Guiding excipient selection for physically stable amorphous solid dispersions: A combined in-vitro in-silico...

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Computational Chemistry

Background:

• Fast screening of amorphous solid dispersions (ASDs) is crucial for pharmaceutical development.
• Existing methods like in-silico prediction and high-throughput experimentation lack comparative data.
• A challenge remains in predicting the physical stability of ASDs under various conditions.

Purpose of the Study:

• To propose and validate a combined miniaturized high-throughput screening (HTS) and computational approach for ASDs.
• To evaluate the physical stability of ASDs using experimental and in-silico methods.
• To correlate computational predictions with experimental observations for ASD stability.

Main Methods:

• Miniaturized HTS of ASDs using polarized light microscopy (PLM) to determine instability onset time.
• Calculation of activity coefficients via conductor-like screening model for real solvents (COSMO-RS) to assess drug-polymer interactions.
• Estimation of wet glass transition temperature (Tg) to account for molecular mobility.

Main Results:

• The combined in-vitro/HTS and in-silico strategy demonstrated an 87% alignment with experimental ASD instability.
• Physical stability is significantly impacted by low molecular mobility and strong drug-polymer interactions.
• COSMO-RS calculations accurately predicted interactions and molecular mobility relevant to ASD stability.

Conclusions:

• The developed strategy offers a reliable method for early-stage industrial screening of ASDs.
• This approach supports the understanding that molecular mobility and drug-polymer interactions are key to ASD physical stability.
• The combined in-vitro/HTS and in-silico method can accelerate pharmaceutical formulation development.