Simultaneous determination of cyclodextrin stability constants as a function of pH and temperature – A tool for drug formulation and process design

Lisa Samuelsen, René Holm*, Jens Christian Sidney Schönbeck

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

Abstract

The stability constant for complex formation is an important physicochemical property used to guide drug formulation development with cyclodextrins. Complex formation depends on both pH and temperature, factors often altered during pharmaceutical processing and manufacturing. Hence, their influence on the stability constant must be considered during drug formulation to define a robust formulation and manufacturing process. This work demonstrated how a mechanistic model, based upon physical chemical laws, for the apparent stability constant as a simultaneous function of pH and temperature accurately could estimate the apparent stability constant for cyclodextrin complexes. The model required multiple thermodynamic inputs, i.e. the pK a value of guest and buffer, measured stability constants for the cyclodextrin complex, the change in enthalpies and the change in heat capacities. A comprehensive set of isothermal titration calorimetry data for β-CD:ibuprofen at six different pH values and four temperatures were compared to the model calculations. A good agreement was observed between the experimental data and the modelled data, indicating that the model could be used to predict the stability constant at any pH and temperature. The model can be used as an important tool during drug formulation and process design to optimize formulation work with cyclodextrins.

Original languageEnglish
Article number102675
JournalJournal of Drug Delivery Science and Technology
Volume65
ISSN1773-2247
DOIs
Publication statusPublished - Oct 2021

Keywords

  • Drug robustness
  • Equilibrium constant
  • Host-guest chemistry
  • Ionization
  • Surface plot
  • van't hoff equation
  • Cyclodextrin
  • Binding constant
  • pH
  • Model
  • Temperature

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