Pharmaceuticals on the Nanoscale: Multi-dimensional Electron Diffraction of Organic Molecular Crystals

Abstract

In the pharmaceutical industry, an understanding of both the molecular structure and the microstructure of potential assets holds the key to controlling their physical and chemical properties. In turn, this may influence how a drug is manufactured or the dosage form via which it is delivered. To characterise these properties, the current ‘gold standards’ used by the industry include single crystal and powder X-ray diffraction alongside other bulk characterisation techniques. However, these techniques lack the ability to probe a sample on the nanoscale. Electron beams can be focused into nano-meter sized probes which means they can be used to study samples at a high spatial resolution. Three dimensional electron diffraction involves the acquisition of a tilt series from a crystallite which enables crystallographers to solve and refine crystal structures of small organic molecules from micron-sized crystals. To complement this, scanning electron diffraction involves the acquisition of a diffraction pattern at each probe position in real space using a converged beam. This can reveal sub-crystal nano-structures and defects which may enhance the understanding of solid-state behaviours which are key to drug development. Both of these techniques are able to reveal a wealth of structural information about a sample. As the next generation of dosage modalities include innovations in nanoengineering, access to spatially resolved structural information at the nanoscale will become increasingly important. In this thesis, the potential for the application of these electron diffraction techniques within the pharmaceutical industry is firstly reviewed, then demonstrated through three separate drug (or pharmaceutically-relevant) systems, namely: (1) in an amorphous solid dispersion of indomethacin, (2) in the purine base xanthine, and (3) in a long acting injectable of cabotegravir (GSK1265744).