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This is Part #8 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Andrew Mansfield Head of Flow Chemistry, Syrris

minute read

This is Part #8 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

minute read
Continuous flow chemistry in 2019 and beyond: our predictions

By Andrew Mansfield on January 18th, 2019 in Flow chemistry, The Flow Chemistry Collection

As 2019 gets under way, we’ve been thinking about what the future holds for continuous processing and flow chemistry in 2019 and beyond. Now this isn’t some Mystic Meg-style crystal ball gazing – we’re basing this on conversations we’ve had with chemists and business leaders, and general shifts in industry.

So what do we think will be big in continuous flow in 2019 and beyond?

Continuous flow scale-up will be big business

Continuous lab-scale flow is a fast-growing market thanks to the commercial availability and ease-of-use of lab scale flow chemistry systems. Lab scale flow has a number of benefits over traditional chemistry methods – some of which are outlined here in a previous blog post. In 2019, we predict that continuous flow scale-up systems will help the transition between research and discovery, and process development at pilot scale and beyond.

There are already a dozen existing API manufacturing processes that have been granted FDA approval and this will only increase following the FDA’s drive towards more continuous manufacturing. This is already driving the need for a robust method of scaling from the lab to the pilot plant. Syrris is currently developing Titan, a modular pilot-to-manufacturing scale continuous flow system, to help chemists develop their chemistry from lab-scale flow chemistry systems – such as the Asia Flow Chemistry System – to pilot and manufacturing scale production of their chemical processes.

Automated reaction self-optimization: rise of the machine (learning)

A big area that has been developing for a few years is automated reaction self-optimization, and we envision this becoming commercially viable in 2019. With the integration of reaction analytics and flow chemistry, this emerging technology will allow the user, via automated methods, to optimize reactions and methods via machine learning (AI).

Reagentless chemistries on the rise

Thanks to the “green” efficiencies they provide – and the increasing number of conversations we’re having with customers from various industries – we predict that the use of reagentless chemistries such as electrochemistry and photochemistry will become more of a focus in 2019.

One of the reasons reagentless chemistries haven’t seen the traction they deserve is that performing them in traditional batch methods is notoriously difficult. Continuous flow chemistry systems make it easy, though, as this blog post on continuous flow electrochemistry explains.

Standard lab apparatus has made access to these chemistries restricted; the benefits of running these processes in a continuous fashion allows easier access, along with added benefits such as precise control of electron and photon transmission to the reactor.

Teamwork makes the dream work

Combining batch and flow technologies will enable chemists to leverage the best of both synthetic techniques. Both batch and flow techniques offer unique advantages in different scenarios and combining both with automated control enables the widest range of chemistry to be carried out. This will be key in the development of multi-stepped, telescoped reaction methodologies.

Reimagining old processes, such as API encapsulation

As our understanding of the range of microfluidic applications increases, we can start to explore these benefits in other processes. The development of techniques such as targeted drug delivery by the encapsulation of API material in polymer matrices allows companies to reformat and reimagine current patents to extend their life.

Blacktrace brands including Syrris and Dolomite Microfluidics are at the forefront of developing novel microfluidic processes that can enable lots of these new applications, so contact us to discuss reimagining your existing chemistries.

Beyond 2019: the future is end-to-end personalized medicine

One for beyond 2019: we see continuous flow chemistry as enabling personalized medicine in the future through end-to-end drug factories.

Imagine factories and machines processing raw materials and producing a tablet at the end, tailored to the customer on demand. Continuous flow chemistry could make the “Star Trek Replicator” a reality – for medicine, at least!

These processes already exist from raw materials to tablet, but they need to be heavily refined. Combining the unique benefits of batch and flow chemistry will enable these processes to be refined to the point of being commercially viable, allowing true end-to-end personalized medicines to emerge.

Continuous flow chemistry in 2019 and beyond: your thoughts?

What are your thoughts on the future of continuous flow chemistry in 2019 and beyond? Let us know in the comments section below!

Curious as to how continuous flow chemistry – or a combined batch and flow approach – could enable your lab to perform faster, more reliable, and more reproducible chemistry? Speak to Syrris today!

