B (Ppib) mRNA. We demonstrate that ¹H-¹⁹F CP MAS experiments performed on the new HFX probe represent a notable advantage over usually acquired direct-detected ¹⁹F experiments. The indirect ¹⁹F DNP enhancement ε_on/off(¹⁹F) = 26 was obtained via ¹H-¹⁹F CP for the pure API impregnated with DNP solution, with an overall 30-fold sensitivity gain compared to the direct-detected ¹⁹F experiment under similar conditions. DNP enhancement value of ε_on/off(¹⁹F) = 42 was obtained via ¹H-¹⁹F CP for the polymeric nanoparticle suspension and ε_on/off(¹⁹F) ≈ 150 were obtained for two different siRNAs in frozen DNP solution.