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

Christian Schönbeck, Tobias Løvgren Madsen, Günther H. Peters, René Holm, Thorsteinn Loftsson

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    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 Υ-cyclodextrin was thoroughly characterized by measuring the concentrations of hydrocortisone and Υ-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 (K 11 =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 Υ-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 Υ-cyclodextrin above the optimum concentration may result in a significant decrease in drug solubility, and the implications for drug formulations are briefly discussed.
    Original languageEnglish
    Article number504-511
    JournalInternational Journal of Pharmaceutics
    Volume531
    Issue number2
    ISSN0378-5173
    DOIs
    Publication statusPublished - 2017

    Keywords

    • Binding constant
    • Calorimetry
    • Cyclodextrin
    • Hydrocortisone
    • Inclusion complex
    • Phase-solubility

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