About Andrew Mansfield

Andrew was formerly a Research Chemist at Pfizer and spent much of his career focusing on introducing flow chemistry technologies, meaning Andrew is well placed to lead Syrris’ flow chemistry offering. Read Andrew’s bio here.

Related posts:
2019 flow chemistry predictions: the rise of the machines

As 2019 gets under way, we’ve been thinking about what the future holds for continuous processing and flow chemistry in 2019 and beyond…

read more
What is flow chemistry and how does it work?

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

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Why perform your chemistry in continuous flow?

So why should your lab consider performing your chemistry using continuous flow chemistry techniques? Discover several reasons including faster and reactions, and accessing novel chemistries not possible in batch

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My first introduction to practical flow chemistry was as a Research Chemist at Pfizer and my first thought was: “why on earth would I want to conduct my chemistry in tiny tubes?” A few years later I was the biggest advocate for it. This blog post explains why…

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The post 2019 flow chemistry predictions: the rise of the machines appeared first on Syrris chemistry blog.

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This is Part #7 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Neal Munyebvu, Technical Support Specialist, Syrris

minute read

This is Part #7 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

minute read
Improving polystyrene production with continuous flow chemistry

Dramatically improving decades-old chemical processes is the stuff legends are made of. From improving efficiency to reducing cost and waste, chemists are looking for new ways to improve the efficiency of polystyrene production and continuous flow polymerization could well be the answer.

Rather than switching to larger scale bulk process to improve efficiency, moving to tiny tubes and glass chops may seem counter-intuitive – but the extra control that researchers are achieving with lab scale flow chemistry equipment provides a compelling argument to think differently about scale up.

What is polystyrene?

Polystyrene is a widely used plastic for a range of applications thanks to its inertness and resilience. It plays a particularly large role in the packaging industry; we’ve all had to dig through layers of polystyrene peanuts to retrieve an exciting new gadget from a box!

Polystyrene production and the need to improve existing styrene polymerization methods

The polymerization of styrene is typically performed by mixing the styrene monomer with an inhibitor such as peroxide or benzoyl. The inhibitor decomposes to form radicals; these radicals attack the double carbon bond of styrene and cause polymerization.

The key aims of polystyrene production methods are high molecular weight, narrow molecular weight distribution, good productivity, and high conversion rates of the styrene monomer to polymer. The molecular weight distribution of styrene polymerization is one of the most important factors as this property affects the end product’s impact and tensile strength, brittleness, hardness, and softening temperature. Optimizing the molecular weight distribution – and maintaining it in scale-up – is particularly important to ensure reproducible polystyrene production at large scales.

Polystyrene production methods have remained largely unchanged since they were first used commercially in 1931. Traditionally, batch emulsion, solution, or suspension polymerization methods have been the preferred choice for polystyrene manufacture. These methods offer limited control in molecular weight, molecular weight distribution, and the conversion of monomer to polymer but have the benefit of enabling easy scale-up. Relying on easy scale-up is no longer a viable tactic, however, due to the introduction of newer lower cost competing materials and this has driven new efforts to improve the efficiency of the polystyrene production process.

How is continuous flow polymerization helping to improve the efficiency of polystyrene production?

Using a Syrris Asia Flow Chemistry System, Professor Ardson dos Santos Vianna (Department of Chemical Engineering, São Paulo State University) enabled a new polystyrene production technique that offers good conversion of the monomer into a high molecular weight polymer, a narrow and reproducible molecular weight distribution, and improved productivity compared to traditional batch methods. This technique produces high-quality polystyrene in a more efficient and reproducible way than other techniques.

The process optimization compromise – and how continuous flow helps

Professor Ardson performed several experiments using a 4 mL fluoropolymer tube reactor and a 250 mL glass microreactor to determine the effect of temperature, concentration, residence time, and inhibitor mass on the overall polymerization reaction. The results of the experiments revealed that process optimization of styrene polymerization is a compromise as not all parameters complement each other; improving the molecular weight distribution may result in a reduction in the conversion of styrene monomer to polymer, for example.

