The unexpected increase of clotrimazole apparent solubility using randomly methylated β‐cyclodextrin |
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| Authors: | Bénédicte Pradines Jean‐François Gallard Bogdan I. Iorga Claire Gueutin Gilles Ponchel Philippe M. Loiseau Kawthar Bouchemal |
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| Affiliation: | 1. Institut Galien Paris Sud, UMR CNRS 8612, Université Paris‐Sud, Faculté de Pharmacie, Chatenay‐Malabry cedex, France;2. BioCis, Biomolécules : conception, isolement, synthèse‐Chimiothérapie Antiparasitaire, UMR CNRS 8076, Université Paris‐Sud, Faculté de Pharmacie, Chatenay‐Malabry cedex, France;3. Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif‐sur‐Yvette, Gif‐sur‐Yvette, France |
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| Abstract: | Clotrimazole (CTZ) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility were obtained from phase solubility diagrams. β‐CD (1.5% w/w) and hydroxypropyl‐β‐CD (40% w/w) offered poor CTZ solubility enhancements (12 and 384 times, respectively). Unexpectedly, the apparent solubility of CTZ was 9980 times increased from 0.4 µg.mL?1 (1.42 μM) without CD to 4.89 mg.mL?1 (14.9 mM) using randomly‐methylated β‐CD (Me‐β‐CD) (40% w/w). This is the highest apparent CTZ solubility improvement ever reported in the literature using conventional CDs. Quantitative nuclear magnetic resonance (1H‐NMR) coupled with two‐dimensional nuclear Overhauser effect (NOESY) experiments and molecular docking calculations showed that the highest interactions with Me‐β‐CD were reported for CTZ two phenyl groups. A lower interaction was reported for chlorophenyl, while imidazole had the weakest interaction with Me‐β‐CD. Copyright © 2015 John Wiley & Sons, Ltd. |
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| Keywords: | clotrimazole cyclodextrins solubilization bidimensionnal 1H‐RMN molecular docking |
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