1174325-91-7Relevant articles and documents
The role of pH and dose/solubility ratio on cocrystal dissolution, drug supersaturation and precipitation
Cardoso, Simone Gon?alves,Kuminek, Gislaine,Machado, Tatiane Cogo,Rodríguez-Hornedo, Naír
, (2020)
Cocrystals that are more soluble than the constituent drug, generate supersaturation levels during dissolution and are predisposed to conversion to the less soluble drug. Drug release studies during cocrystal dissolution generally compare several cocrystals and their crystal structures. However, the influence of drug dose and solubility in different dissolution media has been scarcely reported. The present study aims to investigate how drug dose/solubility ratio (Do=Cdose/Sdrug), cocrystal solubility advantage over drug (SA=Scocrystal/Sdrug), and dissolution media affect cocrystal dissolution-drug supersaturation and precipitation (DSP) behavior. SA and Ksp values of 1:1 cocrystals of meloxicam-salicylic acid (MLX-SLC) and meloxicam-maleic acid (MLX-MLE) were determined at cocrystal/drug eutectic points. Results demonstrate that both cocrystals enhance SA by orders of magnitude (20 to 100 times for the SLC and over 300 times for the MLE cocrystal) in the pH range of 1.6 to 6.5. It is shown that during dissolution, cocrystals regulate the interfacial pH (pHint) to 1.6 for MLX-MLE and 4.5 for MLX-SLC, therefore diminishing the cocrystal dissolution rate dependence on bulk pH. Do values ranged from 2 (pH 6.5) to 410 (pH 1.6) and were mostly determined by the drug solubility dependence on pH. Drug release profiles show that maximum supersaturation (σmax=Cmax/Sdrug)and AUC increased with increasing Do as pH decreased. When Do>>SA, the cocrystal solubility is not sufficient to dissolve the dose so that a dissolution-precipitation quasi-equilibrium state is able to sustain supersaturation for the extent of the experiment (24 h). When Domax values (1.7 and 1.5) near the value of Do (2.3 and 2.4) were observed, where a large fraction of the cocrystal added is dissolved to reach σmax. Two different cocrystal to drug conversion pathways were observed: (1) surface nucleation of the metastable MLX polymorph IV on the dissolving cocrystal preceeded formation of the stable MLX polymorph I in bulk solution (in all conditions without FeSSIF), and (2) bulk nucleation of the stable MLX polymorph (in FeSSIF). The interplay between cocrystal SA, Do, and drug precipitation pathways provide a framework to interpret and understand the DSP behavior of cocrystals.
MELOXICAM CO-CRYSTALS
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Page/Page column 31, (2020/06/01)
Co-crystals of meloxicam co-formers can be prepared by co-crystallization from a polar solvent, such as aqueous dimethyl sulfoxide; or by slurry processes, such as with ethyl acetate. Such co-crystals have improved purities and are physically stable under storage for several months.
Supramolecular architectures of meloxicam carboxylic acid cocrystals, a crystal engineering case study
Cheney, Miranda L.,Weyna, David R.,Shan, Ning,Hanna, Mazen,Wojtas, Lukasz,Zaworotko, Michael J.
experimental part, p. 4401 - 4413 (2011/12/22)
Meloxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility and high permeability prescribed for indications of arthritis, primary dysmenorrhea, fever, and pain. In this contribution, we apply crystal engineering and the supramolecular synthon approach to prepare novel meloxicam cocrystal forms with various pharmaceutically acceptable or toxicologically qualified carboxylic acids. As a result, 19 pharmaceutical cocrystals including one cocrystal of a salt are synthesized by solid-state and solution methods. All resulting cocrystals are characterized by X-ray diffraction, infrared, and thermal analyses. In particular, crystal structures of six meloxicam cocrystals are determined and reported, namely, meloxicam?1-hydroxy-2-naphthoic acid cocrystal (1), meloxicam?glutaric acid cocrystal (2), meloxicam?l- malic acid cocrystal of a salt (3), meloxicam?salicylic acid cocrystal form III (4), meloxicam?fumaric acid cocrystal (5), and meloxicam?succinic acid cocrystal (6). The supramolecular assembly of each cocrystal is analyzed and discussed. It is observed that the meloxicam dimer is robust since this motif is observed in five out of six meloxicam cocrystal structures that have been determined. As part of the continuous development, the resulting meloxicam cocrystal forms will be further investigated to explore improved physicochemical and pharmacological properties.
