A Mechanistic Model for Predicting the Physical Stability of Amorphous Solid Dispersions

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Physical Chemistry

Background:

• Amorphous solid dispersions (ASDs) enhance drug bioavailability by dissolving as a supersaturated solution.
• However, amorphous active pharmaceutical ingredients (APIs) can recrystallize during storage, compromising stability.
• Stabilizing ASDs requires understanding and predicting the kinetics of API recrystallization.

Purpose of the Study:

• To develop and validate a mechanistic model for predicting the physical stability of amorphous solid dispersions (ASDs).
• To incorporate fundamental physical parameters and kinetic/thermodynamic drivers into ASD stability simulations.
• To assess the utility of the model in forecasting recrystallization over extended storage periods.

Main Methods:

• Developed a mechanistic model using coupled differential equations to describe nucleation and growth processes in ASDs.
• Incorporated key physical parameters: supersaturation, diffusivity, and interfacial energy.
• Utilized dynamic mechanical analysis and viscosity measurements to determine API-dependent decoupling coefficients and probe molecular mobility.
• Prepared ASDs using hot melt extrusion (HME) and stored them under controlled temperature conditions to observe recrystallization kinetics.

Main Results:

• The mechanistic model successfully predicted temporal ASD stability by linking physiochemical properties to drug recrystallization.
• Experimental recrystallization kinetics aligned well with the model's predictions.
• The study highlighted the critical importance of considering both thermodynamic and kinetic factors for stable ASD formulation.

Conclusions:

• The developed mechanistic model provides a robust framework for predicting ASD physical stability.
• The model's accuracy confirms its value in understanding and preventing API recrystallization in pharmaceutical formulations.
• This approach aids in the rational design of stable amorphous solid dispersions with enhanced bioavailability.