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Continuous Resolution and Deracemization of Chiral Compounds by Crystallization

Periodic Reporting for period 2 - CORE (Continuous Resolution and Deracemization of Chiral Compounds by Crystallization)

Reporting period: 2018-10-01 to 2020-12-31

The CORE Network is a Marie Skłodowska-Curie European Training Network on Continuous Resolution and Deracemization of Chiral Compounds by Crystallization that ran from October 2016 to December 2020. The CORE Network brought together 14 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.

Most pharmaceutical and specialty compounds 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. Despite their similarity, the biological activity of left- and right-handed molecules can be completely different because of the homochirality of nature. This is exemplified by the drug Thalidomide (Softenon) that was developed by the pharmaceutical company Chemie Grünenthal some 60 years ago: one of the enantiomers prevents morning sickness during pregnancy whereas the other enantiomer influences embryonic development and resulted in children with malformed limbs.

Since most future pharmaceuticals will be chiral, chiral resolution, the process to obtain enantiopure molecules, is of paramount importance. The network proposed a CORE Industrial Toolbox that enables the design of Crystallization-based Continuous Chiral Resolution and Deracemization processes resulting in high enantiopurity, high productivity and high yield for newly developed high-value chiral products such as future pharmaceuticals. This CORE Industrial Toolbox was developed by the 15 Early Stage Researchers (ESRs) while they were trained in the network on their knowledge, personal, organizational and impact skills to become the future outstanding employees of the European pharmaceutical industry.
The CORE Network has made excellent progress to overcome the identified technological challenges in Enabling, Hybrid and Continuous Resolution.

Enabling Resolution.
Crystallization-enabled Resolution can be highly effective and efficient due to the near-perfect selectivity of the solid phase, even in chiral systems. However, there was a lack of underlying fundamental knowledge on solid state, crystallization behaviour and in situ process analysis. The CORE Network ESRs have achieved to 1. Apply in situ Process Analytical Tools to monitor resolution processes, 2. Determine and explain phase diagram and crystallization behaviour in complex multicomponent chiral systems, 3. Uncover scientific relations for forming conglomerates and racemic compounds.

Hybrid Resolution.
The discovery of the far-reaching deracemization process of Viedma Ripening has markedly increased the scientific interest in crystal chirality. Deracemization is a Hybrid Resolution which combines reaction and crystallization steps to transform the unwanted to the preferred enantiomer and in principle reach 100% rather than 50% yield. It is a technological challenge to apply Hybrid Resolution and to fully exploit its innovative opportunity potential. The CORE Network ESRs have explored the synergistic combination of reaction and crystallization towards increased yields and productivities while the library of racemization and non-selective reversible reactions is extended. For instance, a deracemization method for the network model compound praziquantel, which is an essential medicine for schistosomiasis (bilharzia or snail fever) in developing countries, was developed.

Continuous Resolution.
We are on the verge of a paradigm shift from batch to continuous manufacturing in pharmaceutical, specialty chemicals and other industries. This shift is necessary to cope with increased molecular size & complexity, quality & purity specifications and sustainability demands of future manufacturing processes in these industries. Industry now recognizes that it is faced with technological challenges enabling the translation of the conventionally performed batch-wise crystallization processes to continuous crystallization processes. The CORE Network ESRs have created various continuous and semi-continuous resolution process configurations while short-cut and elaborate continuous process models were constructed to allow knowledge-based optimization and control of these processes.

The 15 CORE ESRs have received academic, industrial and transferable skills training in webinars, at network-wide workshops and during open summer schools. All ESRs had a 1 month visit to an academic network partner getting to know fellow ESRs and get training on a relevant research topic. Many peer reviewed papers of ESRs appeared in print while a further number is submitted and in preparation.
The CORE Network identified the industrial model compounds Clopidogrel Imine and Praziquantel for the development of continuous resolution processes and for enabling resolution, respectively. Most of the 15 CORE ESRs had both an academic and an industrial secondment during their project. As part of the CORE Network’s public engagement activities the CORE Network ESRs organised a Crystal Growth and Photo Competition for High Schools students to motivate the scientific interest of high school students. The CORE Industrial Toolbox is planned to be further disseminated in a peer reviewed paper, at various international conferences and to industrial connections.
CORE Toolbox
CORE Summer School 2017 participants
Crystal Growth Competition winning images
CORE Workshop and Mid-term Review participants