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

A new 3.2 mm H-F-X magic angle spinning dynamic nuclear polarization NMR (MAS DNP-NMR) probe was developed with a unique coil design with separate radiofrequency channels for H excitation and C or F detection to enable acquisition of H-F cross-polarization (CP) MAS experiments, direct-detected F spectra with proton decoupling, and acquisition on C with simultaneous double decoupling on the H and 19F channels as well as H-F-C 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 H-F CP MAS experiments performed on the new HFX probe represent a notable advantage over usually acquired direct-detected F experiments. The indirect F DNP enhancement ε(F) = 26 was obtained via H-F CP for the pure API impregnated with DNP solution, with an overall 30-fold sensitivity gain compared to the direct-detected F experiment under similar conditions. DNP enhancement value of ε(F) = 42 was obtained via H-F CP for the polymeric nanoparticle suspension and ε(F) ≈ 150 were obtained for two different siRNAs in frozen DNP solution.