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ENaCt crystallisation_preprint.pdf (765.67 kB)

High-Throughput Oil-Encapsulated Nanodroplet Crystallisation for Organic-Soluble Small Molecule Structure Elucidation and Polymorph Screening (ENaCt)

submitted on 13.12.2019, 16:50 and posted on 20.12.2019, 07:26 by Andrew Tyler, Ronnie Ragbirsingh, Charles McMonagle, Paul Waddell, Sarah Heaps, Jonathan Steed, Paul Thaw, Michael Hall, Michael Probert
Single crystal X-ray diffraction analysis (SCXRD) constitutes a universal approach for the elucidation of molecular structure and for the study of crystalline forms. However, the discovery of viable crystallisation conditions remains both experimentally challenging and resource intensive, in time and quantity of analyte(s). We report a robot-assisted, high-throughput method for the crystallisation of organic-soluble small molecules, employing only micrograms of analyte per experiment. This allows hundreds of crystallisation conditions to be screened in parallel, with minimal overall sample requirements. Crystals suitable for SCXRD analysis are grown from nanolitre droplets of a solution of analyte in organic solvent(s), each of which is encapsulated within an inert oil to control the rate of solvent loss. This encapsulated nanodroplet crystallisation methodology can also be used in the search for new crystal forms, as exemplified through both our discovery of a new (thirteenth) polymorph of the olanzapine precursor ROY and the SCXRD analysis of the “uncrystallisable” agrochemical dithianon.





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Newcastle University



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Declaration of Conflict of Interest

A.R.T., M.J.H. and M.R.P. have filed a patent application based on this work GB1908349.2