Origin of non-linearity in phase solubility: solubilisation by cyclodextrin beyond stoichiometric complexation

Area of Science:

• Pharmaceutical Science
• Physical Chemistry
• Thermodynamics

Background:

• Low drug solubility is a major challenge in pharmaceutical development.
• Cyclodextrins (CDs) are widely used to improve drug solubility via inclusion complex formation.
• The linear relationship predicted by the Higuchi-Connors model often deviates in practice.

Purpose of the Study:

• To elucidate the underlying thermodynamic mechanisms causing non-linear drug solubility curves with cyclodextrins.
• To explain deviations from the expected linear relationship in drug-cyclodextrin systems.

Main Methods:

• Application of rigorous statistical thermodynamic theories, specifically Kirkwood-Buff and McMillan-Mayer theories.
• Analysis of solution theories to model drug-cyclodextrin interactions and their impact on solubility.

Main Results:

• Drug solubility enhancement by cyclodextrins is not solely due to 1:1 inclusion complexation.
• Non-linearity in solubility curves is explained by the interplay of cyclodextrin-drug interactions.
• Drug-induced alterations in cyclodextrin-cyclodextrin interactions also contribute significantly to solubility behavior.

Conclusions:

• The study provides a theoretical framework for understanding complex non-linear drug solubility behavior with cyclodextrins.
• This understanding is crucial for optimizing drug formulation and development strategies.
• The findings highlight the importance of considering multi-component interactions in drug-solubilizer systems.