Solubility Advantage (and Disadvantage) of Pharmaceutical Amorphous Solid Dispersions

Area of Science:

• Pharmaceutical Sciences
• Physical Chemistry
• Materials Science

Background:

• Drug solubility is critical for oral bioavailability.
• Amorphous solid dispersions (ASDs) enhance drug solubility but their behavior in the presence of water is complex.
• The undissolved solute phase in ASDs can be multicomponent (drug, polymer, water).

Purpose of the Study:

• To develop a thermodynamic model for calculating drug chemical potential in multicomponent amorphous systems.
• To estimate the true solubility advantage of ASDs using calorimetric measurements and moisture sorption isotherms.
• To investigate the effect of ASD formation and water partitioning on drug solubility using indomethacin/Eudragit E systems.

Main Methods:

• Development of a complete thermodynamic model for multicomponent amorphous systems.
• Calculation of drug chemical potential in the undissolved solute phase.
• Experimental studies using indomethacin (IMC)/Eudragit E ASDs.
• Calorimetric measurements and moisture sorption isotherms.

Main Results:

• The thermodynamic model accurately estimates the solubility advantage of ASDs.
• ASD formation and water partitioning significantly reduce the solubility advantage of amorphous indomethacin.
• At 70% drug loading, the solubility of IMC in the ASD was lower than its crystalline form.
• Drug solubility can be lowered by stabilization effects in ASDs.

Conclusions:

• Drug chemical potential is the core property governing ASD performance.
• The developed model quantifies drug chemical potential, providing a thermodynamic basis for ASD development.
• Water sorption and stabilization effects in ASDs can lead to reduced drug solubility.
• Understanding drug chemical potential is essential for optimizing ASD formulations.