Solid state phase studies via 3D electron and high pressure X-ray diffraction

Abstract

The study of crystals and associated phase transitions has numerous applications in areas such as energy storage, optoelectronics and pharmaceuticals. Understanding and characterizing these crystals is central to any solid-state research activity and the screening of different polymorphs is an expensive and time-consuming activity. Recent improvements to hardware and software have fuelled developments in electron crystallography, where crystal structures from crystals with dimensions of less than 1 micron is possible. Presently, there are over 150 small molecular structures deposited on the Cambridge Structural Database and this number is rapidly increasing. An attractive feature of electron diffraction is the strong interaction of electrons with matter which allows characterization of sub-micron sized crystals as well as routine location of H atoms in the resulting Fourier difference map. One drawback is that as result of this strong interaction, the diffraction patterns can exhibit dynamical effects caused by multiple scattering events. Chapter 2 outlines a comprehensive and detailed workflow for collecting 3D electron diffraction (3D ED) data via the continuous rotation method on a Tecnai F20 transmission electron microscope. This developmental chapter describes sample preparation, data collection, and hardware and software usage. Successful data collection is detailed as well as structure refinement. Further developments and upgrades are also proposed to optimise the platform for routine data collection on micron and sub-micron crystallites.

Chapter 3 details how 3DED has been used to follow polymorph evolution in the crystallization of glycine from aqueous solution. The three polymorphs of glycine which exist under ambient conditions follow the stability order β < α < γ. The least stable β polymorph forms within the first three minutes, but this begins to yield the α-form after only one minute more.

Both structures could be determined from continuous rotation electron diffraction data collected in less than 20 seconds on crystals of thickness ∼100 nm. Even though the γ-form is thermodynamically the most stable polymorph, kinetics favours the α-form, which dominates after prolonged standing. In the same sample, some β and one crystallite of the γ polymorph were also observed.

Chapter 4 details how time-resolved carbamazepine crystallization from wet (‘bench‘) ethanol has been monitored using a combination of cryoTEM and 3D ED. Carbamazepine is shown to crystallize exclusively as a dihydrate after 180 seconds. When the timescale was reduced to 30 seconds, three further polymorphs could be identified. At 20 seconds, the development of early-stage carbamazepine dihydrate was observed through phase separation. This work reveals two possible crystallization pathways present in this active pharmaceutical ingredient.

Chapter 5 is a study of the crystal structure of Blatter’s radical (1,3- diphenyl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl) investigated between ambient pressure and 6.07 GPa. The sample remains in a compressed form of the ambient pressure phase up to 5.34 GPa, the largest direction of strain being parallel to direction of π-stacking interactions. The bulk modulus is 7.4(6) GPa, with a pressure derivative equal to 9.33(11). As pressure increases, the phenyl groups attached to the N1 and C3 positions of the triazinyl moieties of neighbouring pairs of molecules approach each other, causing the former to begin to rotate between 3.42 to 5.34 GPa. The onset of the phenyl rotation may be interpreted as a second order phase transition which introduces a new mode for accommodating pressure. It is premonitory to a first order, isosymmetric phase transition which occurs on increasing pressure from 5.34 to 5.54 GPa. Although the phase transition is driven by volume minimisation, rather than relief of unfavourable contacts, it is accompanied by a sharp jump in the orientation of the rotation angle of the phenyl group. DFT calculations suggest that the adoption of a more planar conformation by the triazinyl moiety at the phase transition is owed to relief of intramolecular H∙∙∙H contacts at the transition. Although no dimerization of the radicals occurs, the π- stacking interactions are compressed by 0.341(3) Å between ambient pressure and 6.07 GPa.

Chapter 6 details the response of two different polymorphs of Blatter’s radical derivatives to increasing pressure. The polymorphs’ principal differences are centred around how the π-stacks are formed from their respective symmetry elements, causing differences in the distribution of voids. Under increasing pressure, there is continuous change in the lattice parameters, with substantial compression via the π-stacks present in both polymorphs. Further analyses of the interacting dimers and unit-cell volume partitioning via Monte Carlo procedures reveal a subtle second order phase transition at 2.84 GPa. Preliminary calculations suggest the π-stacks’ compressibility in both polymorphs is due to the volume minimisation and hence free energy contribution.