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 (PQ) 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.