Conformational Self-Poisoning in Crystal Growth

Liu, Yumin; Marinova, Veselina; Davey, Roger J.; Gabriele, Benjamin; Salvalaglio, Matteo; Cruz-Cabeza, Aurora J.

Abstract

With the ever-increasing complexity of new drug compounds, their crystallization is becoming more challenging than ever. Controlling the crystallization of present and future drugs will remain a chimera unless we gain an improved understanding of the effects of molecular flexibility on crystal nucleation and growth at the molecular level. As a contribution to this understanding, we report here the growth kinetics of a series of diacids with chain lengths from 4 to 10 carbon atoms. These compounds are ideal for such a study since (a) they all crystallize as linear conformers, (b) their crystal structures are very similar across the series, and (c) their molecular flexibility increases with increasing chain length. Upon analysis of their crystal growth behavior, we stumbled upon a surprising finding: the growth of these crystals along the length increases linearly for the series up to the diacid containing seven carbon atoms, beyond which the rates drop dramatically. Such a dramatic decrease in growth rates at longer chain lengths cannot be explained by the crystal structure differences of the diacids. To gain further insights, we explored the conformational landscapes of two diacids in solution using well-tempered metadynamics simulations. With increasing chain length, the conformational landscape becomes more complex, with folded conformations becoming more important for long chain acids. Our simulations show that some of the minor conformers present in the solution act as potent crystal growth inhibitors (a phenomenon we refer to as conformational self-poisoning). To the best of our knowledge, this work represents the first report of conformational self-poisoning in crystal growth, with experimental evidence supported by a molecular-level mechanism. While this effect is bad news for crystallization scientists, who must work with complex flexible compounds, for these diacids, we show that selected solvents are able to disfavor the problematic conformers in the solution, turning off the self-poisoning effect.

Citation

Liu, Y., Marinova, V., Davey, R. J., Gabriele, B., Salvalaglio, M., & Cruz-Cabeza, A. J. (2025). Conformational Self-Poisoning in Crystal Growth. JACS Au, 5(4), 1781-1790. https://doi.org/10.1021/jacsau.5c00043

• Journal Article Type: Article
• Acceptance Date: Mar 4, 2025
• Online Publication Date: Mar 18, 2025
• Publication Date: Apr 28, 2025
• Deposit Date: May 13, 2025
• Publicly Available Date: May 13, 2025
• Journal: JACS Au
• Print ISSN: 2691-3704
• Electronic ISSN: 2691-3704
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 4
• Pages: 1781-1790
• DOI: https://doi.org/10.1021/jacsau.5c00043
• Keywords: self-poisoning, growth inhibition, crystal growth, molecular flexibility, metadynamics
• Public URL: https://durham-repository.worktribe.com/output/3901167