Dynamic nuclear polarisation enhanced N-14 overtone MAS NMR spectroscopy

Dynamic nuclear polarisation (DNP) has been used to obtain magic angle spinning (NOT)-N-14 (nitrogen-14 overtone) solid-state NMR spectra from several model amino acids, with both direct and indirect observation of the (NOT)-N-14 signal. The crystalline solids were impregnated with biradical solutions of organic liquids that do not dissolve the crystalline phase. The bulk phase was then polarized via H-1 spin diffusion from the highly-polarized surface H-1 nuclei, resulting in H-1 DNP signal enhancements of around two orders of magnitude. Cross polarisation from H-1 nuclei directly to the N-14 overtone transition is demonstrated under magic angle spinning, using a standard pulse sequence with a relatively short contact time (on the order of 100 ms). This method can be used to acquire N-14 overtone MAS powder patterns that match closely with simulated line shapes, allowing isotropic chemical shifts and quadrupolar parameters to be measured. DNP enhancement also allows the rapid acquisition of D-2 (NOT)-N-14 heteronuclear correlation spectra from natural abundance powder samples. H-1-(NOT)-N-14 HETCOR and C-13-(NOT)-N-14 HMQC pulse sequences were used to observe all single-bond H-N and C-N correlations in histidine hydrochloride monohydrate, with the spectra obtained in a matter of hours. Due to the high natural abundance of the N-14 isotope (99.6%) and the advantages of observing the overtone transition, these methods provide an attractive route to the observation of C-N correlations from samples at natural isotopic abundance and enable the high resolution measurement of N-14 chemical shifts and quadrupolar interaction parameters.

Dynamic Nuclear Polarization Enhanced NMR Spectroscopy for Pharmaceutical Formulations

David Lyndon Emsley, Aaron James Rossini

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 (epsilon) 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 C-13 and N-15 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 H-1-N-15 correlation spectra, revealing direct contacts between povidone and the API. The API domain sizes within the formulations were determined by measuring the variation of e as a function of the polarization time and numerically modeling nuclear spin diffusion. Here we measure an API particle radius of 0.3 mu m with a single particle model, while modeling with a Weibull distribution of particle sizes suggests most particles possess radii of around 0.07 mu m.

AMER CHEMICAL SOC2014

Solid-state NMR of a paramagnetic DIAD-Fe-II catalyst: Sensitivity, resolution enhancement, and structure-based assignments

David Lyndon Emsley, Yong Zhang

A general protocol for the structural characterization of paramagnetic molecular solids using solid-state NMR is provided and illustrated by the characterization of a high-spin FeII catalyst precursor. We show how good NMR performance can be obtained on a molecular powder sample at natural abundance by using very fast (> 30 kHz) magic angle spinning (MAS), even though the individual NMR resonances have highly anisotropic shifts and very short relaxation times. The results include the optimization of broadband heteronuclear (proton-carbon) recoupling sequences for polarization transfer; the observation of single or multiple quantum correlation spectra between coupled spins as a tool for removing the inhomogeneous bulk magnetic susceptibility (BMS) broadening; and the combination of NMR experiments and density functional theory calculations, to yield assignments.

AMER CHEMICAL SOC2006

Polymorphs of Theophylline Characterized by DNP Enhanced Solid-State NMR

David Lyndon Emsley, David Benjamin Roger Antoine Gajan, Arthur César Pinon, Aaron James Rossini

We show how dynamic nuclear polarization (DNP) enhanced solid-state NMR spectroscopy can be used to characterize polymorphs and solvates of organic solids. We applied DNP to three polymorphs and one hydrated form of the asthma drug molecule theophylline. For some forms of theophylline, sample grinding and impregnation with the radical-containing solution, which are necessary to prepare the samples for DNP, were found to induce polymorphic transitions or desolvation between some forms. We present protocols for sample preparation for solid-state magic-angle spinning (MAS) DNP experiments that avoid the polymorphic phase transitions in theophylline. These protocols include cryogrinding, grinding under inert atmosphere, and the appropriate choice of the impregnating liquid. By applying these procedures, we subsequently demonstrate that two-dimensional correlation experiments, such as H-1-C-13 and H-1-N-15 HETCOR or C-13-C-13 INADEQUATE, can be obtained at natural isotopic abundance in reasonable times, thus enabling more advanced structural characterization of polymorphs.

American Chemical Society2015