Applying Material Science Principles to Chemical Stability: Modelling Solid State Autoxidation in Mifepristone...

Area of Science:

• Solid-state chemistry
• Pharmaceutical sciences
• Materials science

Background:

• Crystal disorder from manufacturing affects drug stability.
• Autoxidative stability of disordered solid drugs is understudied.
• Mifepristone (MFP) serves as a model compound.

Purpose of the Study:

• Investigate the impact of crystal disorder on Mifepristone (MFP) autoxidation.
• Develop a predictive stability model for disordered MFP.
• Understand degradation pathways and kinetics.

Main Methods:

• Ball-milling to induce varying degrees of crystal disorder in MFP.
• Raman spectroscopy with partial least square (PLS) regression for quantifying disorder.
• Accelerated stability testing under various conditions (temperature, humidity).
• Liquid chromatography for evaluating degradation.
• Diffusion and Arrhenius models for kinetic analysis and prediction.

Main Results:

• Ball-milling created MFP samples with different levels of disorder/amorphous content.
• Observed competition between recrystallization and autoxidative degradation.
• Degradation kinetics were dependent on amorphous content and stability conditions.
• Developed a predictive model for MFP degradation using an extended Arrhenius equation.

Conclusions:

• Predictive stability models are useful for identifying autoxidative instability in non-crystalline/partially crystalline drugs.
• Amorphous phases in MFP are susceptible to degradation.
• Material science principles can identify drug product instability.