The biannual CORE newsletter has the goal to keep you updated on all CORE related activities.
Welcome to the final newsletter from the CORE Network
As Network activities conclude at the end of December 2020, this is the final newsletter from the CORE Network, and is a compilation of highlights from the work and activities produced by us over the past four years. The newsletter also contains information about an upcoming CORE-related webinar organised as part of the British Association for Crystal Growth/Cambridge Crystallographic Data Centre's Crystal Conversations series.
We would like to thank all of our ESRs for their hard work. It has been a pleasure to see our Early Stage Researchers (ESRs) grow in confidence and ability as the Network progressed. This hard work shows for instance in the high quality journal papers that appeared during the lifetime of the network. Below you will find a selection of papers that appeared this year, with more to follow.
We would also like to thank our Beneficiary and Associate Partners, and External Experts, for their support. We would like to take the opportunity to thank you all for following our work for the duration of the project, and encourage you to keep following us on our social media channels. Finally, none of this would have been possible without the financial support of the Marie Skłodowska-Curie Innovative Training Network programme.
We wish everyone the very best of luck for the future.
Joop ter Horst (CORE Network Coordinator) and Elias Vlieg (Core Network Dissemination Committee Chair).
"Crystallization-Enhanced Resolution and Deracemization of Chiral Compounds" British Association for Crystal Growth/Cambridge Crystallographic Data Centre Webinar by Prof. Joop ter Horst, 3 December 2020
The discovery of Viedma Ripening as a crystallization-enhanced deracemization technique stimulated the research on the crystallization of chiral compounds in complex multicomponent systems. After highlighting various examples of crystallization-enhanced resolution and deracemization, Prof. ter Horst will discuss how to enable such deracemization processes. Finally, he will discuss the industrial application of crystallization-enhanced deracemization processes such as Viedma Ripening.
A total of 35 journal articles have been published by Network members since the beginning of the project. This is an excellent achievement, and our ESRs and academics continue to produce publications, with seven articles produced in 2020 alone. Articles that appeared in 2020 are listed below.
Jan-Joris Devogelaer, Hugo Meekes, Paul Tinnemans, Elias Vlieg and René de Gelder (2020) Angewandte Chemie
A significant amount of attention has been given to the design and synthesis of co‐crystals by both industry and academia because of its potential to change a molecule's physicochemical properties. Yet, difficulties arise when searching for adequate combinations of molecules (or coformers) to form co‐crystals, hampering the efficient exploration of the target's solid‐state landscape. This paper reports on the application of a data‐driven co‐crystal prediction method based on two types of artificial neural network models and co‐crystal data present in the Cambridge Structural Database. The models accept pairs of coformers and predict whether a co‐crystal is likely to form. By combining the output of multiple models of both types, our approach shows to have excellent performance on the proposed co‐crystal training and validation sets, and has an estimated accuracy of 80 % for molecules for which previous co‐crystallization data is unavailable.
Francesca Breveglieri, Iaroslav Baglai, Michel Leeman, Willem L. Noorduin, Richard M. Kellogg and Marco Mazzotti (2020) Organic Process Research & Development
Solid-state deracemization via temperature cycles is a technique that has been shown to be effective to isolate the pure enantiomer of a conglomerate-forming compound. This process has a large number of operating parameters that can be adjusted according to system-specific properties. On the one hand, this feature makes the process flexible and prone to optimization. On the other hand, the design space is so large that experimental optimization of the process can become long and cumbersome. In this work, we achieve two results. First, we show that deracemization via temperature cycles works very effectively for two new experimental systems, namely, the chiral compounds 2-(benzylideneamino)-2-(2-chlorophenyl)acetamide (CPG) and 3,3-dimethyl-2-((naphthalen-2-ylmethylene)amino)butanenitrile (tLEU). Second, we propose a new approach for the design of an effective deracemization process via temperature cycles for a new compound. Therefore, in this work, we investigate the effect of different operating conditions, namely, the initial enantiomeric excess, the cooling rate, the temperature range, and the catalyst concentration, on the performance of deracemization via temperature cycles for the new compounds CPG and tLEU and for N-(2-methylbenzylidene)phenylglycine amide (NMPA), which was already studied in a previous paper. On the basis of these outcomes, we conclude by proposing a model-free screening strategy for the design of an effective deracemization process via temperature cycles for a new compound.
Heike Lorenz and Andreas Seidel-Morgenstern (2020) Annual Review of Chemical and Biomolecular Engineering
Enantiomer separation and the isolation of natural products from plants pose challenging separation problems resulting from the similarity of molecules and the number of compounds present in synthesis or extract mixtures. Furthermore, limited theory is available to predict productivities for possible alternative separation techniques. The application and performance of chromatography- and crystallization-based processes are demonstrated for various case studies devoted to isolating valuable target compounds from complex initial mixtures. In all cases, the first emphasis is set to determine the process-specific phase equilibria to identify feasible process options. For all examples considered, yields and productivities are evaluated and compared for different scenarios. Guidelines to approach and solve similar separation tasks are given.