  • Aggressive reaction parameters, such as high temperatures (115 oC), high monomer concentration, and reduced solvent use led to increased conversion rates (up to 66.8%)
  • Increasing incidence time of reaction and initial mass of initiator led to increased conversion
  • However, the greatest molecular weight was achieved with a conversion rate of just 27.9%, while the largest conversion rate of 66.8% yielded significantly lower molecular weights

By switching to continuous flow methods, Professor Ardson was able to dramatically improve upon decades-old chemistry. The level of reaction parameter control that continuous flow chemistry technology offers enabled fine-tuning of the chemistry well beyond what is possible with traditional batch chemistry reactors. Accurately pushing the limits of each reaction parameter enabled Professor Ardson to determine greatly improved reaction conditions to perform styrene polymerization with a high molecular weight and narrow molecular weight distribution, good productivity, and good conversion of monomer to polymer.

The promising future of continuous flow polymerization

Professor Ardson has demonstrated continuous flow polymerization as a promising alternative to traditional batch chemistry methods.

Continuous flow glass micro/millireactors offer significant advantages over traditional batch reactors for styrene polymerization, including;

  • High surface-to-volume ratios, which minimize temperature fluctuations
  • Laminar flow, offering reproducible mixing
  • Increased safety due to smaller reagent volumes
  • Accurate maintenance of pressures

The paper demonstrated that both microreactors and millireactors offer greater productivity (0.1 kg/m3/s) compared to tubular reactors (0.029 kg/m3/s) and batch reactors (0.019 kg/m3/s). Microreactors offer the greatest productivity, but clogging is a concern as the monomer and polymer are insoluble, so millireactors seem like the most promising choice for future studies, with one suggestion being to connect multiple millireactors in parallel to dramatically increase the throughput while maintaining a high conversion rate.

Much work is still needed to discover the ultimate compromise between conversion rates, molecular weights, and molecular weight distribution before the polystyrene manufacturing industry can fully benefit, but it’s clear that improving the polystyrene production process may well be achieved with continuous flow manufacture.

Further reading on styrene polymerization in continuous flow reactors Talk to Syrris about your chemistry

You may be surprised at the types of chemistry that can be performed – and improved – using continuous flow technology. Speak to a Syrris flow chemistry expert today to discuss your chemistry.

About Neal Munyebvu (MChem)

As a Flow Chemistry Technical Specialist for the Syrris Support Team, Neal is responsible for installing Asia Flow Chemistry Systems in client sites around the world, helping chemists overcome issues, and enabling chemists to get the most out of their flow chemistry equipment. Read Neal’s bio here.

Follow us on social media to be kept up-to-date on Syrris and other industry news
Related posts:
What is flow chemistry and how does it work?

by Andrew Mansfield | Apr 17, 2018 | Batch chemistry, Flow chemistry, Scale-up, The Flow Chemistry Collection

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

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Why perform your chemistry in continuous flow?

by Andrew Mansfield | May 15, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

So why should your lab consider performing your chemistry using continuous flow chemistry techniques? Discover several reasons including faster and reactions, and accessing novel chemistries not possible in batch

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Continuous flow chemistry in the pharmaceutical industry

by Andrew Mansfield | Sep 27, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

My first introduction to practical flow chemistry was as a Research Chemist at Pfizer and my first thought was: “why on earth would I want to conduct my chemistry in tiny tubes?” A few years later I was the biggest advocate for it. This blog post explains why…

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Electrochemistry made easy with continuous flow chemistry techniques

by Andrew Mansfield | Oct 10, 2018 | Flow chemistry, The Flow Chemistry Collection

Over the past 5 years or so the development of continuous flow electrochemical cells has made selective syntheses with high reactant-to-product conversions possible. These devices offer an easy access to electrochemical techniques which is driving its current re-assessment as a viable, attractive synthetic method. Discover more in this blog post.

