Ionic salt cocrystals studied via multinuclear solid-state magnetic resonance: a case study of lithium 4-methoxybenzoate:L-proline polymorphs

Abstract

Lithium salts continue to find pharmaceutical applications, particularly as psychiatric medications. As with any active pharmaceutical ingredient, structural polymorphism is an important concern for lithium-based medications that can influence solubility and other physicochemical properties. Here we report a 13C, 1H, and 7Li magic-angle spinning solid-state nuclear magnetic resonance (MAS SSNMR) study of two 1:1 polymorphic ionic cocrystals of lithium 4-methoxybenzoate and L-proline (L4MPRO(α) and L4MPRO(β)). One-dimensional 13C cross-polarization MAS and two-dimensional heteronuclear correlation NMR spectra hint at differential mobilities of the proline and benzoate moieties for the two polymorphs. Five key resonances differ in 13C chemical shift by more than 1 ppm between the two polymorphs, clearly distinguishing between them. Gauge-including projector-augmented-wave density functional theory calculations of 13C and 1H magnetic shielding constants correlate strongly with the experimental chemical shifts for both polymorphs. R2 and root-mean-square deviation metrics are shown to be insufficient in the case of 13C, but sufficient in the case of 1H, for differentiating between the polymorphs. 7Li satellite-transition MAS NMR of both polymorphs are identical, as are the computed lithium magnetic shielding constants, demonstrating the insensitivity of 7Li NMR to polymorphism in these samples. This work highlights the utility of solid-state NMR spectroscopy for examining ionic salt cocrystals and also highlights some caveats in this regard.