Soluble 1:1 complexes and insoluble 3:2 complexes - Understanding the phase-solubility diagram of hydrocortisone and γ-cyclodextrin

International Journal of Pharmaceutics
Christian SchönbeckThorsteinn Loftsson

Abstract

The molecular mechanisms underlying the drug-solubilizing properties of γ-cyclodextrin were explored using hydrocortisone as a model drug. The BS-type phase-solubility diagram of hydrocortisone with γ-cyclodextrin was thoroughly characterized by measuring the concentrations of hydrocortisone and γ-cyclodextrin in solution and the solid phase. The drug-solubilizer interaction was also studied by isothermal titration calorimetry from which a precise value of the 1:1 binding constant (K11=4.01mM-1 at 20°C) was obtained. The formation of water-soluble 1:1 complexes is responsible for the initial increase in hydrocortisone solubility while the precipitation of entities with a 3:2 ratio of γ-cyclodextrin:hydrocortisone is responsible for the plateau and the ensuing strong decrease in solubility once all solid hydrocortisone is used up. The complete phase-solubility diagram is well accounted for by a model employing the 1:1 binding constant and the solubility product of the precipitating 3:2 entity (K32S=5.51 mM5). For such systems, a small surplus of γ-cyclodextrin above the optimum concentration may result in a significant decrease in drug solubility, and the implications for drug formulations are briefly discussed.

Citations

May 13, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Phennapha SaokhamThorsteinn Loftsson
Jan 5, 2019·Molecular Pharmaceutics·Christian SchönbeckBryan Houston
Jul 13, 2019·The Journal of Physical Chemistry. B·Christian Schönbeck, René Holm

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