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.