A rational approach towards development of amorphous solid dispersions: Experimental and computational techniques

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Computational Chemistry

Background:

• Drug-polymer miscibility is crucial for amorphous solid dispersion formulation performance.
• Understanding the interactions between active pharmaceutical ingredients (APIs) and polymers is key to developing stable and effective drug products.
• GENE-A and hydroxypropyl methylcellulose-acetate succinate (HPMC-AS) were selected for this study.

Purpose of the Study:

• To determine the drug-polymer miscibility of GENE-A and HPMC-AS.
• To evaluate the thermodynamic and kinetic aspects of their mixing behavior.
• To utilize both computational modeling and experimental techniques for a comprehensive analysis.

Main Methods:

• Computational approach: Calculation of Flory-Huggins interaction parameter (χ) and Gibbs free energy of mixing using Materials Studio.
• Experimental approach: Solid-state nuclear magnetic resonance (ssNMR) to measure proton relaxation times.
• Temperature range: 25-100°C for thermodynamic calculations; Room temperature (RT) and 40°C for ssNMR experiments.

Main Results:

• Thermodynamic modeling predicted favorable mixing with negative Gibbs free energy across the studied temperature range.
• ssNMR data showed near-identical proton relaxation times for GENE-A and HPMC-AS in solid dispersion.
• Evidence of nanoscale phase mixing (<10nm) was observed for the API and polymer up to 6 months.

Conclusions:

• Both computational and experimental results consistently indicate favorable phase mixing between GENE-A and HPMC-AS.
• The study confirms good miscibility of the drug-polymer system.
• This suggests potential for stable amorphous solid dispersions.