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

Resumé

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

Citer dette

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title = "Soluble 1:1 Complexes and Insoluble 3:2 Complexes: Understanding the Phase-Solubility Diagram of Hydrocortisone and γ-Cyclodextrin",
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.",
keywords = "Binding constant, Calorimetry, Cyclodextrin, Hydrocortisone, Inclusion complex, Phase-solubility, Binding constant, Calorimetry, Cyclodextrin, Hydrocortisone, Inclusion complex, Phase-solubility",
author = "Sch{\"o}nbeck, {Jens Christian Sidney} and Madsen, {Tobias L{\o}vgren} and Peters, {G{\"u}nther H.} and Ren{\'e} Holm and Thorsteinn Loftsson",
year = "2017",
doi = "10.1016/j.ijpharm.2017.05.024",
language = "English",
volume = "531",
pages = "504--511",
journal = "International Journal of Pharmaceutics",
issn = "0378-5173",
publisher = "Elsevier BV",
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Soluble 1:1 Complexes and Insoluble 3:2 Complexes : Understanding the Phase-Solubility Diagram of Hydrocortisone and γ-Cyclodextrin. / Schönbeck, Jens Christian Sidney; Madsen, Tobias Løvgren; Peters, Günther H.; Holm, René; Loftsson, Thorsteinn.

I: International Journal of Pharmaceutics, Bind 531, Nr. 2, 2017, s. 504-511.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Soluble 1:1 Complexes and Insoluble 3:2 Complexes

T2 - Understanding the Phase-Solubility Diagram of Hydrocortisone and γ-Cyclodextrin

AU - Schönbeck, Jens Christian Sidney

AU - Madsen, Tobias Løvgren

AU - Peters, Günther H.

AU - Holm, René

AU - Loftsson, Thorsteinn

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Binding constant

KW - Calorimetry

KW - Cyclodextrin

KW - Hydrocortisone

KW - Inclusion complex

KW - Phase-solubility

KW - Binding constant

KW - Calorimetry

KW - Cyclodextrin

KW - Hydrocortisone

KW - Inclusion complex

KW - Phase-solubility

U2 - 10.1016/j.ijpharm.2017.05.024

DO - 10.1016/j.ijpharm.2017.05.024

M3 - Journal article

VL - 531

SP - 504

EP - 511

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

IS - 2

ER -