(623g) Unlocking Atomistic Insights: The Impact of Small Chemical Modifications on Crystal Polymorphism and Hydration Behavior

Chemical modifications of structurally related molecules often lead to distinct physicochemical properties, such as differences in crystallization tendencies, crystal polymorphism, and hydration behavior. However, the atomistic origins connecting molecular structure to these properties are not always well understood. This presentation describes two case studies demonstrating how small chemical changes influence three-dimensional (3-D) conformations, packing arrangements, and intermolecular interactions by combining computational chemistry with experimental approaches.

The first study focuses on the development challenges of ombitasvir and pibrentasvir. Using fully atomistic molecular dynamics (MD) simulations, we analyzed their conformational ensembles. The results revealed that ombitasvir exhibits a variety of conformations (cis/trans, cis/cis, trans/cis, and trans/trans) with easy interconversion between them, whereas pibrentasvir predominantly adopts cis/cis conformers. The difference in conformational flexibility had significant implications for drug development, particularly in crystallizability and crystal form complexity, making ombitasvir and pibrentasvir representative of key challenges in contemporary solid-state chemistry.

The second study investigates the phosphate prodrugs foslevodopa and foscarbidopa, which, despite their structural similarity, exhibit notable differences in crystal form complexity and hydration behavior. We identified specific conformational features that influence their polymorphism and examined solution-phase conformations that may drive crystallization. Using Crystal Structure Prediction (CSP), we predicted the stability relationships between crystal structures with varying water stoichiometries. Our findings demonstrate that intermolecular interactions play a key role in the formation of anhydrates and hydrates under different temperature and humidity conditions. This understanding was crucial for ensuring the consistent and robust delivery of the commercial drug substance during manufacturing.

All authors are employees of AbbVie and may own AbbVie stock. AbbVie sponsored and funded the study; contributed to the design; participated in the interpretation of data, review, and approval of the publication.