Crystallization of Elusive Polymorphs of Meloxicam Informed by Crystal Structure Prediction

In this work, crystalstructure prediction (CSP) calculations wereused to guide the crystallization of three elusive polymorphic formsof meloxicam (MLX): II, III, and V. Despite having been discoveredover 20 years ago and described in terms of their powder X-ray diffractionpatterns, none of them were reported to be crystallized in a pureform by any researcher other than the authors of the original MLXpatent. Our numerous crystallization experiments to repeat the disclosedexamples failed and led us to employ CSP calculations to indicatepossible crystallization pathways to these forms. The obtained crystalenergy landscape featured primarily structures stabilized by NH & BULL;& BULL;& BULL;O Sdimers, present also in the most stable, commercially available crystalform of MLX, but several low-energy and low-density structures stabilizedby NH & BULL;& BULL;& BULL;N dimers were also found. As a result, it wassuggested to attempt (1) desolvation experiments which have a capacityto lead to low-density structures, (2) employing crystallization additiveswith the ability to influence hydrogen bond interactions, and (3)fast solvent removal techniques to promote kinetically stable forms.The performed experiments led to the crystallization of pure formsII, III, and V, in addition to the discovery of new MLX solvates andone cocrystal with pyrazole. Desolvation was found to be the besttechnique leading to elusive polymorphs. Solid-state NMR experimentsperformed for the obtained solids proved that in all three forms anNH & BULL;& BULL;& BULL;N hydrogen bond motif is present, as indicatedby CSP calculations. Crystalstructure prediction calculations were used to indicatethe most probable crystallization experiments of three polymorphsof meloxicam, leading to pure forms of these elusive solids.

Automated summary

Crystal structure prediction calculations were used to guide the crystallization of three elusive polymorphs of meloxicam. Through numerous failed experiments, possible crystallization pathways were identified using CSP calculations, leading to the successful crystallization of pure forms II, III, and V.