Crosslinking: An avenue to develop stable amorphous solid dispersion with high drug loading and tailored physical...

Area of Science:

• Pharmaceutical Sciences
• Materials Science

Background:

• Amorphous solid dispersions (ASDs) are crucial for improving the solubility and bioavailability of poorly soluble drugs.
• Ketoconazole (KTZ) is a model antifungal drug often formulated as an ASD.
• Controlling molecular mobility and physical stability of ASDs is key for effective drug delivery.

Purpose of the Study:

• To investigate the influence of crosslinking on the molecular mobility and physical stability of ketoconazole (KTZ) ASDs.
• To evaluate the impact of crosslinker concentration and crosslinking conditions on KTZ ASD properties.
• To assess the effect of crosslinking on drug release and supersaturation.

Main Methods:

• Preparation of KTZ ASDs with high drug loading (95% w/w) using thermal crosslinking.
• Investigation of molecular mobility using rheological measurements (viscosity) and dynamic mechanical analysis (α-relaxation time).
• Assessment of physical stability through crystallization inhibition studies and exposure to elevated temperature and humidity.
• Dissolution studies to evaluate drug release and supersaturation generation.

Main Results:

• Increased crosslinker concentration progressively decreased molecular mobility (increased viscosity and α-relaxation time).
• Higher crosslinker concentration and elevated crosslinking temperature significantly enhanced physical stability and inhibited crystallization.
• Formulated ASDs exhibited pronounced stability under challenging conditions (heat, humidity).
• Crosslinked systems generated and maintained drug supersaturation for extended periods during dissolution.

Conclusions:

• Crosslinking density is an effective strategy to enhance the physical stability of high-drug-loading ASDs.
• Crosslinking offers a tunable method to control molecular mobility and drug release kinetics.
• The developed crosslinked KTZ ASDs demonstrate superior stability and improved dissolution performance.