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Lookup NU author(s): Jessica Metherall, Professor Mike ProbertORCiD, Dr Michael HallORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Co-crystals are composed of two or more chemically inequivalent molecular species, excluding solvents, generally in a stoichiometric ratio. Co-crystals are particularly important in pharmaceutical development, where a suitable co-crystal can significantly improve the physiochemical and pharmacokinetic properties of an active pharmaceutical ingredient. However, co-crystal discovery remains both practically challenging and resource intensive, requiring the extensive searching of complex experimental space. Herein, we demonstrate a high-throughput (HTP) nanoscale co-crystallisation method for the rapid screening of large areas of co-crystallisation space with minimal sample requirements, based on Encapsulated Nanodroplet Crystallisation (ENaCt). HTP co-crystallisation screening by ENaCt allowed rapid access to all 18 possible binary co-crystal combinations of 3 small molecules and 6 co-formers (A/B), through the use of 3,456 individual experiments exploring solvent, encapsulating oil and stoichiometry, including 10 novel binary co-crystal structures elucidated by single crystal X-ray diffraction (SCXRD). Higher-order co-crystal (HOC) discovery, accessing co-crystals containing three or more molecules, is one of the most challenging co-crystal research areas, due to the highly complex experimental landscape that must be navigated. Herein, we further exemplify the power of ENaCt co-crystallisation by applicaton to HOC discovery. HTP ENaCt co-crystallisation screening of three component (A/B/C) and four component (A/B/C/D) combinations gave ready access to both ternary and quaternary HOCs, each containing three or four different molecular species respectively. In total, 13,056 individual ENaCt experiments are presented resulting in 54 co-crystal structures by SCXRD, including 17 novel binary co-crystals, 8 novel ternary co-crystals and 4 novel quaternary co-crystals. ENaCt co-crystallisation is thus demonstrated to be a highly impactful and efficient tool in the search for small molecule co-crystals, through the employment of parallelised HTP nanoscale experimental workflows.
Author(s): Metherall JP, Corner PA, McCabe JF, Probert MR, Hall MJ
Publication type: Article
Publication status: Published
Journal: Chemical Science
Year: 2025
Pages: epub ahead of print
Online publication date: 22/04/2025
Acceptance date: 21/04/2025
Date deposited: 30/04/2025
ISSN (electronic): 2041-6539
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/D4SC07556K
DOI: 10.1039/D4SC07556K
Data Access Statement: The data supporting this article have been included as part of the ESI. CCDC 2372065-2372114, 2428848-2428851 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structure.
Notes: preprint on ChemRxiv DOI: 10.26434/chemrxiv-2024-40s32
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