Encapsulated Nanodroplet Crystallization of Organic-Soluble Small Molecules

Andrew R Tyler; Ronnie Ragbirsingh; Charles J McMonagle; Paul G Waddell; Sarah E Heaps; Jonathan W Steed; Paul Thaw; Michael J Hall; Michael R Probert

doi:10.1016/j.chempr.2020.04.009

Encapsulated Nanodroplet Crystallization of Organic-Soluble Small Molecules

Chem. 2020 Jul 9;6(7):1755-1765. doi: 10.1016/j.chempr.2020.04.009.

Authors

Andrew R Tyler¹, Ronnie Ragbirsingh¹, Charles J McMonagle¹, Paul G Waddell¹, Sarah E Heaps², Jonathan W Steed³, Paul Thaw⁴, Michael J Hall¹, Michael R Probert¹

Affiliations

¹ Chemistry, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
² School of Mathematics, Statistics and Physics, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
³ Department of Chemistry, Durham University, Durham DH1 3LE, UK.
⁴ SPT Labtech, Melbourn Science Park, Melbourn, Hertfordshire SG8 6HB, UK.

Abstract

Single-crystal X-ray diffraction analysis (SCXRD) constitutes a universal approach for the elucidation of molecular structure and the study of crystalline forms. However, the discovery of viable crystallization conditions remains both experimentally challenging and resource intensive in both time and the quantity of analyte(s). We report a robot-assisted, high-throughput method for the crystallization of organic-soluble small molecules in which we employ only micrograms of analyte per experiment. This allows hundreds of crystallization conditions to be screened in parallel with minimal overall sample requirements. Crystals suitable for SCXRD are grown from nanoliter 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 crystallization methodology can also be used to search for new crystal forms, as exemplified through both our discovery of a new (13^th) polymorph of the olanzapine precursor ROY and SCXRD analysis of the "uncrystallizable" agrochemical dithianon.

Keywords: ENaCt; ROY; X-ray diffraction; crystallization; dithianon; high-throughput; oil encapsulation; polymorph; single crystal; small molecule.