35Cl–1H Heteronuclear correlation magic-angle spinning nuclear magnetic resonance experiments for probing pharmaceutical salts

Abstract

Heteronuclear multiple-quantum coherence (HMQC) pulse sequences for establishing heteronuclear correlation in solid-state nuclear magnetic resonance (NMR) between 35Cl and 1H nuclei in chloride salts under fast (60 kHz) magic-angle spinning (MAS) and at high magnetic field (a 1H Larmor frequency of 850 MHz) are investigated. Specifically, recoupling of the 35Cl–1H dipolar interaction using rotary resonance recoupling with phase inversion every rotor period or the symmetry-based SR421 pulse sequences are compared. In our implementation of the population transfer (PT) dipolar (D) HMQC experiment, the satellite transitions of the 35Cl nuclei are saturated with an off-resonance WURST sweep, at a low nutation frequency, over the second spinning sideband, whereby the WURST pulse must be of the same duration as the recoupling time. Numerical simulations of the 35Cl–1H MAS D-HMQC experiment performed separately for each crystallite orientation in a powder provide insight into the orientation dependence of changes in the second-order quadrupolar-broadened 35Cl MAS NMR lineshape under the application of dipolar recoupling. Two-dimensional 35Cl–1H PT-D-HMQC MAS NMR spectra are presented for the amino acids glycine·HCl and l-tyrosine·HCl and the pharmaceuticals cimetidine·HCl, amitriptyline·HCl and lidocaine·HCl·H2O. Experimentally observed 35Cl lineshapes are compared with those simulated for 35Cl chemical shift and quadrupolar parameters as calculated using the gauge-including projector-augmented wave (GIPAW) method: the calculated quadrupolar product (PQ) values exceed those measured experimentally by a factor of between 1.3 and 1.9.