Half-Day Hands-on Course

The first part of the training course will be led by Assoc. Prof. DI Dr. Heidrun Gruber-Woelfler of Graz University of Technology and will be looking at the theory of synthesis in Flow and to an introduction to work-up, crystallisation and filtration processes.

The second part of the training course will be led by Dr Thomas McGlone Technical Operations Manager at CMAC National Facility.

Attendees will have at their disposal 4 different stations with 4 different DEMOS and will gain insights of an end to end continuous process.

-3 stations will focus on different synthesis reactions (see specs below).

-A fourth station will feature a model compound run through 4 unit operations – synthesis, work-up, crystallisation and filtration. These will be linked into a continuous, ‘end-to-end process’. This will give delegates the opportunity to observe some downstream operations (following synthesis).

Assoc.Prof. Heidrun Gruber-Woelfler
Graz University of Technology

Hands-on course Instructor

 

Assoc.Prof. Heidrun Gruber-Woelfler studied technical chemistry at Graz University of Technology, Austria with a focus on chemical engineering. After her PhD dealing with organometallic catalysis, she did her Post-Doc in the area of continuous processes for the synthesis and purification of active pharmaceutical ingredients and finished her habilitation (venia docendi) in the field of Pharmaceutical Engineering in 2018.

Since 2007 she is the head of the research group “Continuous Processes” at the Institute of Process and Particle Engineering, Graz University of Technology and since July 2017 Deputy Director of the Center of Continuous Flow Synthesis and Processing (CCFlow) in Graz. Her current projects deal with heterogeneous (bio)catalysis for API synthesis, continuous processes, reactor design including additive manufacturing as well as in-line analyses.

Dr Thomas McGlone
Technical Operations Manager – CMAC

Technical Operations Manager – CMAC

Chemistry MSci Graduate from the University of Glasgow. He also completed his PhD at Glasgow under the supervision of Professor Lee Cronin within the area of inorganic synthesis, crystallisation and characterisation. Thomas joined CMAC in 2011 as a knowledge exchange postdoctoral researcher, working with Fujifilm and Syngenta. He then worked with the CMAC Tier 1 companies, GSK, Novartis and Astrazeneca on the Exquisite particles project. All of these projects investigated the feasibility of moving from batch to continuous crystallisation including practical aspects such as fouling. Thomas then joined the core Phase II CMAC centre programme, working to develop a workflow for the design of a continuous crystallisation process. An additional interest is process analytical technology and how this can be applied to monitor crystallisation processes.

Thomas is now the Technical Operations Manager for the CMAC National Facility and is responsible for managing the instrument scientists and research technician team, health and safety, and overseeing CMAC’s multi-million pound asset base.

SYNTHESIS REACTIONS PERFORMED BY

High T/p flow synthesis of organic azides with online monitoring by FT-IR

Reaction: Conversion of an organic mesylate to an organic azide followed by in-situ FT-IR to demonstrate formation of an organic azide & consumption of NaN3

Over the course of the practical session the optimisation of a high temperature & pressure flow reaction (195 C, 20 bar) will be demonstrated using glass flow reactors (Labtrix®).  By coupling the flow reactor to a ReactIR FTIR flow cell (Mettler Toledo), real-time feedback on the consumption of NaN3 & formation of the organic azide will be demonstrated.  The application of short reaction times also prevents decomposition of the resulting organic azide.  When considering to scale-up, optimisation of the flow reaction to use stoichiometric quantities of NaN3 increases the operational efficiency & reduces manufacturing costs.  The application of a flow reactor is beneficial as there is no headspace, this further increases process safety as it reduces the risk associated with the build-up of hydrazoic acid.

Multi-phase synthesis and multistage extraction of indigo.

Reaction: Multi-phase synthesis and multistage extraction of indigo

This demonstration will show a complete integration from upstream to downstream processing with a microreactor. The use of the multi-purpose Corning® Lab Reactor from Corning® Advanced-Flow™ Reactors (AFR) enables the synthesis of indigo through the aldol condensation pathway. This multi-phasic reaction highlights the key advantages of Corning’s AFR technology. The patented HEART shape design of Corning’s fluidic modules allows for a high mass transfer capacity (about 100 times higher than a traditional batch reactor) which benefits multiphasic systems (liquid, gas and even slurry solution in some cases). The integration of the heat exchange pathway brings a significant advantage in terms of heat transfer (about 1000 times better than a batch reactor). And the glass fluidic module has high chemical compatibility along with retaining visual access over the full part of the fluidic module.

