What Are the Important Factors That Influence API Crystallization in Miscible Amorphous API-Excipient Mixtures during...

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Physical Chemistry

Background:

• Amorphous solid dispersions (ASDs) and coamorphous systems are crucial for drug delivery, but their physical instability, particularly crystallization, poses challenges.
• Understanding the mechanisms of physical instability in amorphous active pharmaceutical ingredients (APIs) and the role of excipients in preventing crystallization is vital for drug product development.

Purpose of the Study:

• To examine factors influencing the long-term physical stability of amorphous API-excipient mixtures stored in the glassy state.
• To identify key parameters, specifically reduced molecular mobility and API-excipient interactions, that inhibit crystallization in amorphous solid dispersions.

Main Methods:

• Review of 78 studies reporting stable amorphous API-excipient systems stored below the glass transition temperature (Tg) for one year or more.
• Analysis of the impact of the difference between Tg and storage temperature (Tg - T) on physical stability.
• Investigation of molecular interactions (e.g., hydrogen bonding, proton transfer) using spectroscopic data.

Main Results:

• Significant physical stability was observed in 30 out of 78 studies even when Tg - T was less than 50 K (3-47 °C), indicating factors beyond reduced mobility are important.
• Molecular interactions like hydrogen bonding and disruption of API self-associations were prevalent in stable systems with Tg - T < 50 K.
• Crystallized systems often lacked detectable molecular interactions, even with substantial Tg - T values.

Conclusions:

• Long-term physical stability of amorphous solid dispersions depends on both reduced molecular mobility and specific API-excipient molecular interactions.
• Factors such as hydrogen bonding and disruption of API self-associations play a critical role in inhibiting crystallization, especially at temperatures closer to Tg.
• The impact of relative humidity and excipient water sorption on mobility and interactions must also be considered for robust formulation design.