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The rise of biocatalysis in continuous flow

by Andrew Mansfield | Oct 24, 2018 | Flow chemistry, The Flow Chemistry Collection

Continuous flow biocatalysis is fast becoming a key area of focus for chemists with applications in fine chemicals, drugs, biotherapeutics, and biofuels to name a few. This is reflected in the rapidly-growing number of publications and patents featuring continuous flow biocatalysis; this blog post explores why.

read more
Improving polystyrene production with continuous flow chemistry

by Neal Munyebvu | Dec 5, 2018 | Flow chemistry, The Flow Chemistry Collection

From improving efficiency to reducing cost and waste, chemists are looking for new ways to improve the efficiency of polystyrene production and continuous flow polymerization could well be the answer…

read more

The post Improving polystyrene production with continuous flow chemistry appeared first on Syrris chemistry blog.

Read Full Article
  • Show original
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This is Part #5 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Andrew Mansfield Head of Flow Chemistry, Syrris

minute read

This is Part #5 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

minute read
The rise of biocatalysis in continuous flow

By Andrew Mansfield on October 24th, 2018 in Flow chemistry, The Flow Chemistry Collection

Flow chemistry has application in a diverse range of areas and has the potential to improve on many chemical processes. The increased use of these enabling technologies for research and development applications has increased rapidly over the last 15 years with the development of commercially available apparatus and the increase in academic literature and take-up from industry.

The area of continuous flow biocatalysis is fast becoming a key area of focus for chemists with applications in the production of fine chemicals, drugs, biotherapeutics, and biofuels to name a few. This is reflected in the adoption of flow techniques in modern laboratories and the increased knowledge of these techniques in industry and academia. Continuous flow biocatalysis use is demonstrated in the significantly increased number of publications over the last few years.

The graph below shows the total number of patents and publications in continuous flow biocatalysis since 2000. This graph was constructed using data from SciFinder with the terms ‘‘continuous flow biocatalysis’’. Data was analyzed to January 2018.(¹)

Why perform continuous flow biocatalysis?

In traditional biocatalysis systems batch stirred tank reactors are the most common method and rightly so as this is the most widely available type of reactor. This method, however, has relatively low volumetric productivity and the collision of the enzyme with stirrers and impellers causes degradation and attrition of the enzyme. The use of free enzymes in batch reactions suffers from the limitations of recycling and recovery of the biocatalyst.

Flow chemistry has a lot to offer and shows several advantages over traditional methods. The method has the potential to increase rates of biotransformations due to its increased mass transfer making its use more economical by decreasing reaction times and increasing throughput of material. Immobilization of enzymes allows for better stability, reduces product purification, allows better control of substrate contact time and its recyclability reduces costs and extends their applicability for production.

Whole cells vs. purified proteins

There are two general types of biocatalysis, whole-cell, and purified protein biocatalysis. Whole cell catalysis uses the whole organism such as Escherichia coli (E. coli) for the transformation, while purified protein biocatalysis uses an extracted protein without the cell present.

Whole-cell biocatalysis relies on the substrate entering and exiting the cell for the transformation to take place. There are two approaches to whole-cell catalysis: fermentation and biocatalysis. It is biocatalysis that is of interest to chemists. The advantages of whole cell biocatalysis are that it’s less expensive than using purified proteins and the disadvantages being that the cell membrane limits the penetration of the substrate and product making the reaction slower compared to purified protein,

Purified enzymes, however, have the advantage of being specific in their transformations, but this makes enzymes typically quite specific for substrates. When using purified enzymes, the substrate is only required to diffuse into the active site of the protein and not through the cell membrane. Also, compared with whole cells, the concentration of the desired enzyme is higher compared to the same mass. However, the purification process can be expensive and sometimes these purified proteins can be unstable outside of the cell structure.

While both types of biocatalysis are used in continuous flow systems, the use of immobilized enzymes shows the most advantage for this application.

Immobilizing enzymes

There are a range of methods for the immobilization of enzymes and ideally, they should show the same properties. Most have several, including;

  • A large surface area
  • Chemical and thermal stability
  • Suitable (and enough) functional groups for attachment
  • Ease of regeneration
  • Insolubility in water
  • Rigidity and mechanical strength
  • Low cost

The most fundamental immobilization techniques are entrapment, adsorption, covalence, affinity, cross-linking, and encapsulation as shown below.

