35Cl solid-state NMR of HCl salts of active pharmaceutical ingredients: structural prediction, spectral fingerprinting and polymorph recognition

Abstract

A series of HCl salts of active pharmaceutical ingredients (APIs) have been characterized via³⁵Cl solid-state NMR (SSNMR) spectroscopy and first-principles plane-wave density functional theory (DFT) calculations of ³⁵Cl NMR interaction tensors. ³⁵Cl NMR spectra have been acquired at both standard (9.4 T) and high (21.1 T) magnetic field strengths, on stationary samples and under conditions of magic-angle spinning (MAS). The ³⁵Cl electric field gradient (EFG) and chemical shift (CS) tensor parameters are readily extracted from analytical simulations of these spectra. These parameters are distinct for each sample, indicating that these spectra can be used as fingerprints for identifying unique solid phases. It is possible to correlate the ³⁵Cl EFG parameters (the quadrupolar coupling constant, C_Q, and the asymmetry parameter, η_Q) to the hydrogen-bonding environments of each chlorine anion, and several simple trends are observed. ³⁵Cl EFG tensors obtained from plane-wave DFT calculations are found to be in good agreement with experiment, and unique structural insights are gained by considering the predicted EFG tensor orientations and the signs of the quadrupolar coupling constants. ³⁵Cl SSNMR can be easily applied for the differentiation of polymorphs of HCl APIs, since the spectra are sensitive to even the subtlest changes in the chlorine anion environments. We discuss the application of this combination of techniques as both standalone and complementary NMR crystallography methodologies for structural characterization and potential high-throughput screening of polymorphs of HCl APIs.