DNP-Enhanced Solid-State NMR Spectroscopy of Active Pharmaceutical Ingredients

Li Zhao, Iowa State University
Arthur C. Pinon, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Lyndon Emsley, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Aaron J. Rossini, Iowa State University

This is a manuscript of Zhao, Li, Arthur C. Pinon, Lyndon Emsley, and Aaron J. Rossini. "DNP‐Enhanced Solid‐State NMR Spectroscopy of Active Pharmaceutical Ingredients." Magnetic Resonance in Chemistry. doi:10.1002/mrc.4688. Posted with permission.


Solid-state NMR has become a valuable tool for the characterization of both pure and formulated active pharmaceutical ingredients (APIs). However, NMR generally suffers from poor sensitivity that often restricts NMR experiments to nuclei with favorable properties, concentrated samples and acquisition of 1D NMR spectra. Here we review how dynamic nuclear polarization (DNP) can be applied to routinely enhance the sensitivity of solid-state NMR experiments by one to two orders of magnitude for both pure and formulated APIs. Sample preparation protocols for relayed DNP experiments and experiments on directly-doped APIs are detailed. Numerical spin diffusion models illustrate the dependence of relayed DNP enhancements on the relaxation properties and particle size of the solids and can be used for particle size determination when the other factors are known. We then describe the advanced solid-state NMR experiments that have been enabled by DNP and how they provide unique insight into the molecular and macroscopic structure of APIs. For example, with large sensitivity gains provided by DNP natural isotopic abundance 13C-13C DQ-SQ homonuclear correlation NMR spectra of pure APIs can be routinely acquired. DNP-enhanced solid-state NMR also enables solid-state NMR experiments with unreceptive quadrupolar nuclei such as 2H, 14N and 35Cl that are commonly found in APIs. Applications of DNP-enhanced solid-state NMR for the molecular level characterization of low API load formulations such as commercial tablets and amorphous solid dispersions are described. Future perspectives for DNP-enhanced solid-state NMR experiments on APIs are briefly discussed.