Extreme Conditions Crystallography of Polymorphic Co-crystals

Abstract

This work has two principal sections. The first section is a study of the hydrogen bonding in a series of urea inclusion compounds, utilising neutron diffraction methods and a novel technique for growing neutron diffraction-suitable single crystals. The second section focusses on high pressure crystallography as a technique for exploring polymorphic landscapes, of a series of acid-base co-crystals, and the well-known active pharmaceutical ingredient 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY).
Single crystal neutron structures at several temperatures have been determined for -phase urea inclusion compounds containing hexadecane, 1,6-dibromohexane and 2,7-octanedione guests. The neutron structure of the ‘partial channel’ co-crystal of urea and DMF is also reported. This includes an in-depth discussion and analysis of the structure and bonding of this urea series, in particular, how the guest compound affects the symmetry and hydrogen bonding of the host urea network. Additionally, the challenge of obtaining crystals suitable for neutron diffraction is addressed and a new heating/cooling device to aid crystallisation is presented.
Pyridine and formic acid have been crystallised at differing ratios by both cryo-crystallisation and compression in a diamond anvil cell. Mixtures of the liquids in 1:1, 1:2 and 1:4 ratios all crystallise at high pressure, while only the 1:1 and 1:4 compositions were crystallised by in situ low temperature capillary crystallisation. The 1:2 structure crystallised by high pressure is a previously unknown co-crystal of pyridine - formic acid. For the 1:4 mixture, a new polymorph has been identified at a pressure of 14.2 kbar with a distinctly different structure and bonding pattern to that of the previously reported low temperature form.
Five new co-crystals of 2,6-dimethylpyridine (DMP) with formic acid (FA) were crystallised by application of pressure in a diamond anvil cell and by in situ cryo-crystallisation. Mixtures in ratios 1:1, 1:2 and 1:3 of DMP: FA have been crystallised via both methods. Both the 1:2 and 1:3 co-crystals exhibit high pressure/low temperature polymorphism.
ROY has been crystallised from acetone solution using a diamond anvil cell. The needle-like form obtained, named ONP shows similarities with the ORP, ON and Y forms, determined by Raman spectroscopy. The ONP crystals were recovered from the pressure cell by freezing with liquid nitrogen. Synchrotron X-ray data were collected on the sample, although no structure solution and refinement was possible. The unit cell of the ONP shows a crystallographic relationship to the ORP form.