NMR Crystallography at 1 GHz: Insight into a Rich World of Binary Forms of Meloxicam

NMR crystallography, which is based on both diffraction- and solid-state NMR-based observables, can deliver a precise description of the crystal structure of powdered samples of pharmaceuticals. On the other hand, it is by no means a straightforward technique, not least because of the overcrowding of solid-state NMR spectra and difficulties in reliably assigning all resonances, even when advanced 2D techniques are applied. In this work, we showcase the advantages of using very high magnetic field spectrometers in NMR crystallography to solve the structural puzzles posed by four new binary forms of meloxicam (MLX), an anti-inflammatory drug. In particular, we revealed a hidden disorder in the scXRD-determined crystal structure of one of the polymorphic forms of MLX with pyrazole (POL). In this instance, we discovered, through the use of ¹⁵N solid-state NMR data, that there is an exchange between two possible tautomeric forms, and by calculating the weighted average of ¹⁵N shielding constants, we determined the occupancy of the disordered sites to be 70:30. For the next two binaries, with pyrazine (MLX:PNA) and imidazole in a 1:2 ratio (MLX:IMI 1:2), we solved their crystal structures from powder XRD data and determined the protonation state mainly through the use of quadrupolar product (P_Q) of ¹⁴N, derived from ¹H-¹⁴N T-HMQC experiments recorded at two different magnetic field strengths. The signal assignment was done with a set of ¹H-¹H DQ-SQ Back-to-Back, ¹H-¹³C and ¹H-¹⁵N HETCOR experiments. For MLX:PNA, we found a very unusual tautomer of MLX inside this crystal, the one which has not been found in any other MLX forms discovered so far. For MLX:IMI 1:2, we established it to be an ionic cocrystal. Finally, for the second MLX binary with imidazole in 1:1 ratio (MLX:IMI 1:1), we used solid-state NMR data to first unambiguously prove that this is a salt and that it comprises one of the two possible tautomers of the MLX anion. This enabled reliable crystal structure prediction calculations for this form, leading to its final crystal structure through Rietveld refinement against the experimental powder XRD pattern.