Self-association and cyclodextrin solubilization of drugs.

Area of Science:

• Pharmaceutical Sciences
• Physical Chemistry
• Drug Delivery Systems

Background:

• Phase-solubility diagrams are a common method for characterizing drug-cyclodextrin interactions.
• Linear (A(L)) and positive deviation (A(P)) diagrams are traditionally interpreted to indicate specific complex stoichiometries.
• Previous assumptions about interpreting these diagrams may be oversimplified.

Purpose of the Study:

• To investigate the reliability of phase-solubility diagrams for determining drug/cyclodextrin complex stoichiometry.
• To explore the behavior of various drugs and cyclodextrins, including charged and uncharged variants.
• To identify potential limitations and alternative complexation mechanisms.

Main Methods:

• Construction and analysis of phase-solubility diagrams for diverse drug compounds and cyclodextrins.
• Investigation of cholesterol, ibuprofen, diflunisal, alprazolam, 17beta-estradiol, and diethylstilbestrol.
• Comparison with Job's plots and molecular docking studies.

Main Results:

• Phase-solubility diagrams for cholesterol showed A(P) type, but did not fit higher-order cyclodextrin complexation with charged cyclodextrins.
• Ibuprofen and diflunisal diagrams suggested 2:1 drug/cyclodextrin complexes (A(L) type), contradicting 1:1 findings from other methods.
• Drug/cyclodextrin complexes can self-associate into soluble aggregates, facilitating further drug solubilization via non-inclusion complexation.

Conclusions:

• Simple phase-solubility studies are insufficient for accurately determining drug/cyclodextrin complex stoichiometry.
• Complex self-association and non-inclusion complexation play significant roles in drug solubilization.
• A more comprehensive approach is needed to understand drug-cyclodextrin interactions.