Continuous Chiral Resolution by Integration of Membrane and Crystallisation Technologies

Applications are invited for a PhD project on Continuous Chiral Resolution by Integration of Membrane and Crystallisation Technologies.

Amino acids, enzymes and cell receptors are chiral. Chiral molecules occur in left-handed and right-handed configurations that can be considered as mirror images (enantiomers), and that, like hands, cannot be superimposed onto each other. Therefore, most pharmaceuticals and pesticides, which usually act on enzymes and cell receptors, are chiral. Despite their similarity, the biological activity of pharmaceutical enantiomers can be completely different. This is exemplified by the drug Thalidomide (Softenon): one of the enantiomers prevents morning sickness during pregnancy whereas the other enantiomer influences embryonic development and resulted in children with malformed limbs.

Chiral resolution, the process to obtain enantiopure molecules, will increase its already sizeable importance in the pharmaceutical industry where future drug products will be larger and contain more chiral centres while their quality and purity will need to meet increasingly stringent demands. However, separation of these enantiomers in highly pure crystalline products from a complex multicomponent mixture is a challenge.

Although continuous membrane technologies could potentially be used to achieve enantiomer enrichment, they cannot reach enantiomer purity levels close to 100%. While crystallisation-enabled Resolution can be highly effective and efficient due to the near-perfect selectivity of the solid phase, it relies on the formation of a conglomerate mixture of enantiopure crystals from a racemic solution. However, in racemic solutions, only 5-10% of the chiral compounds form such conglomerates while the majority of the chiral compounds form a racemic compound, crystals in which both enantiomers are present in equal amounts.

The PhD project aims at combining and integrating membrane technologies for resolution with crystallisation-enabled resolution technologies. Starting from a racemic solution, the membranes will provide enantiomer enrichment which, through crystallisation, will lead to enantiopurity. The pharmaceutical industry has adopted continuous manufacturing processes as the way forward and this project will deliver approaches and tools for integrated continuous membrane crystallisation enhanced resolution processes.

Within the PhD project we will first evaluate the continuous crystallisation behaviour of enantiomers in various levels of enantiomeric excess. In parallel we will construct process models to be used for optimization and control of the membrane crystallisation process. Then, we will design, construct and operate the process integration of membrane cascade and crystallisation to achieve enhanced resolution.

The project runs within the international network between Joop ter Horst’s group at the University of Strathclyde, Jia Wei Chew’s group in the Singapore Membrane Technology Centre in the School of Chemical and Biomedical Engineering (SCBE) of the Nanyang Technological University (NTU) in Singapore and the group of Richard Lakerveld on model-based simulation and optimization at the HKUST in Hong Kong. Secondments will be provided by Jia Wei Chew (NTU) on the integration of the membrane cascade and crystallisation and Richard Lakerveld (HKUST) on process modelling of the integrated system.

This project aligns with CMAC Future Manufacturing Research Hub (www.cmac.ac.uk) located in state-of-the-art labs in the Technology & Innovation Centre.

This project can highly benefit from the cooperation with the Marie Skłodowska-Curie Innovative Training Network Continuous Resolution and Deracemization of Chiral Compounds by Crystallization (CORE), coordinated by Professor Joop ter Horst www.coreitn.eu. The CORE Network brings together 8 academic and 7 industrial partners from 6 European countries resulting in an unparalleled combination of chirality, synthesis and crystallization training and research covering the areas of Chemical Engineering, Chemistry and Applied Physics.

Techniques to be used:

The student will experience an intense research environment as their project is aligned to CMAC/CORE/CPACT. The student will be a member of the CMAC Doctoral Training Centre and will undertake Strathclyde’s Postgraduate Certificate in Researcher Professional Development (PG Cert RPD). The student will contribute to monthly group meetings, with weekly one-on-one specific meetings with supervisors Ter Horst and Nordon.

The student can access a large suite of high quality research equipment within CMAC, present their work at national and international conferences and take part in local research days such as the CMAC open days and CPACT Research Days.