Adsorption of biocatalysts onto solid supports (or carriers) relies on hydrophobic, salt bridge, van der Waals, and hydrogen bonding interactions between the protein or cell, and the immobilization support. Adsorption is easier to perform and can avoid enzyme denaturation through minimal distortion to the protein. However, immobilization lifetimes and efficiencies can be lower than comparable covalent immobilization.

In the case of covalent binding (covalence), the supporting material is functionalized with an active group (e.g., amine, epoxy, etc.) and the enzymes are covalently bonded to the surface through them. The major benefit of covalent immobilization is the potential for improved catalyst lifetime due to decreased leaching.

Affinity immobilization revolves around enzymes having different affinities for immobilization supports under different conditions.

Entrapment immobilization is achieved by trapping the biocatalysts into a caged network via covalent or non-covalent interactions with an immobilization support. One of the methods is direct immobilization onto the microchannel wall. Another approach utilized enzyme immobilization on a solid support inside the microchannel, e.g., on micro- and nanoparticles, porous polymer monoliths or membranes.

Continuous flow biocatalysis examples

There are a steadily-growing plethora of publications now available for continuous flow biocatalysis; here are some of our favourites.

Bioreduction of β-ketoesters by immobilized microorganisms

In this example, researchers at the Universidade Federal do Rio de Janeiro have demonstrated an interesting alternative on the bioreduction of β-ketoesters by immobilized microorganisms².

The group had previously shown the successful bioreduction of β-ketoesters under batch conditions using K. marxianus and Rhodotorula rubra cells and transferred the conditions a continuous flow methodology. The immobilization of microorganisms by calcium alginate entrapment allows systems of this type to be more robust and readily reused and recycled, a big advantage over using whole cells which cannot be recycled. Using this methodology, the group obtained β-hydroxyesters in excellent yields and high enantiomeric excess (>99%). By varying the β-ketoester structure and immobilized microorganism the absolute stereochemistry could also be controlled.

An enantioselective preparation of O-Acetylcyanohydrin in a three-step telescoped continuous process

Researchers at the Department of Chemistry at the University of Cambridge, IBG-1: Biotechnology (Germany), and INB (Aachen University of Applied Sciences) have demonstrated an enantioselective preparation of O-Acetylcyanohydrin in a three-step telescoped continuous process³. This is particularly interesting as biocatalytic multistep approaches to chiral fine chemicals are still rare.

Candida Antarctica CalB and Arabidopsis thaliana AtHNL were employed in a robust continuous telescoped process, involving an in-situ HCN generation followed by addition to aldehydes. High stereocontrol was observed in the subsequent hydrocyanation reaction. An in-line chemical acetylation enabled stabilization of newly formed cyanohydrins and gave access to a class of O-acetylcyanohydrins with very good conversions and ee values over the three steps (75–99% conversion; 40–98% ee).

This method proved to be advantageous over the batch protocols in terms of reaction time (40 min vs. 345 min) and ease of operation, opening access to reactions which have often been neglected due to safety concerns. The modular components enabled an accurate control of two sequential biotransformations, safe handling of an in-situ generated hazardous gas, and in-line stabilization of products.

Synthesis of Geraniol esters for the food, flavor, and fragrance industries

This example from the Department of Chemical Engineering (Institute of Chemical Technology, Mumbai) has demonstrated the synthesis of Geraniol esters, used in the perfume, flavor, and beverage industries⁴.

The global demand for flavors, perfumes, and fragrances forecasts to grow 3.9% per year, reaching $26.3 billion (USD) in 2020. The importance for the synthesis of short-chain fatty acids, esters, and aroma compounds are gaining economic importance at a commercial level. With an evolving demand for green processes, adoption of biocatalysis has been drastically increased in this area.

In this study, a continuous-flow packed bed reactor of immobilized Candida antarctica lipase B (Novozym 435) was employed. Optimization of process parameters such as biocatalyst screening, and the effect of solvent, mole ratio, temperature and acyl donors were studied. Maximum conversion of ~87% of geranyl propionate was achieved in 15 minute residence time at 70 °C using geraniol and propionic acid with a 1:1 mol ratio. Novozym 435 was found to be the most active and stable biocatalyst among all tested.

