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, Z' = 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 NH₂¹H 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 HH 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.