Crystallisation in Structured Ternary Fluids for Enhanced Control


   Department of Chemistry

  ,  Applications accepted all year round  Funded PhD Project (UK Students Only)

About the Project

In crystallisation from solution, a ubiquitous process in both industry and the natural world, nucleation is usually the rate-determining step, followed by much faster crystal growth. Consequently, crystals typically exist in the nm-size range for such limited times that our understanding of the crystallisation process, and hence our ability to control it, remains limited. This is readily apparent from the Ritonavir crisis of 1998, where the drug Ritonavir, used for the treatment of HIV, became ineffective as the formulation had transformed into a more stable, and less soluble, crystalline form. The crisis arose from the failure to obtain the thermodynamically most stable form of the Ritonavir drug from standard crystallisation methods. This problem still remains. However, we have discovered a simple and practical solution to these problems: the use of structured ternary fluids.

Structured ternary fluids (STFs) consist of two immiscible liquids, typically an oil and water, and a hydrotrope, e.g. ethanol, that is miscible with both liquids. Our pioneering studies1 in this new area have revealed unique kinetics of higher nucleation rate / slower crystal growth in STFs that help enable enhanced crystallisation control. In particular, STFs can be used to create numerous crystal nuclei that grow sufficiently slowly past the nm-size range that the required crystalline form can be targeted.

This PhD will capitalise on our pioneering studies with the aim of demonstrating unprecedented crystallisation control in STFs under ambient conditions of both organic compounds (e.g. pharmaceutical compounds) and inorganic materials (e.g. titania, graphite, quartz). The aim will be to show that STFs provide the capabilities of (i) identifying the stable crystalline form to prevent a future Ritonavir-type disaster by forcing the crystallisation to occur under thermodynamic control, (ii) identifying metastable crystalline forms that provide beneficial properties, such as increased rate of drug dissolution and bioavailability, and (iii) crystallising under ambient conditions inorganic compounds, such as quartz and graphite, which normally only form under high temperatures and pressures. The project will also seek to expand the scope of ternary and multicomponent systems to crystallisation in topical deep eutectic solvents, a relatively new class of ionic fluids physicochemically similar to ionic liquids (e.g. choline chloride/urea). The experimental work in this project will proceed in close collaboration with computational investigations that are already underway in the Chemistry Department at Durham University. The project will involve training in all the key experimental techniques that an industrial solid-state chemist and researcher needs, including X-ray diffraction, thermal analysis, IR and Raman spectroscopy and electron microscopy.

Durham University has particular strengths in crystallisation and soft matter. It hosts the Durham Centre for Soft Matter and an EPSRC Centre for Doctoral Training in soft matter (SOFI2) together with the Universities of Leeds and Edinburgh. Durham University's collegiate system offers all students further opportunities for interdisciplinary and extracurricular activities. Durham itself is a picturesque medieval city in northeast England, centred on a World Heritage Site consisting of the 11th century Castle (now part of the University) and Durham Cathedral.

Chemistry (6) Engineering (12)

References

1) J. J. Maunder, J. A. Aguilar, P. Hodgkinson and S. J. Cooper, Chem. Sci., 2022, 13, 13132.

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