Interesting reviews and further reading

There are some nice reviews to look through for some extra reading. All have a range of chemistries and applications which may be useful:

Conclusion

There is a common misconception that enzymes are unstable and expensive, work only under high dilution, and do not lend themselves well to scalable chemical processing. However, there are ever-increasing numbers of biotransformations being performed in a continuous manner. They offer many different solutions for chemical and biochemical problems with the goal of enhancing selectivity and yield of complex reactions.

References
  1. Continuous flow biocatalysis, Joshua Britton, Sudipta Majumdar, and Gregory A. Weiss, Chem. Soc. Rev., 2018, 47, 5891—5918
  2. Biocatalyzed Acetins Production under Continuous-Flow Conditions: Valorization of Glycerol Derived from Biodiesel Industry, Rodrigo O. M. A. de Souza et al, J. Flow Chem, 2013, 3(2), 41-45
  3. An Orthogonal Biocatalytic Approach for the Safe Generation and Use of HCN in a Multistep Continuous Preparation of Chiral O-Acetylcyanohydrins, Steve V. Let et al, Synlett 2016, 27, 262–266
  4. Synthesis of Geraniol Esters in a Continuos-Flow Packed-Bed Reactor of Immobilized Lipase: Optimization of Process Parameters and Kinetic Modelling, Ganapati D. Yadav, Appl Biochem Biotechnol. 2018, 184(2), 630-643
Speak to Syrris about your chemistry

If you’re interested in performing your biocatalysis – or any other type of chemistry – in continuous flow, just fill in the contact form and one of my colleagues or myself will get back to you.

About Andrew Mansfield

Andrew was formerly a Research Chemist at Pfizer and spent much of his career focusing on introducing flow chemistry technologies, meaning Andrew is well placed to lead Syrris’ flow chemistry offering. Read Andrew’s bio here.

Related posts:
What is flow chemistry and how does it work?

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

read more
Why perform your chemistry in continuous flow?

So why should your lab consider performing your chemistry using continuous flow chemistry techniques? Discover several reasons including faster and reactions, and accessing novel chemistries not possible in batch

read more
Continuous flow chemistry in the pharmaceutical industry

My first introduction to practical flow chemistry was as a Research Chemist at Pfizer and my first thought was: “why on earth would I want to conduct my chemistry in tiny tubes?” A few years later I was the biggest advocate for it. This blog post explains why…

read more
Electrochemistry made easy with continuous flow chemistry techniques

Over the past 5 years or so the development of continuous flow electrochemical cells has made selective syntheses with high reactant-to-product conversions possible. These devices offer an easy access to electrochemical techniques which is driving its current re-assessment as a viable, attractive synthetic method. Discover more in this blog post.

read more

The post The rise of biocatalysis in continuous flow appeared first on Syrris chemistry blog.

Read Full Article
  • Show original
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This is Part #4 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Andrew Mansfield Head of Flow Chemistry, Syrris

minute read

This is Part #4 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

minute read
Electrochemistry made easy with continuous flow chemistry techniques

By Andrew Mansfield on October 10th, 2018 in Flow chemistry, The Flow Chemistry Collection

Electrochemistry has a huge potential to offer synthetic organic chemists. The use of electrochemistry in modern laboratories, however, is generally quite low. This is largely due to the absence of suitable equipment that allows non-electrochemists a ‘convenient’ method to carry out this chemistry. For this technique to be more readily accepted as a routine procedure chemists need an easier, more user-friendly way to access it.

Electrochemistry techniques in the past have relied on electrolysis in glass reactors that lead to poor reaction control, low selectivity, and reproducibility and slow reaction rates. These systems can be easily set-up but because of the reasons stated above, there has been a reluctance to adopt them.

Over the past 5 years or so the development of continuous flow electrochemical cells has made selective syntheses with high reactant-to-product conversions possible, more often with a single pass through the device. These devices offer an easy access to electrochemical techniques which is driving its current re-assessment as a viable, attractive synthetic method.

