Correlation between the stability constant and pH for β-cyclodextrin complexes

Lisa Samuelsen, René Holm, Audrey Lathuile, Jens Christian Sidney Schönbeck

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

In drug formulations, cyclodextrins are used to increase aqueous solubility and chemical stability of drugs via formation of inclusion complexes. For ionizable drug molecules, the complexation strength depends on pH. Increased ionization leads to a more soluble drug, but also results in destabilization of cyclodextrin complexes. Therefore, formulation scientists aim to find a balance between increased drug solubility and high complexation strength. In this work, a theoretical expression for the dependency between the stability constant and pH is presented, allowing the accurate prediction of the stability constant at any pH. The theoretical expression requires three out of four input parameters; the pKa of the free guest molecule, the pKa of the complex, and the stability constants for the neutral and fully ionized complex. Stability constants for β-cyclodextrin and ibuprofen complexes were determined by isothermal titration calorimetry at seven pH values (2.5–5.5) and four temperatures (15–55 °C). All these measured stability constants complied with the theoretical expression. Ten additional data sets from the literature comprising eight different drug molecules and three different cyclodextrins confirmed the ability of the theoretical expression to account for the observed pH-dependence of stability constants.
Original languageEnglish
Article number118523
JournalInternational Journal of Pharmaceutics
Volume2019
Issue number568
ISSN0378-5173
DOIs
Publication statusPublished - 2019

Keywords

  • pH-dependency
  • Equilibrium constant
  • Guest molecule
  • Hydrophobic interactions
  • Ionization
  • Drug formulation

Cite this

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title = "Correlation between the stability constant and pH for β-cyclodextrin complexes",
abstract = "In drug formulations, cyclodextrins are used to increase aqueous solubility and chemical stability of drugs via formation of inclusion complexes. For ionizable drug molecules, the complexation strength depends on pH. Increased ionization leads to a more soluble drug, but also results in destabilization of cyclodextrin complexes. Therefore, formulation scientists aim to find a balance between increased drug solubility and high complexation strength. In this work, a theoretical expression for the dependency between the stability constant and pH is presented, allowing the accurate prediction of the stability constant at any pH. The theoretical expression requires three out of four input parameters; the pKa of the free guest molecule, the pKa of the complex, and the stability constants for the neutral and fully ionized complex. Stability constants for β-cyclodextrin and ibuprofen complexes were determined by isothermal titration calorimetry at seven pH values (2.5–5.5) and four temperatures (15–55 °C). All these measured stability constants complied with the theoretical expression. Ten additional data sets from the literature comprising eight different drug molecules and three different cyclodextrins confirmed the ability of the theoretical expression to account for the observed pH-dependence of stability constants.",
keywords = "pH-dependency, Equilibrium constant, Guest molecule, Hydrophobic interactions, Ionization, Drug formulation",
author = "Lisa Samuelsen and Ren{\'e} Holm and Audrey Lathuile and Sch{\"o}nbeck, {Jens Christian Sidney}",
year = "2019",
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language = "English",
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journal = "International Journal of Pharmaceutics",
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Correlation between the stability constant and pH for β-cyclodextrin complexes. / Samuelsen, Lisa; Holm, René; Lathuile, Audrey; Schönbeck, Jens Christian Sidney.

In: International Journal of Pharmaceutics, Vol. 2019, No. 568, 118523, 2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Correlation between the stability constant and pH for β-cyclodextrin complexes

AU - Samuelsen, Lisa

AU - Holm, René

AU - Lathuile, Audrey

AU - Schönbeck, Jens Christian Sidney

PY - 2019

Y1 - 2019

N2 - In drug formulations, cyclodextrins are used to increase aqueous solubility and chemical stability of drugs via formation of inclusion complexes. For ionizable drug molecules, the complexation strength depends on pH. Increased ionization leads to a more soluble drug, but also results in destabilization of cyclodextrin complexes. Therefore, formulation scientists aim to find a balance between increased drug solubility and high complexation strength. In this work, a theoretical expression for the dependency between the stability constant and pH is presented, allowing the accurate prediction of the stability constant at any pH. The theoretical expression requires three out of four input parameters; the pKa of the free guest molecule, the pKa of the complex, and the stability constants for the neutral and fully ionized complex. Stability constants for β-cyclodextrin and ibuprofen complexes were determined by isothermal titration calorimetry at seven pH values (2.5–5.5) and four temperatures (15–55 °C). All these measured stability constants complied with the theoretical expression. Ten additional data sets from the literature comprising eight different drug molecules and three different cyclodextrins confirmed the ability of the theoretical expression to account for the observed pH-dependence of stability constants.

AB - In drug formulations, cyclodextrins are used to increase aqueous solubility and chemical stability of drugs via formation of inclusion complexes. For ionizable drug molecules, the complexation strength depends on pH. Increased ionization leads to a more soluble drug, but also results in destabilization of cyclodextrin complexes. Therefore, formulation scientists aim to find a balance between increased drug solubility and high complexation strength. In this work, a theoretical expression for the dependency between the stability constant and pH is presented, allowing the accurate prediction of the stability constant at any pH. The theoretical expression requires three out of four input parameters; the pKa of the free guest molecule, the pKa of the complex, and the stability constants for the neutral and fully ionized complex. Stability constants for β-cyclodextrin and ibuprofen complexes were determined by isothermal titration calorimetry at seven pH values (2.5–5.5) and four temperatures (15–55 °C). All these measured stability constants complied with the theoretical expression. Ten additional data sets from the literature comprising eight different drug molecules and three different cyclodextrins confirmed the ability of the theoretical expression to account for the observed pH-dependence of stability constants.

KW - pH-dependency

KW - Equilibrium constant

KW - Guest molecule

KW - Hydrophobic interactions

KW - Ionization

KW - Drug formulation

U2 - 10.1016/j.ijpharm.2019.118523

DO - 10.1016/j.ijpharm.2019.118523

M3 - Journal article

VL - 2019

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

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ER -