Thermodynamic Modeling of Solvent-Impact on Phase Separation in Amorphous Solid Dispersions during Drying

Area of Science:

• Pharmaceutical Sciences
• Chemical Engineering
• Materials Science

Background:

• Amorphous solid dispersions (ASDs) are key pharmaceutical formulations produced via solvent-based processes.
• Unwanted liquid-liquid phase separation during drying can lead to heterogeneities and affect drug bioperformance.
• The impact of solvent choice on ASD drying and product quality is often overlooked in process design.

Purpose of the Study:

• To investigate the phase behavior and drying process of API/polymer/solvent systems from a thermodynamic perspective.
• To predict and validate phase changes during the drying of ASDs.
• To understand the influence of solvent mixtures on ASD formation and stability.

Main Methods:

• Thermodynamic modeling using the PC-SAFT (Perturbed-Chain Statistical Associating Fluid Theory) model.
• Prediction of phase behavior and drying curves for specific API/polymer/solvent systems.
• Validation of model predictions using confocal Raman spectroscopy.

Main Results:

• The study successfully predicted phase behavior and drying curves for ASDs containing hydroxypropyl methylcellulose acetate succinate and naproxen.
• Acetone/water and ethanol/water solvent mixtures were investigated, revealing distinct drying behaviors.
• Confocal Raman spectroscopy validated the thermodynamic model's predictions, confirming its utility in understanding ASD formation.

Conclusions:

• Thermodynamic modeling provides valuable insights into preventing phase separation during ASD drying.
• Understanding solvent-specific phase behavior is critical for designing robust and reproducible ASD manufacturing processes.
• This approach aids in optimizing ASD formulations to ensure consistent drug product quality and bioperformance.