Experimental and computational studies of physicochemical properties influence NSAID-cyclodextrin complexation

Area of Science:

• Pharmaceutical Sciences
• Physical Chemistry
• Computational Chemistry

Background:

• Poorly water-soluble drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), present formulation challenges.
• Cyclodextrins (CDs) are widely used to enhance the solubility and bioavailability of such drugs.
• Understanding the physicochemical basis of drug-cyclodextrin complexation is crucial for effective drug delivery.

Purpose of the Study:

• To investigate the physicochemical properties of active pharmaceutical ingredients (APIs) that influence cyclodextrin complexation.
• To evaluate the complexation ability of native beta-cyclodextrin (B-CD) and its hydroxypropyl derivatives with four NSAIDs.
• To explore the thermodynamics and geometry of drug-CD interactions using computational methods.

Main Methods:

• Phase solubility experiments were conducted to assess drug-cyclodextrin complexation.
• Differential scanning calorimetry (DSC) was used to confirm complex formation.
• Molecular modeling, including molecular dynamics simulations (MDS), was employed to estimate drug properties (Log P, S o) and analyze drug-CD docking thermodynamics and geometry.

Main Results:

• NSAID solubility increased with cyclodextrin concentration, showing an AL profile for derivatives and a plateau (type B profile) for native B-CD.
• Computational estimates of NSAID Log P and aqueous solubility (S o) correlated well with literature data.
• Complexation efficacy was primarily governed by the NSAID's chemical structure, not by B-CD side chain modifications.
• Molecular dynamics simulations revealed distinct geometries for each NSAID-CD complex and highlighted the dominant role of hydrophobic interactions in complex stabilization.

Conclusions:

• The chemical structure of the NSAID is the primary determinant of its complexation with cyclodextrins and the resulting solubility enhancement.
• While hydrophobic interactions significantly stabilize drug-CD complexes, electrostatic and solvation energies are smaller and more variable.
• These findings provide valuable insights for designing effective drug formulations using cyclodextrin complexation technology.