Basic principles of organic electrosynthesis

During an organic electrochemical reaction, organic molecules are activated by the addition or removal of electrons at the surface of an electrode through a heterogeneous process. An electrosynthetic reaction typically requires two electrodes (anode and cathode) in contact with a solution that contains an electrolyte. An electrolyte is a salt that provides ions to improve the conductivity of the solution.

Electrochemistry can be performed in a variety of different methods either Potentiostatic mode (where the voltage across the electrodes is controlled) or Galvanostatic mode (where the current across the electrodes is controlled).

  • There are several variables that can be explored in the development of electrosynthetic methods;
    the nature of the electrode
  • the voltage/current applied
  • whether the chemistry is performed at the anode or cathode
  • whether the electrodes are simply either side of the cell or are separated (e.g. by an ion permeable membrane)
Advantages of organic electrosynthesis
  • The reaction selectivity can be controlled with the potential applied at the working electrode. Meaning the selection of one electrophore as opposed to another with a similar structure can be achieved. Unlike with the use of redox reagents, the potential can be modified at will
  • The reaction rate can be controlled by adjusting the current density or applied potential
  • As in classical organic chemistry, the degree of transformation of a molecule (regarding its oxidation state) can be controlled by managing the number of electrons supplied
  • The nature of the electrode and the composition of the electrolyte can be used as reaction parameters to control selectivity and reaction rate
  • The electrosynthetic experimental conditions and pathway can be predicted
  • The reaction conditions are typically mild since in general, electrolysis is performed at room temperature and atmospheric pressure
Electrochemistry as a “green” application

If we consider that our reaction is performed with the addition or removal of electrons it’s easy to consider that our reactions will be REDOX – reductions or oxidations. These reactions often use hazardous and polluting reducing or oxidizing reagents such as OsO4, Pb(OAc)4, NaH etc.; by eliminating the need of these we can consider electrochemistry to be a ‘greener’ method.

Our chemistry is mediated by electrons, so we often perform our chemistry as room temperature reducing energy consumption. We can also consider our electrodes as heterogeneous catalysts allowing less waste in the work-up of our reactions. Furthermore, ionic liquids are often used replacing organic solvents which are readily recovered.

The development of continuous flow electrochemical cells enables us to access this greener method and perform unique transformations enabling selectivity and transformations not possible by other techniques.

Continuous electrochemistry in flow

Traditional methods of electrochemistry involve the use of ‘beaker cells’. Typically, in electrochemical literature, the precise description of this apparatus is not properly described. While electrode material is given, the geometries, positioning, and dimensions are not giving rise to difficulties in reproducing experimentation. The development of continuous flow electrochemical equipment eliminates a lot of the problems with reproducing experimental procedures and confines variables to the electrode material and the synthetic procedure.

Electrochemistry is a surface phenomenon meaning large surface area to volume ratios are required. This is something we know a lot about if we are familiar with flow chemistry in general. Flow reactors have a large surface area to volume ratio compared to equivalent volume batch reactors. It’s not a big leap to design a flow electrochemical reactor that creates a high surface area to volume ratio in respect to the electrode.

One thing to consider with traditional methods of electrochemistry is that the electrodes are separated by a larger distance compared with there flow equivalent. A large distance between electrodes gives rise to loss of control of the charge passing between them resulting in ‘electron gradients’. The diagram below illustrates this with a simple oxidation. A range of electrons in our reaction can give rise to a loss in selectivity.

In a flow electrochemical cell, the distance between the electrodes is drastically reduced. By reducing the distance between the electrodes, we can precisely control the electrons equivalents in our reaction and therefore increase selectivity.

Most continuous flow electrochemistry cells are based on a parallel plate set-up, that is, a pair of electrode plates are divided by a small distance by a gasket that generates a flow pathway. The nature of the electrodes and the current or voltage applied across them controls the number of electrons equivalents passing between them into the reaction mixture. This electron flow can be considered as the reagent. The flow rate and concentration of the reaction mixture dictate the potential applied across the electrodes to generate the precise number of electron equivalents. This allows us greater control of our reagent and selectivity.

