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Dynamic Nuclear Polarization Enhanced NMR Spectroscopy for Pharmaceutical Formulations
Journal of the American Chemical Society (2014)
  • Aaron J. Rossini, Université de Lyon
  • Cory M. Widdifield, ETH Zurich
  • Alexandre Zagdoun, Université de Lyon
  • Moreno Lelli, Université de Lyon
  • Martin Schwarzwalder, ETH Zürich
  • Christophe Coperet, ETH Zürich
  • Anne Lesage, University of Lyon
  • Lyndon Emsley, University of Lyon
Dynamic nuclear polarization (DNP) enhanced solid-state NMR spectroscopy at 9.4 T is demonstrated for the detailed atomic-level characterization of commercial pharmaceutical formulations. To enable DNP experiments without major modifications of the formulations, the gently ground tablets are impregnated with solutions of biradical polarizing agents. The organic liquid used for impregnation (here 1,1,2,2-tetrachloroethane) is chosen so that the active pharmaceutical ingredient (API) is minimally perturbed. DNP enhancements (ε) of between 40 and 90 at 105 K were obtained for the microparticulate API within four different commercial formulations of the over-the-counter antihistamine drug cetirizine dihydrochloride. The different formulations contain between 4.8 and 8.7 wt % API. DNP enables the rapid acquisition with natural isotopic abundances of one- and two-dimensional 13C and 15N solid-state NMR spectra of the formulations while preserving the microstructure of the API particles. Here this allowed immediate identification of the amorphous form of the API in the tablet. API–excipient interactions were observed in high-sensitivity 1H–15N correlation spectra, revealing direct contacts between povidone and the API. The API domain sizes within the formulations were determined by measuring the variation of ε as a function of the polarization time and numerically modeling nuclear spin diffusion. Here we measure an API particle radius of 0.3 μm with a single particle model, while modeling with a Weibull distribution of particle sizes suggests most particles possess radii of around 0.07 μm.
Publication Date
January 10, 2014
Publisher Statement
Reprinted (adapted) with permission from Journal of the American Chemical Society,136(6); 2324-2334. Doi: 10.1021/ja4092038. Copyright 2014 American Chemical Society.
Citation Information
Aaron J. Rossini, Cory M. Widdifield, Alexandre Zagdoun, Moreno Lelli, et al.. "Dynamic Nuclear Polarization Enhanced NMR Spectroscopy for Pharmaceutical Formulations" Journal of the American Chemical Society Vol. 136 Iss. 6 (2014) p. 2324 - 2334
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