Solid-state nuclear magnetic resonance (NMR) spectroscopy provides powerful information about local atomic structure in solids. 13C is by far the most frequently utilized nucleus for the analysis of pharmaceuticals. Other NMR-active nuclei in organic compounds and hydrochloride pharmaceuticals such as 14/15N, 17O and 35Cl are less commonly observed due to their unfavorable NMR properties that result in low sensitivity (viz. low natural abundance and/or high quadrupolar couplings). Furthermore, currently utilized onedimensional techniques offer minimal information regarding spatial proximities between atoms. Recently, the solid-state NMR field has been revolutionized by sensitivity enhancement approaches such as fast magic angle spinning and proton (1H) detection or dynamic nuclear polarization (DNP). In this contribution, we show how fast magic angle spinning (MAS), 1H detection and DNP can be used to accelerate the acquisition of 14/15N, 17O and 35Cl solid-state NMR spectra. The solid-state NMR methods presented here will improve structural characterization of pharmaceuticals via NMR crystallography approaches.
First, we present recently developed fast magic angle spinning (MAS) and 1H detection approaches such as frequency-selective (FS) heteronuclear multiple quantum coherence (HMQC) and FS resonance-echo saturation-pulse double-resonance (RESPDOR) NMR experiments to accelerate the acquisition of 2D 1H-14N heteronuclear correlation (HETCOR) spectra and distance measurements, respectively.1 These methods are used to distinguish salts and cocrystals in multicomponent active pharmaceutical ingredients (APIs).1 Notably, we show that 1H-14N distances and hence NH bond lengths can be measured in minutes. Next, we use DNP-enhanced 2D HETCOR NMR techniques with 1H, 13C, 15N, and 35Cl to probe the locations of chloride ions in HCl pharmaceuticals.
Alternatively, fast MAS proton detection methods also facilitate the rapid characterization of 35Cl sites. These techniques allow the measurement of 13C-35Cl and 1H-35Cl distances, respectively, which agree well with plane-wave DFT calculations. Finally, 17O NMR of organic compounds has hitherto been impossible without isotopic enrichment, due to the very low natural abundance of the 17O isotope (0.038%). Here, we show that DNP can facilitate the acquisition of natural abundance 17O NMR spectra of organic compounds in reasonable experimental times of 4-10 hours. In samples containing multiple, overlapping 17O sites such as salicylic acid, we show that the two sites can be resolved based on the differences in 1H chemical shifts by obtaining a 2D 1H-17O spectrum at natural abundance.
References: 1. Wijesekara, A. V.; Venkatesh, A.; Lampkin, B. J.; VanVeller, B.; Lubach, J. W.; Nagapudi, K.; Hung, I.; Gor’kov, P. L.; Gan, Z.; Rossini, A. J. Fast Acquisition of Proton-Detected HETCOR Solid-State NMR Spectra of Quadrupolar Nuclei and Rapid Measurement of NH Bond Lengths by Frequency Selective HMQC and RESPDOR Pulse Sequences. Chem. Eur. J. 2020, 26 (35), 7881-7888.