Soluble 1:1 Complexes and Insoluble 3:2 Complexes: Understanding the Phase-Solubility Diagram of Hydrocortisone and γ-Cyclodextrin

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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.
OriginalsprogEngelsk
TidsskriftInternational Journal of Pharmaceutics
Vol/bind531
Udgave nummer2
Sider (fra-til)504-511
Antal sider8
ISSN0378-5173
DOI
StatusUdgivet - 2017

Emneord

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

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