Bioinspired co-crystals of Imatinib providing enhanced kinetic solubility
| Autor: | Cornelius Harlacher, Maude Reggane, Johannes Wiest, Marco Saedtler, Klaus Müller-Buschbaum, Bruno Galli, Sven H. Zottnick, Marcus Gutmann, Ina Dix, Lorenz Meinel, Philippe Piechon, Ulrike Holzgrabe |
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| Rok vydání: | 2018 |
| Předmět: |
Magnetic Resonance Spectroscopy
Chemistry Pharmaceutical Nucleation Pharmaceutical Science Biological Availability 02 engineering and technology 030226 pharmacology & pharmacy Permeability 03 medical and health sciences 0302 clinical medicine Phase (matter) Gallic Acid Solubility Dissolution Active ingredient Supersaturation Chemistry Water General Medicine 021001 nanoscience & nanotechnology Combinatorial chemistry Drug Liberation Membrane Imatinib mesylate Imatinib Mesylate Thermodynamics 0210 nano-technology Crystallization Biotechnology |
| Zdroj: | European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 128 |
| ISSN: | 1873-3441 |
| Popis: | Realizing the full potential of co-crystals enhanced kinetic solubility demands a comprehensive understanding of the mechanisms of dissolution, phase conversion, nucleation and crystal growth, and of the complex interplay between the active pharmaceutical ingredient (API), the coformer and co-existing forms in aqueous media. One blueprint provided by nature to keep poorly water-soluble bases in solution is the complexation with phenolic acids. Consequently, we followed a bioinspired strategy for the engineering of co-crystals of a poorly water-soluble molecule - Imatinib - with a phenolic acid, syringic acid (SYA). The dynamics of dissolution and solution-mediated phase transformations were monitored by Nuclear Magnetic Resonance (NMR) spectroscopy, providing mechanistic insights into the 60 fold-increased long lasting concentrations achieved by the syringate co-crystals as compared to Imatinib base and Imatinib mesylate. This lasting effect was linked to SYA's ability to delay the formation and nucleation of Imatinib hydrate - the thermodynamically stable form in aqueous media - through a metastable association of SYA with Imatinib in solution. Results from permeability studies evidenced that SYA did not impact Imatinib's permeability across membranes while suggesting improved bioavailability through higher kinetic solubility at the biological barriers. These results reflect that some degree of hydrophobicity of the coformer might be key to extend the kinetic solubility of co-crystals with hydrophobic APIs. Understanding how kinetic supersaturation can be shaped by the selection of an interactive coformer may help achieving the needed performance of new forms of poorly water-soluble, slowly dissolving APIs. |
| Databáze: | OpenAIRE |
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