Carola Tortora, Christina Mai, Francesca Cascella, Michael Mauksch, Andreas Seidel-Morgenstern, Heike Lorenz and Svetlana B. Tsogoeva (2020) ChemPhysChem
Viedma deracemization is based on solution phase racemization, dissolution of racemic or scalemic conglomerates and crystal growth through autocatalytic cluster formation. With rate limiting racemization, its acceleration by appropriate catalysts may result in speeding up deracemization. A conglomerate‐forming chiral compound may principally racemize directly, or via reverse of its formation reaction. For a hydrazine derivative, we investigated available racemization pathways in presence of pyrrolidine or thiourea amine as base catalysts: via Mannich or aza‐Michael reaction steps and their reverse, or by enolization. Racemization by enolization was computationally found to dominate, both under water‐free conditions and in presence of water, involving a multitude of different pathways. Faster racemization in presence of water resulted indeed in more rapid deracemization, when the base was pyrrolidine. Under water‐free conditions, the role of water as enolization catalyst is assumed by chiral hydrazine itself – in autocatalytic racemization and in which both reactant and product are catalysts.
Lina C. Harfouche, Nicolas Couvrat, Morgane Sanselme, Clément Brandel, Yohann Cartigny, Samuel Petit and Gérard Coquerel (2020) Crystal Growth & Design
A cocrystal screening of the chiral drug “proxyphylline” (PXL) and achiral coformers was performed using dry or solvent assisted grinding and evaporation methods, yielding 10 different original solid forms with a 1:1 stoichiometry. Among them, three anhydrous cocrystals and a monohydrated conglomerate forming system have been identified with salicylic acid (SA). The crystal structures of the monohydrate and one of the racemic anhydrous forms were determined by X-ray single crystal experiments. The dehydration mechanism of the hydrate has been investigated by thermal analysis, X-ray powder diffraction, and water sorption–desorption cycles. The importance of water molecules in the crystal structure and the concomitant loss of both water and SA (cocrystal former) during the dehydration suggest a destructive mechanism.
Lina C. Harfouche, Clément Brandel, Yohann Cartigny, Samuel Petit and Gérard Coquerel (2020) Chemical Engineering & Technology
The monohydrated co‐crystal composed of the chiral active pharmaceutical ingredient proxyphylline, salicylic acid, and water was successfully resolved by preferential crystallization from a water/ethanol mixture. To the best of our knowledge, this is the first report of preferential crystallization applied to such a system and the results reveal that unusually high enantiomeric excess values can be attained in the mother liquor. These robust and reproducible results underline the potential of preferential crystallization to resolve co‐crystal systems.
Aliou Mbodji, Gabin Gbabode, Morgane Sanselme, Yohann Cartigny, Nicolas Couvrat, Michel Leeman, Valérie Dupray, Richard M. Kellogg and Gérard Coquerel (2020) Crystal Growth & Design
We established that ethylammonium chlocyphos also belongs to a family of conglomerate-forming systems composed of chlocyphos and alkyl amine. The pure enantiomer and racemic mixture exhibit very close X-ray powder diffraction patterns but with some peak shifts. This led to consider that ethylammonium chlocyphos could crystallize as a conglomerate but with partial solid solutions close to the pure enantiomer. The crystal structures of the pure (S)- and (R)-ethylammonium chlocyphos were solved using single-crystal data. The temperature–composition binary phase diagram between the two enantiomers of ethylammonium chlocyphos system was investigated to determine the limit of the solid solutions. This was confirmed by a Tammann plot related to the eutectic invariant characterizing the melting of the conglomerate. The limit of the composition range of the partial solid solutions was confirmed by X-ray powder diffraction measurements on different enantiomeric compositions.
An image by ESRs Carola Tortora and Francesca Cascella was chosen as the cover for this issue of ChemPhysChem. The cover feature summarizes the results of a joint computational and experimental study demonstrating that faster racemization through water‐catalyzed enolization could result in faster deracemization of a scalemic slurry of a chiral hydrazine derivative.
An image by ESRs Carola Tortora and Giuseppe Belletti was chosen as the cover for this issue of Chemistry: A European Journal. The picture displays a population of racemic conglomerate crystals of a BINOL derivative undergoing deracemization through Viedma ripening, leading to the formation of enantiopure crystals. This research represents the first successful Viedma ripening deracemization of a chiral compound with the use of a cheap and green source, such as UV light, as a racemization tool.
ESR Ryusei Oketani (University of Rouen) was invited to submit for the cover of this issue of Chemistry: A European Journal. The image depicts pyramid‐like tetrahedron of the quaternary phase diagram showing where symmetry breaking can take place.
