Exploring the salt–cocrystal continuum with solid-state NMR using natural-abundance samples: implications for crystal engineering

Abstract

The salt–cocrystal continuum is a well known phenomenon in crystal engineering and has been studied here in several multicomponent solids with solid-state NMR (700 MHz) using 15N-1H heteronuclear dipolar coupling. The measurement is made at ultrafast (60–70 kHz) magic angle spinning (MAS) frequency. The experiment is sensitive enough to determine the proton position even in a continuum situation and can be performed on minimal amounts of microcrystalline or even amorphous solids with natural-abundance 15N samples. Such a measurement gives reliable values of N—H distances and is therefore a direct indication of the position of the proton in the salt–cocrystal continuum. The crystal structures of the relevant solids have also been determined at a high level of accuracy and the results of the X-ray and NMR experiments are compared.

Exploring short strong hydrogen bonds engineered in organic acid molecular crystals for temperature dependent proton migration behaviour using single crystal synchrotron X-ray diffraction (SCSXRD)

“…[14][15][16] Solid-state proton transfer processes across HBs, including temperature dependent proton migration, are typically followed using neutron diffraction; a method which allows the unambiguous determination of H-atom positions and, often important in such studies, also reveals H-atom anisotropic displacement parameters (ADPs). 17 Other experimental methods such as 14 NQR (nuclear quadrupole resonance) spectroscopy, 18 X-ray photoelectron spectroscopy 19 and solidstate NMR 20,21 combined with computational methods 22,23 can offer alternatives to diffraction methods in determining H-atom positions. Recently, X-ray diffraction has been shown to be useful in such studies, notwithstanding the fact that the precision of the determination of H-atom parameters is lower.…”

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

“…Solid-state NMR spectroscopy is a powerful probe of molecular structure for cocrystals, salts and pure APIs. 8,[18][19][20][21] With regards to discriminating between salts and cocrystals, isotropic 15 N chemical shifts are very sensitive to the local environment of the nitrogen atoms and protonation usually induces a substantial shift to lower frequency as compared to the API free base, particularly for heterocyclic bases. 22-24 15 N solid-state NMR spectroscopy has been extensively applied to determine the protonation states of the basic nitrogen atoms of APIs within salts, cocrystals and other solid drug forms, such as amorphous solid dispersions.…”

“…30 Brown and co-workers also showed that solid-state 1 H- 15 N scalar attached proton tests (APT)/J-resolved experiments 31 could be used to definitively determine if a particular nitrogen was protonated and hence differentiate salts from cocrystals. 25 Very recently Desiraju and co-workers have applied proton detected, fast MAS, cross-polarization (CP) variable contact time (CP-VC) experiments to measure 1 H- 15 N dipolar couplings and interatomic distances in simple salts and cocrystals with natural isotopic abundance of 15 N. 8 1 H and 13 C chemical shifts, 2D 1 H-1 H homonuclear correlation and 2D 1 H- 13 C heteronuclear correlation (HETCOR) experiments have also proven useful to locate hydrogen atom positions and probe interactions between APIs and coformers. 20,26,[32][33][34] Brunklaus and co-workers have used 1 H and 13 C solid-state NMR experiments in combination with DFT calculations and powder X-ray diffraction (P-XRD) to solve the crystal structures of multicomponent solids.…”

“…25 Measurement of 1 H-15 N dipolar couplings with CP-VC experiments required 3 to 5 days per sample, even though fast MAS and proton detection were employed to boost sensitivity. 8 Schnell and Saalwachter applied proton detected 1 H-15 N transferred echo double resonance (TEDOR) experiments to measure N-H bond lengths in histidine•HCl•H 2 O, although, total experiment times were not provided. 41 High field dynamic nuclear polarization (DNP) has recently emerged as a method to enhance the sensitivity of solid-state NMR by several orders of magnitude.…”

The salt–cocrystal spectrum in salicylic acid–adenine: the influence of crystal structure on proton-transfer balance

“…Often research efforts have been focused on different solid forms of salt-cocrystal multicomponent systems. Because of the participation of diverse functional groups from different molecules in multicomponent crystals, the design and control of crystalline solids often faces significant challenges (Fischer et al, 2016;Golovnev et al, 2016;Rajput et al, 2017).…”