In this demonstration, the synthesis of indigo will be easy to follow through the entire process.  The addition of two downstream processes will highlight how various technologies can be easily integrated and provide significant advantages for new product development. First, an inline separation will enable the separation of the water phase from the organic phase containing the indigo. This will be done using membrane technology developed by Zaiput Flow Technologies. This unique technology relies on interfacial tension between the phases and doesn’t require gravity (as shown during trials done on the International Space Station).

Then a counter-current multistage extraction will be carried out with a dedicated lab scale platform from Zaiput Flow Technologies. The platform integrates the phase separation unit as well as pumping system and is fully autonomous. Each platform is equivalent to up to five stages of extraction. This is of high value when manufacturers need to recover product in a different solvent, whether it is for purification or to combine with further synthesis steps.

The integration of Zaiput’s inline separation/extraction and Corning AFR technologies provides a demonstration of a scalable, integrated continuous process intensification platform.

Continuous multistep organolithium transformation


Reaction: Deprotonation of propionate, followed by its reaction with an electrophilic aldehyde and a subsequent quench to afford the aldol product

The Modular MicroReaction System (MMRS), is a globally unique piece of equipment for research and development work from Ehrfeld Mikrotechnik. With this system we provide users with a multiplicity of options for developing new processes and intensifying their existing ones. The modular design is the heart of the MMRS. Mounted on a base plate in the sizes A5 to A3, the micro- and milli-structured mixers, reactors and heat exchangers can be combined with maximized flexibility for an individually customized configuration. The MMRS offers optimum preconditions for imaging a multi-stage synthesis reaction in a minimized timeframe, and for performing this automatically. Thanks to automation capabilities like the LabManager®, developed specifically for laboratory applications, or by using your own solution, you will swiftly obtain a large amount of data on all process parameters – an important advantage in research and development work. The MMRS always gives you the degree of flexibility you need for feasibility studies and small-scale syntheses. Our MMRS modules have proved especially efficacious in sophisticated reactions like severely exothermic ones or when using toxic and potentially explosive substances. Further pluses include the sturdy construction and simple cleaning since almost all modules can be dismantled. With this intelligent laboratory toolkit, we offer research institutions and companies an entry into continuous reaction technology, with expandable scenarios: from MMRS, there is a seamless progression into the pilot and production scales: our spectrum includes the add-on reactor groupings Miprowa®, FlowPlate® and ART®, plus numerous special models.

FlowPlate® MicroReactors are the innovative solution for small and frequently changing product quantities with high quality, a fast time-to-market – these are the major challenges in the pharmaceutical and fine chemical industry. Thanks to this premium toolkit, developed by Lonza and exclusively distributed world-wide by Ehrfeld Mikrotechnik, active pharmaceutical ingredients (APIs) and fine chemicals can be researched and produced more competitively. In fact, campaign-based on-demand production under cGMP conditions and production up to ton scale are available within a very short time. High pressure resistance up to 100 bar offers new process windows for users. The compact design can be expanded modularly; plates with different channel design can be replaced easily, even in the case of a built-in reactor. The plate design can be flexibly adjusted to specific customer requirements and process tasks. The Cleaning-In-Place (CIP) process is easy to apply thanks to the process channel, which is free from dead volume with a closed and seal-free single-channel design.

During the practical session, we will demonstrate a fully automated multi-step organometallic reaction in our modular platform MMRS including the FlowPlate® Lab reactor – the smallest in the range but superbly equipped: it is optimally suited for feasibility studies in the laboratory, process development and pre-clinical research especially for multi-step synthesis. The exchangeable micro-structured process plate contains up to 10 inlets and outlets along the reaction channel. This ensures high flexibility for a variety of different processes. The flow process in the entire channel can be visually monitored through a sight glass. The real-time in-process monitoring of the reaction will be shown using various integrated sensors topped with an inline NIR. In our chosen model reaction, the deprotonation of tert-butyl propionate by LDA will be monitored using the inline NIR. Here, the disappearance of the ester C=O stretch can be clearly quantified. The second part of the reaction of the formed enolate with an aldehyde will lead the metallated intermediate. A subsequent in-situ quench with water generates the desired aldol product. Organometallic reactions are widely used in the pharmaceutical industry for the API production. These reactions are characterized by fast reaction speed, high exothermicity and low reaction temperatures due to kinetic driven byproducts. The use of the MMRS reactor platform with integrated PAT enables a fast and easy way to optimize reactions in terms of yield, selectivity and conversion at significant higher reaction temperatures.