We would like to congratulate all of our ESRs for their dedication and enthusiasm throughout the project. In the four years of the project, ESRs have attended various international conferences and disseminated our work to the scientific community.
Although some of the CORE ESRs continue to work for the Network and start to approach the conclusion of their studies, a number of them have found success - in terms of completing their vivas or finding employment, or both - following the conclusion of their Marie-Curie Fellowships.
The Network has also been active in dissemination activities, producing videos that inform the science community, and the general public, about the important work carried out by our ESRs and partners. The success of the Network was profiled in an article published by the European Commission.
Since 2019, we have had five viva successes.
Carola Tortora (Friedrich-Alexander University Erlangen) "Organocatalysts and Enzymes for Racemization", July 2020
Johannes Hoffmann (University of Strathclyde) "Continuous Crystallization enables Chiral Synthesis", June 2020
Lina Harfouche (University of Rouen) "Screening of Chiral Solid State and Phase Diagram", May 2020
Aliou Mbodji (University of Rouen) "Discovering Conglomerates", May 2020
Ryusei Oketani (University of Rouen) "Optimization of Second Order Asymmetric Transformation (SOAT)", December 2019
ESR Post-Fellowship Successes
ESR Johannes Hoffmann began a post as Material Science Technology Engineer at Janssen Pharmaceutical companies of Johnson and Johnson in February 2020.
ESRs Lina Harfouche and Carola Tortora have both begun postdoctoral positions: Lina at the University of Rouen and Carola at Sapienza University of Rome. Lina began their new posts in September 2020.
ESR Ryusei Oketani has been appointed Assistant Professor at the University of Osaka. He will leave his previous postdoctoral position at Université libre de Bruxelles in January and begin his professorship in February 2021.
CORE Project Success
In July 2019, the European Commission published a success story about the CORE ITN:
The EU-funded CORE project is helping to develop safer, more effective medicines by improving the processes pharmaceutical companies use to separate mirror-image pharmaceutical molecules, which will boost the industry's efficiency and competitiveness.
In June 2020, colleagues at the University of Strathclyde, Otto-von-Guericke University Magdeburg and Max Planck Institute for Dynamics of Complex Technical Systems, Germany (MPI) collaborated on the creation of two short videos about the CORE Network.
The first video provides a general overview of the network aims and the impact of the research, and features contributions from Project Coordinator Prof. Joop ter Horst, Beneficiary Partner Prof. Andreas Seidel-Morgenstern and Associate Partner Prof. Heike Lorenz, as well as CORE ESRs Francesca Cascella and Raghunath Venkatramanan.
The second video focuses specifically on the science behind the project, and features CORE ESR Maxime Charpentier explaining the story of the drug Praziquantel and how the network contributes to improving the drug's effectiveness.
During the CORE project, the 15 ESRs spent part of their research training with network partners undertaking visits/secondments. The goal of each visit/secondment was to prepare joint scientific papers. For all ESRs, visits/secondments were planned at the secondary supervisor institute, at an academic partner, as well as at an industrial partner. In addition to their knowledge skills development, the secondments provided interdisciplinary training, and intersectoral awareness was facilitated. The duration of each secondment was planned together with the host supervisors.
We would like to take the time to thank all of the hosts who have taken on our ESRs over the years. We would also like to thank the ESRs for taking part and working collaboratively with each other.
With seven published papers so far, and more in the making, Work Package 3 has already contributed well towards the goal of continuous resolution of chiral conglomerate-forming compounds and of racemic compound-forming systems at the eutectic. Process simulations and experimental work based on either preferential crystallization and temperature cycling have been the main routes investigated considering several case studies.
WP4: Hybrid Resolution (ESRs 5 to 9) With some of the ESRs already finished, the results of this work package are nearing completion. In all topics covered by WP4, significant progress has been made, often through the collaboration of several ESRs.
Mitigating the bottle-neck of racemization has been the topic of Giulio Valenti (using a separate reaction cell) and of a collaboration of Carola Tortora and Giuseppe Belletti (using photoracemization in combination with Viedma ripening for the first time). Francesca Breveglieri has experimentally mapped out the parameter space of temperature cycling, while Ryusei Oketani has studied second-order asymmetric transformation in great detail and compared it with other racemization routes.
WP5: Enabling Resolution (ESRs 10 to 15)
With some of the ESRs finished or close to finishing, Work Package 5 has focused on different tasks covering i) co-crystal predictions and analysis for new conglomerate-forming systems; ii) conglomerate detection using second harmonic generation (SHG); iii) resolution of racemic systems through their stable/metastable conglomerate and of conglomerate co-crystals by means of preferential crystallization processes and iv) development of Process Analytical Tools (PAT) for online monitoring of resolution processes. Eight publications by this WP are now available and more have been submitted/will soon be submitted.