Advances in Flow Chemistry

Sarah Holme

The first day of the annual Flow Chemistry Europe proceedings saw high calibre speakers from across Europe presenting on many very real and significant advances from the forefront of flow chemistry research, a technology that is leading modern chemistry today.

Read some of the highlights of the day below - talks from Professor Steven Archibald, University of Hull, UK; Timothy Noel, Assistant Professor at Eindhoven University of Technology, Netherlands; Samuel Marre from University De Bordeaux, France; and Mike Hawes, CEO of Syrris Ltd, UK.

‘Lab-on-a-chip devices for synthesis and quality control of positron emission tomography radiopharmaceuticals’ by Steven Archibald, Professor at University of Hull, UK’

‘Dose-on-demand radiotracer production is the generation of a single patient dose using a compact synthesis unit at the hospital site. The research presented develops Lab-on-a-chip modules for isotope processing, synthesis and routine quality control tests using microfluidic devices.’

A positron emission tomography (PET) scan is a type of imaging test that uses a radioactive substance called a tracer, administered to the patient IV, to look for diseases in the body, for example cancer.

Professor Archibald presented work performed by his group to develop a process for ‘dose on demand’ production of radiopharmaceuticals for PET using a number of isotopes, namely Fluorine 18 (18F), Carbon 11 (11C) and Gallium 68 (68Ga).

The goal is to apply this process in a hospital environment to be quicker and cheaper than current methods, using less material and allowing for automation of the process.

Design and development of a highly sophisticated lab-on-a-chip was presented, which had been developed initially for 18F. The chip is a completely integrated, microfluidic device which permits a miniaturised version of the radiolabelling process all on one disposable chip. The chip incorporates a miniaturised cyclotron, synthesis and purification module, and a comprehensive QC process, using only minimal reagents (~200uL) compared to traditional cyclotron volumes (3-5ml).

Professor Archibald explained how QC is the most important stage prior to patient administration, and the most involved. There are many different factors that need to be QC checked such as pH, appearance, activity and impurities such as endotoxins and solvents, requiring elements such as UV spec determination, electrochemical detection and chromatography.

Details on developing 11C for use with the lab on a chip dosage production were also given. 11C has half-life of 20 minutes (unlike the other two tracers which have longer half-lives) and they are therefore aiming for a combined synthesis/processing and QC time of 20 minutes. Synthesis and processing takes 4-5 minutes so the target is ready to get the lengthy but crucial QC process to as short a time as possible whilst still remaining effective.

Professor Archibald concluded that the focus of this work ultimately is patient benefit – better processing allows researchers to widen the spectrum of agents that can be used as radiopharmaceuticals, improving PET and ultimately improving patient diagnosis.

‘Gas-liquid photochemical reactions in flow’ from Timothy Noel, Assistant professor, Eindhoven University of Technology, Netherlands

‘In this oral communication, we will report on the acceleration of gas-liquid photocatalytic reactions in continuous photomicroreactors. We will go into detail on both engineering and chemical/catalytic aspects of continuous-flow photochemistry.’

Photochemistry makes use of the fact that light can speed up and often simplify some molecular synthesis reactions. Dr Noel introduced the potential of photochemistry and discussed a number of hurdles that have to be overcome - the fact that most molecules are only activated by UV light and also the problem of scale up. 

Dr Noel explained how a combination of Photoredox catalysis and organocatalysis allows the absorption and use of visible light drive reactions (Nicewicz, D. A., & MacMillan, D. W. (2008). Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science, 322(5898), 77-80).

Photochemistry is limited by penetration of light into whatever vessel is used; this gets more pronounced the larger the vessel used, meaning longer reaction times and challenges when trying to scale up reactions. The team have addressed this by developing photochemistry in flow reactor instead of a batch reactor. Flow micro reactors mean

• Easier scale up
• More uniform irradiation
• Shorter reaction times
• Increased heat and mass transfer
• Better safety with exothermic, explosive and toxic reagents
• Scale up is simplified simply by using multiple photo reactors

Dr Noel showed four examples of the numerous reactions they have developed in flow reactors using photo catalysis and discussed one in more detail - Metal free photocatalytic aerobic disulphide formation in flow. Dr Noel explained that they have managed to create a hugely accelerated reaction, 100% conversion and a much cleaner end product, data which has recently been published (Straathof, N. J., Su, Y., Hessel, V., & Noël, T. (2016). Accelerated gas-liquid visible light photoredox catalysis with continuous-flow photochemical microreactors. Nature protocols, 11(1), 10-21).

Supercritical Microfluidics: Investigating and using supercritical fluids at small scales by Samuel Marre from University De Bordeaux, France

‘This talk will highlight the interest of combining continuous supercritical fluids processes with micro reactors for various applications including new methods to access thermodynamics data and nanomaterials synthesis in harsh conditions’

Dr Marre presented on how it is possible to use supercritical fluids to overcome limitations of working with microfluidics. He explained that increasing the pressure within a reactor allows you to work at permissible temperatures creatingsupercritical fluids.

Benefits of supercritical fluids include

• No surface tension
• High solubilisation
• Low fluid resistance

Supercritical fluids have applications in Thermodynamics (supercritical water upgrading of heavy crude oil), Organic processing and Investigation of geological storage.

Dr Malle explained how supercritical fluids in Organic material processing allowed fast micro mixing, high supersaturation, a solvent free approach and good processing for nanoparticles, as detailed in a recent publication from the group (Couto, R. et al., (2015). Microfluidic supercritical antisolvent continuous processing and direct spray-coating of poly (3-hexylthiophene) nanoparticles for OFET devices. Chemical Communications, 51(6), 1008-1011).

Dr Malle described a basic 6cm/2cm micro reactor that allowed control of parameters including temperature, pressure, mixing time, flow rate. With careful control of these parameters it is possible to influence density and viscosity, and Dr Malle explained that it is even possible to control the shape of nanomaterials into e.g. cubes, rods, tetrapods and triangles. 

The talk concluded with the message that supercritical fluids are an excellent compromise of gas phase synthesis and liquid phase synthesis and provide the benefits of both.

Recent Innovations in the scale up of Flow Chemistry from one of the few suppliers of flow chemistry systems Mike Hawes, CEO of Syrris Ltd, UK

The ‘Technology spotlight’ talk of the day was given by Dr Hawes who gave an overview of Syrris lab scale and large scale flow chemistry systems. He began by stressing the importance of attention to the flow system as a whole and not just the reactors.

Dr Hawes discussed several recent advances in the production of nanoparticles on flow systems, including Ni nanoparticle formation, silver nanowire production, and finally monodispersed gold particles encapsulated in carboxylic acid terminated PEG for protein attachment.

A key message from these was that there is greater control possible with flow systems compared to batch or microwaves.

Dr Hawes went on to present on large scale flow chemistry, explaining that it has the potential to maintain the benefits of lab scale and add more, such as process sustainability, decreased material usage, batch to batch variation and costs. Syrris have just developed a large scale system called Titan

Dr Hawes introduced the Fluidic Factory 3D printer which has been developed specifically for the fabrication of fluidically sealed chambers.

Dr Hawes concluded by talking briefly about the sale up of droplet chemistry, notable for high levels of control, high-throughput and the ability to produce very monodispersed droplets, down to 20 microns. Dr Hawes gave an example where it had been used for nanoparticle production for sodium alginate gelation.

The Flow Chemistry Society will be hosting Flow Chemistry Congress in Miami, FL, USA on 2 - 3 November 2016. 

Sarah Holme is a freelance writer living in Cambridge, UK