Dynamic nuclear polarization of amorphous and crystalline small molecules

Abstract

Solid-state NMR has emerged to become an important technique in the studies of pharmaceutical formulations consisting of active pharmaceutical ingredients (API) and excipients. Dynamic nuclear polarization (DNP), which improves NMR sensitivity by 2-3 orders of magnitude, can potentially reduce the necessary experimental time for formulations that have low API contents. However, conventionally DNP samples are prepared in cryoprotecting glassing agents such as glycerol/water or DMSO/water, which may not be suitable for studies of pharmaceuticals. In this thesis, we examined the performance of solvent-free DNP in amorphous and crystalline orthoterphenyl (OTP) in order to gauge the feasibility of applying DNP to pharmaceutical solid-state NMR experiments and to study the effect of inter-molecular structure, or lack thereof, on the DNP enhancement. We found that while DNP of amorphous OTP benefits from greater signal enhancement due to a more homogeneous distribution of radical polarization agent, DNP of crystalline OTP features better spectral resolution but requires heavy deuteration to attenuate proton relaxation. Further application of DNP to nanocrystalline acetaminophen embedded in cellulose membrane as an undissolved suspension in organic solvent was less successful due to the fast methyl group motion within the acetaminophen molecule. Deuterium NMR study of crystalline d₃-acetaminophen showed the methyl group relaxation time is significantly reduced at low temperature (109 K), which negatively impacts DNP performance. A topical review of recent developments on high-field (16.4 T) DNP, as well as updates on the temperature-jump DNP experiment and descriptions of several ²H NMR studies of molecular dynamics, are also presented as part of this thesis.