Hydrotropy: monomer-micelle equilibrium and minimum hydrotrope concentration

Area of Science:

• Physical Chemistry
• Pharmaceutical Sciences
• Solution Chemistry

Background:

• Hydrotropes are cosolvents that increase drug aqueous solubility.
• Their mechanism is often likened to micelle formation with a critical micelle concentration (CMC).
• Hydrotropes exhibit a minimum hydrotrope concentration (MHC) for solubilization, even without aggregation.

Purpose of the Study:

• To clarify the role of micellization in hydrotropy.
• To elucidate the origin of MHC in both aggregating and non-aggregating hydrotropes.
• To re-evaluate the traditional understanding of hydrotropy and MHC.

Main Methods:

• Rigorous Kirkwood-Buff (KB) theory of solutions.
• Analysis of hydrotrope-drug-water interactions.
• Comparison of micellar and non-micellar hydrotropy.

Main Results:

• Micellar hydrotropy is driven by preferential drug-hydrotrope interactions.
• Micelle formation can decrease solubilization efficiency per hydrotrope molecule.
• MHC arises from drug-induced hydrotrope self-association, not bulk solution structure.
• Hydrotrope self-aggregation in bulk solution prevents MHC.

Conclusions:

• The traditional analogy between hydrotropy and micellization requires revision.
• MHC's origin lies in the local solution structure around the drug molecule.
• Understanding hydrotropy necessitates focusing on solute-solvent interactions rather than bulk properties.