Combined effect of cosolvent and cyclodextrin on solubilization of nonpolar drugs.
Solubility enhancement has broad implications in parenteral formulation design. A simple mathematical model has been developed to describe the combined effect of cosolvency and complexation on nonpolar drug solubilization. The total drug solubility is determined by the summation of three drug species present in the solution: free drug [D], drug-ligand binary complex [DL], and drug-ligand-cosolvent ternary complex [DLC]. The proposed model established the dependencies of these three species upon the intrinsic drug solubility, [D(u)], the cosolvent solubilizing power, sigma, the binary and ternary intrinsic complexation constants, K(b)(int) and K(t)(int), and the cosolvent destabilizing powers for the binary and the ternary complexes, rho(b) and rho(t). A nonpolar solute, Fluasterone, is used to evaluate the newly generated equation. The model explains the decline in drug solubility produced by low cosolvent concentrations as well as the increase in the solubility produced by high cosolvent concentrations that are observed at all cyclodextrin concentrations.
Li
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Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, USA.
Zhao
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Yalkowsky
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D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000970:Antineoplastic Agents / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000737:chemistry*; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000737:chemistry; D000431:Ethanol / Q000737:chemistry; D007700:Kinetics; D008432:Mathematical Computing; D008956:Models, Chemical; D015203:Reproducibility of Results; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D047392:beta-Cyclodextrins
D000970:Antineoplastic Agents; D003505:Cyclodextrins; D012997:Solvents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000431:Ethanol; D003687:Dehydroepiandrosterone; C106219:5-androstene-16-fluoro-17-one