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Continuous Resolution and Deracemization of Chiral Compounds by Crystallization

Periodic Reporting for period 1 - CORE (Continuous Resolution and Deracemization of Chiral Compounds by Crystallization)

Reporting period: 2016-10-01 to 2018-09-30

CORE is a Marie Skłodowska-Curie European Training Network on Continuous Resolution and Deracemization of Chiral Compounds by Crystallization which started on the 1 October 2016. The CORE Network brings 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.

CORE Industrial Toolbox
Since most future pharmaceuticals will be chiral, chiral resolution, the process to obtain enantiopure molecules, is of paramount importance. The research objective of the CORE Network is to develop a CORE Industrial Toolbox for Crystallization-based Continuous Chiral Resolution. Within the CORE Network this toolbox is developed by the 15 Early Stage Researchers (ESRs) while they are trained on their knowledge, personal, organizational and impact skills to become the future outstanding employees of the European pharmaceutical industry [see figure 1]. The CORE Industrial Toolbox will enable the design of high yield and highly efficient continuous processing for newly developed high-value chiral products such as future pharmaceuticals.
The CORE Network is on schedule to reach its aims 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 is 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 while the library of racemization and non-selective reversible reactions is extended.

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 batchwise 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 for 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 [see figures 2 and 3]. 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. Four peer reviewed papers of ESRs appeared in print while a further large number is submitted and in preparation.

ESR4 Brigitta Bodak (2018) Population-Based Mathematical Model of Solid-State Deracemization via Temperature Cycles, Crystal Growth and Design
ESR5 Giuseppe Belletti (2018) Role of Additives during Deracemization Using Temperature Cycling, Crystal Growth and Design
ESR7 Ryusei Oketani (2018) Practical Role of Racemization Rates in Deracemization Kinetics and Process Productivities, Crystal Growth and Design
ESR8 Francesca Breveglieri (2018) Deracemization of NMPA via Temperature Cycles, Crystal Growth and Design
The 15 CORE ESRs are scheduled to have both an academic and an industrial secondment in the coming year. These collaborations with fellow ESRs and network partners will further contribute to development of the CORE Industrial Toolbox. The CORE Network as further identified 2 industrial model compounds to be used for the development of continuous resolution processes and for enabling resolution and to allow for a validation of the CORE Industrial Toolbox. The CORE Industrial Toolbox will be disseminated in a peer reviewed paper, at various international conferences and to industrial connections.

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 photos were judged by the participants at the photo exhibition of the international crystallization conference BIWIC, September 2018 in Rouen, France. The prize winning high school student groups will receive a plaque and certificate [see figure 4]. The photo exhibition will now travel to the University of Strathclyde in Glasgow, UK.