DNP‐enhanced solid‐state NMR spectroscopy of active pharmaceutical ingredients

Abstract

Solid-state NMR spectroscopy 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 one-dimensional (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, C- C double-quantum single-quantum homonuclear correlation NMR spectra of pure APIs can be routinely acquired. DNP also enables solid-state NMR experiments with unreceptive quadrupolar nuclei such as H, N, and Cl that are commonly found in APIs. Applications of DNP-enhanced solid-state NMR spectroscopy 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.

Materials Characterization by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy

“…Subsequently, relayed DNP was shown to be a general method to polarize microcrystalline organic solids, including pharmaceuticals. [46][47][48] Alternatively, DNP NMR was performed on amorphous solid dispersions (ASD) of pharmaceuticals and polymers by directly incorporating the PA during synthesis. 49 Relayed DNP has enabled a number of challenging solid-state NMR experiments on organic solids including natural isotopic abundance 2D double-quantum 13 C-13 C correlation ( Figure 5C Sn solid-state NMR spectra of Sn-β catalysts prepared by different synthetic procedures illustrate that the sample preparation greatly affects the distribution of tin-sites within the zeolite framework ( Figure 5D).…”

Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy

“…[44][45][46][47] In a modern DNP experiment the high spin polarization of unpaired electrons are transferred to NMR active nuclei, typically 1 H. [44][45][46][47] DNP can be used to hyperpolarize the 1 H nuclei in the interior of powdered microcrystalline solids, such as APIs, in an approach known as relayed DNP. [48][49][50][51][52] Typically, powdered organic solids are prepared for a relayed DNP experiment by grinding them to reduce particle size, then impregnating 53 the powders with a suitable liquid containing a dissolved radical polarizing agent. 49,52 The liquid used for the impregnation step must also be a non-solvent for the solid material and should also be compatible with DNP.…”

“…[48][49][50][51][52] Typically, powdered organic solids are prepared for a relayed DNP experiment by grinding them to reduce particle size, then impregnating 53 the powders with a suitable liquid containing a dissolved radical polarizing agent. 49,52 The liquid used for the impregnation step must also be a non-solvent for the solid material and should also be compatible with DNP. 54 During a relayed DNP experiment, DNP-enhanced 1 H polarization builds up at the surface of the impregnated particles 7 and is then transported into the interior of the particles by H spin diffusion.…”

“…54 During a relayed DNP experiment, DNP-enhanced 1 H polarization builds up at the surface of the impregnated particles 7 and is then transported into the interior of the particles by H spin diffusion. [48][49][50]52 Sensitivity gains of up to two orders of magnitude have been obtained for organic solids, including APIs, with the relayed DNP approach. [48][49][50][51][52] This has enabled solid-state NMR experiments on microcrystalline solids which were previously considered challenging or impossible.…”

“…[48][49][50]52 Sensitivity gains of up to two orders of magnitude have been obtained for organic solids, including APIs, with the relayed DNP approach. [48][49][50][51][52] This has enabled solid-state NMR experiments on microcrystalline solids which were previously considered challenging or impossible. For example, relayed DNP has also been applied to enhance the sensitivity of natural isotopic abundance 13 C and 15 N solid-state NMR experiments on formulated APIs with low drug loading 50 and enabled acquisition of dipolar and scalar 13 C-13 C homonuclear 49,50,55-58 and 13 C-15 N heteronuclear 2D correlation NMR spectra.…”