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Lookup NU author(s): Professor Mike ProbertORCiD, Dr Michael HallORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Polymorphism, when a substance can exist in more than one crystalline form yet return to the same liquid or solution phase, is characterized by differences in packing or molecular conformation. Polymorphs often exhibit differing physical properties, and are therefore particularly important in the development of materials and pharmaceuticals. However, gaining a thorough understanding of the solid-state landscape of a molecule requires exhaustive experimental screening of crystallization conditions, a particular challenge when using classical crystallization methods. We show that high-throughput Encapsulated Nanodroplet Crystallization (ENaCt) can enable the rapid and efficient exploration of the solid-state landscape of highly polymorphic molecules, through an in-depth study of 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile (ROY), the most polymorphic small molecule known. An ENaCt screen encompassing 1,536 individual crystallization experiments, spanning 320 unique conditions, resulted in direct access to single crystals, suitable for X-ray diffraction analysis, for all six of the known polymorphs accessible from solution (Y, R, YN, ON, ORP and R18). In addition, two polymorphs (Y04 and Y19) previously accessed only via melt and heteroseeded melt experiments, and a new polymorph of ROY (O22) were obtained. Furthermore, ENaCt screening resulted in the identification of the first ROY solvate (ROY•methyl anthranilate) and the first example of a ROY dimer, formed via in situ oxidation. ENaCt is thus shown to be an impactful tool for the experimental mapping of the solid-state landscape of highly polymorphic molecules and, through the discovery of a new polymorph O22, has ensured that tetradecamorphic ROY retains the record for the most polymorphic small molecule.
Author(s): Weatherson J, Probert MR, Hall MJ
Publication type: Article
Publication status: Published
Journal: Journal of the American Chemical Society
Year: 2025
Pages: epub ahead of print
Online publication date: 25/03/2025
Acceptance date: 18/03/2025
Date deposited: 26/03/2025
ISSN (print): 0002-7863
ISSN (electronic): 1520-5126
Publisher: American Chemical Society
URL: https://doi.org/10.1021/jacs.4c17826
DOI: 10.1021/jacs.4c17826
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