Cyclodextrin inclusion as a pharmaceutical reaction field: kinetic, pathway and structural control beyond equilibrium

Area of Science:

• Physical Chemistry
• Pharmaceutical Sciences
• Supramolecular Chemistry

Background:

• Cyclodextrins (CDs) are common pharmaceutical excipients.
• Traditional evaluation uses equilibrium thermodynamics.
• Many degradation pathways (oxidation, photochemistry) occur under nonequilibrium conditions, not explained by binding constants alone.

Purpose of the Study:

• To present CDs as molecular reaction fields that control reaction kinetics and pathways.
• To illustrate how CDs modulate kinetic accessibility, pathway competition, and structural distributions.
• To provide a framework for understanding formulation-dependent stability and designing CD-based stabilization strategies under nonequilibrium conditions.

Main Methods:

• Review of representative systems demonstrating CD control.
• Integration of kinetic analysis and time-resolved spectroscopy.
• Application of multivariate approaches, including singular value decomposition (SVD).

Main Results:

• CDs modulate reaction behavior beyond simple equilibrium complexation.
• Demonstrated kinetic suppression of radical encounters (e.g., edaravone oxidation).
• Observed pathway reorganization in photochemistry (e.g., ketoprofen) and structural equilibrium bias (e.g., avobenzone).

Conclusions:

• CDs function as molecular-scale reaction fields influencing reaction dynamics.
• This perspective is crucial for understanding and predicting drug stability in formulations.
• Offers design principles for leveraging CDs to enhance drug stability under dynamic, nonequilibrium conditions.