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

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.