(W1230-01-05) Early-Stage Polymer Selection in Development of Stable Amorphous Solid Dispersion by Integrating Molecular Dynamics Simulation and Experimental Techniques

Purpose: Amorphous solid dispersion (ASD) is an attractive formulation strategy for active pharmaceutical ingredients (API) with poor solubility. Development of ASD requires selection of a polymer that can form a stable ASD, which is a time, cost, and material-intensive effort.

Methods: In this contribution, we demonstrate the use of molecular modeling tools such as molecular dynamics (MD) simulation in conjunction with experimental techniques to help prioritize polymers that are likely to form stable ASDs. The predicted results were validated through a comprehensive characterization of ASDs using PXRD (powder X-ray Diffraction), ssNMR (solid-state nuclear magnetic resonance spectroscopy), and DSC (differential scanning calorimetry).  We further characterized the intermolecular interactions in ASD using FTIR and density functional theory-based IR calculations.

Results: We found that free energy of mixing calculated using MD, where API and polymer interactions are explicitly modeled, is an important descriptor that can rank the polymers from most to least favorable ASD in terms of thermodynamic stability.  Based on the experimental melting point depression (including Flory-Huggins estimates of free energy of mixing) and accelerated stability studies, we found that the MD-based free energy of mixing results was able to correctly identify favorable and unfavorable set of polymer candidates that can form thermodynamically stable ASDs. FTIR and density functional theory-based IR calculations showed that the ASDs indeed exhibit drug-polymer interactions at a molecular level. In addition, intermolecular interactions were found to be different across ASDs.

Conclusion: Although we demonstrated promising results based on a novel in-house API and across several polymers, we hope this work attracts more interest in utilizing and further validating MD more routinely for early-stage polymer selection in a fast-paced drug-development process.