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The unexpected increase of clotrimazole apparent solubility using randomly methylated β-cyclodextrin
Bénédicte Pradines1, Jean-François Gallard, Bogdan I Iorga
1Institut Galien Paris Sud, UMR CNRS 8612, Université Paris-Sud, Faculté de Pharmacie, 5, rue J-B. Clément, 92296, Chatenay-Malabry cedex, France; BioCis, Biomolécules : conception, isolement, synthèse-Chimiothérapie Antiparasitaire, UMR CNRS 8076, Université Paris-Sud, Faculté de Pharmacie, 5, rue J-B. Clément, 92296, Châtenay-Malabry cedex, France.
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 ((1) H-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.
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