Discovering the Solid-State Secrets of Lorlatinib by NMR Crystallography: To Hydrogen Bond or not to Hydrogen Bond

Lorlatinib is an active pharmaceutical ingredient (API) used in the treatment of lung cancer. Here, an NMR crystallography analysis is presented whereby the single-crystal X-ray diffraction structure (CSD: 2205098) determination is complemented by multinuclear (1H, 13C, 14/15N, 19F) magic-angle spinning (MAS) solid-state NMR and gauge-including projector augmented wave (GIPAW) calculation of NMR chemical shifts. Lorlatinib crystallises in the P21 space group, with two distinct molecules in the asymmetric unit cell, Z0 = 2. Three of the four NH2 hydrogen atoms form intermolecular hydrogen bonds, N30-H...N15 between the two distinct molecules and N30-H...O2 between two equivalent molecules. This is reflected in one of the NH2 1H chemical shifts being significantly lower, 4.0 ppm compared to 7.0 ppm. Two-dimensional 1H-13C, 14N-1H and 1H (double-quantum, DQ)-1H (single-quantum, SQ) MAS NMR spectra are presented. The 1H resonances are assigned and specific H & DBLBOND;& DBLBOND;H proximities corresponding to the observed DQ peaks are identified. The resolution enhancement at a 1H Larmor frequency of 1 GHz as compared to 500 or 600 MHz is demonstrated.& COPY; 2023 The Authors. Published by Elsevier Inc. on behalf of American Pharmacists Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Automated summary

Lorlatinib is an active pharmaceutical ingredient used to treat lung cancer. This study presents the NMR crystallography analysis of Lorlatinib, combining single-crystal X-ray diffraction structure determination, solid-state NMR, and NMR chemical shift calculation. The crystal structure of Lorlatinib is described, including the presence of intermolecular hydrogen bonds. The study also demonstrates the resolution enhancement in MAS NMR at a higher Larmor frequency.