NMR Crystallography in Pharmaceutical Development

Abstract

NMR crystallography is the combined use of experimental solid-state nuclear magnetic resonance (NMR) with density-functional theory (DFT) calculation of NMR parameters for a structure, as obtained, for example, by complementary diffraction or crystal structure prediction (CSP) approaches. We give an overview of how NMR crystallography can be applied to active pharmaceutical ingredients (APIs) and their formulations, including considering polymorphism, solvates and hydrates, salt and co-crystal formation, and amorphous dispersions. Specifically, the use of the gauge-including projector augmented wave (GIPAW) method, as implemented, for instance, in CASTEP or Quantum Espresso, is widely employed to calculate NMR chemical shifts for nuclei such as 1H, 13C, 14/15N, 19F, and 35Cl, as well as quadrupolar parameters for spin I ≥ 1 nuclei such as 14N and 35Cl, complementing experimental data obtained using magic-angle spinning (MAS). We describe the application of key MAS NMR experiments such as cross-polarisation (CP) MAS, notably for polymorph fingerprinting and determination of the number of distinct molecules in the asymmetric unit cell (Z′), and 1H-based two-dimensional experiments including heteronuclear correlation and double-quantum (DQ) MAS. Experiments probing internuclear dipolar couplings provide structural insight via identifying specific atomic proximities and determining specific distances and characterise dynamic processes via quantitative measurement of dipolar couplings.