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

23 Pages Posted: 5 Jan 2020 Sneak Peek Status: Review Complete

See all articles by Andrew Tyler

Andrew Tyler

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry

Ronnie Ragbirsingh

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry

Charles James McMonagle

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry

Paul Gordon Waddell

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry

Sarah Elizabeth Heaps

University of Newcastle - School of Mathematics, Statistics and Physics

Jonathan William Steed

Durham University - Department of Chemistry

Paul Thaw

TTP Labtech Ltd.

Michael John Hall

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry

Michael Richard Probert

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry

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Abstract

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.

Keywords: crystallisation, single crystal X-ray diffraction, ENaCt, polymorph, ROY, dithianon, uncrystallisable

Suggested Citation

Tyler, Andrew and Ragbirsingh, Ronnie and McMonagle, Charles James and Waddell, Paul Gordon and Heaps, Sarah Elizabeth and Steed, Jonathan William and Thaw, Paul and Hall, Michael John and Probert, Michael Richard, High-Throughput Oil-Encapsulated Nanodroplet Crystallisation for Organic-Soluble Small Molecule Structure Elucidation and Polymorph Screening (December 27, 2019). CHEMJOURNAL-D-19-01297. Available at SSRN: https://ssrn.com/abstract=3509916 or http://dx.doi.org/10.2139/ssrn.3509916
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Andrew Tyler

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry ( email )

Newcastle on Tyne
United Kingdom

Ronnie Ragbirsingh

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry ( email )

Newcastle on Tyne
United Kingdom

Charles James McMonagle

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry ( email )

Newcastle on Tyne
United Kingdom

Paul Gordon Waddell

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry ( email )

Newcastle on Tyne
United Kingdom

Sarah Elizabeth Heaps

University of Newcastle - School of Mathematics, Statistics and Physics ( email )

Newcastle on Tyne
United Kingdom

Jonathan William Steed

Durham University - Department of Chemistry ( email )

Old Elvet
Mill Hill Lane
Durham, DH1 3HP
United Kingdom

Paul Thaw

TTP Labtech Ltd. ( email )

Melbourn
United Kingdom

Michael John Hall (Contact Author)

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry ( email )

Newcastle on Tyne
United Kingdom

Michael Richard Probert

University of Newcastle, School of Natural and Environmental Sciences, Department of Chemistry ( email )

Newcastle on Tyne
United Kingdom

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