Characterizing Drug-Polymer Interactions in Aqueous Solution with Analytical Ultracentrifugation

Area of Science:

• Pharmaceutical Sciences
• Physical Chemistry

Background:

• Characterizing drug-polymer interactions is crucial for developing amorphous solid dispersions.
• Poorly water-soluble drugs often require advanced formulation strategies.
• Analytical ultracentrifugation (AUC) offers high-resolution insights into molecular interactions.

Purpose of the Study:

• To establish sedimentation velocity analytical ultracentrifugation (AUC) as a method for characterizing drug-polymer interactions in aqueous media.
• To investigate the interactions between ketoconazole (KTZ) and polymers like Soluplus and polyacrylic acid (PAA).
• To correlate observed drug-polymer interactions with in vitro dissolution behavior of amorphous solid dispersions.

Main Methods:

• Sedimentation velocity analytical ultracentrifugation (AUC) was employed to analyze drug-polymer mixtures in aqueous buffers.
• The sedimentation coefficient of ketoconazole (KTZ) was monitored in the presence of polyacrylic acid (PAA) and Soluplus.
• Isothermal titration calorimetry (ITC) and in vitro dissolution tests were used for comparative analysis.

Main Results:

• AUC revealed distinct interactions: KTZ-Soluplus showed a complete shift to faster sedimentation, while KTZ-PAA exhibited a split peak indicating free and bound drug.
• Analysis of carbamazepine with HPMCAS showed multiple drug-polymer species, mirroring the polymer's own sedimentation profile.
• AUC provided high hydrodynamic resolution, complementing ITC and dissolution data.

Conclusions:

• Sedimentation velocity AUC is a powerful tool for characterizing drug-polymer interactions in solution.
• These interactions influence the performance of amorphous solid dispersions, potentially prolonging drug supersaturation.
• AUC addresses a key challenge in understanding the dissolution mechanisms of advanced drug formulations.