Solid-State NMR Analysis of a Boron-Containing Pharmaceutical Hydrochloride Salt

Abstract

A novel crystalline form of the boron-containing antibacterial drug (S)-3-(aminomethyl)-7-(3-hydroxypropoxy)benzo[c] [1,2]oxaborol-1(3H)-ol hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) and single-crystal X-ray diffraction techniques. After determination of the crystal structure by X-ray diffraction, SSNMR spectroscopy of this form is performed to obtain structural information using experimental approaches based on dipolar correlation, chemical shift analysis, and quadrupolar interaction analysis. 1H SSNMR experiments at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling, 2D SSNMR experiments based on (1)H–(13)C and (1)H–(11)B dipolar heteronuclear correlation, and density functional theory (DFT) calculations are combined in a novel approach to obtain a nearly complete assignment of the (1)H spectrum of this crystalline phase. (11)B and (35)Cl chemical shift and quadrupolar parameters are obtained using the analysis of MAS spectra and are found to be accurately reproduced using DFT calculations. NMR chemical shielding and electric field gradient parameters obtained using these methods are related to hydrogen-bonding trends in the crystal structure. The results illustrate the increasing capability of SSNMR techniques involving (1)H, (11)B, and (35)Cl SSNMR in the analysis of the crystal structure of a pharmaceutical compound containing covalently bonded boron.