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This work aims to explore crystal structures of binary forms of meloxicam using advanced NMR techniques.

March 14, 2026Molecular Pharmaceutics0 citationsOpen Access

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

PNPrzemysław NowakPolish Mother’s Memorial Hospital Research Institute AJAgata JeziornaLodz University of Technology MOMarcin OszajcaJagiellonian University

Key Points

This work aims to explore crystal structures of binary forms of meloxicam using advanced NMR techniques.
Utilized high magnetic field NMR spectrometers
Analyzed multiple binary forms of meloxicam using solid-state NMR and powder XRD
Calculated occupancy levels of disordered sites
Examined unique tautomers through variety of NMR experiments
Revealed hidden disorder in the crystal structure of meloxicam with pyrazole
Determined occupancy of disordered sites as 70:30
Identified an unusual tautomer in meloxicam with pyrazine
Established ionic cocrystal structure for meloxicam with imidazole

Abstract

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.

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