By reducing the gap between the electrodes, we can often reduce or eliminate the need for electrolytes in our reaction, increasing their ‘green’ potential.

Using these continuous electrochemical techniques can deliver reaction throughputs of up to multiple grams per hour. As electrochemistry is surface dependent, increasing the size of the electrodes can potentially increase this further.

Preparative microfluidic electrosynthesis of drug metabolites: a published example

There is in an ever-growing number of literature examples using continuous electrochemistry that we could discuss here; a simple literature search will give you something to read.

One example of electrosynthesis that is increasing in popularity in the pharmaceutical domain is the direct synthesis of drug metabolites which is the one I want to highlight.

The understanding of how drugs are metabolized and their interaction in the body is of major importance in the pharmaceutical industry. Before any drug candidate is taken forward for further development a full understanding of its metabolites needs to be understood.
In vivo, a drug molecule undergoes its first chemical transformation within the liver via CYP450-catalyzed oxidation. The chemical outcome of the first pass hepatic oxidation is key information to any drug development process. However, this often gives rise to a number of metabolites that require structural elucidation and resynthesis.

If we consider the drug discovery process, a chemist is required to synthesize a targeted compound. Many synthesize require numerous reaction steps and purifications. If the chemist is lucky enough to obtain a lead compound a toxicity study is required to progress further in its development. This gives rise to several drug metabolites which themselves require investigation. The chemist then must go back in the lab and resynthesize these metabolites, more often via different methods. This is time-consuming and expensive.

Researchers at the Sanford-Burnham Medical Research Institute In an effort to replicate these hepatic oxidations were the first to show that continuous electrochemistry can be used to simulate CYP450 oxidation and synthesize oxidative drug metabolite in a single step. This has a huge impact on the whole drug discovery process.

The figure below illustrates the use of a simple electrochemical flow cell and the oxidative pathway in generating oxidative drug metabolites.

Several commercial drugs were subjected to continuous-flow electrolysis in the study. They were chosen for their various chemical reactivity: their metabolites in vivo are generated via aromatic hydroxylation, alkyl oxidation, glutathione conjugation, or sulfoxidation. The chemists went on to demonstrate that their metabolites could be synthesized by flow electrolysis with a throughput of 10 to 100 mg/hour, more than enough for further study.

What is nice to show from this chemistry is the precise control of the electron equivalents into the reaction. The example below shows the selective oxidation of Diclofenac, one of the dugs in the study. By controlling the electron flux we demonstrate the optimization process in converting the starting material to its oxidized product.

You can read the paper for yourselves: Preparative Microfluidic Electrosynthesis of Drug Metabolites, Romain Stalder and Gregory P. Roth, ACS Med. Chem. Lett., 2013, 4 (11), pp 1119–1123

The future of continuous flow electrochemistry

The development of continuous flow electrochemistry techniques is opening up the toolbox for synthetic organic chemists. With easy to use reaction set-ups the hurdle to access this synthetic technique is greatly reduced. With the precise control of reaction parameters flow electrochemistry offers the potential for high selectivities and productivities over traditional techniques. Coupled with the greener methodologies, continuous flow electrochemistry offers an exciting prospect for modern chemistry.

Speak to Syrris about your chemistry

Curious as to how you could implement continuous flow electrochemistry in your lab? Then fill in the contact form and one of my colleagues or myself will get back to you.

About Andrew Mansfield

Andrew was formerly a Research Chemist at Pfizer and spent much of his career focusing on introducing flow chemistry technologies, meaning Andrew is well placed to lead Syrris’ flow chemistry offering. Read Andrew’s bio here.

Related posts:
Electrochemistry made easy with continuous flow chemistry techniques

by Andrew Mansfield | Oct 10, 2018 | Flow chemistry, The Flow Chemistry Collection

Over the past 5 years or so the development of continuous flow electrochemical cells has made selective syntheses with high reactant-to-product conversions possible. These devices offer an easy access to electrochemical techniques which is driving its current re-assessment as a viable, attractive synthetic method. Discover more in this blog post.

Continuous flow chemistry in the pharmaceutical industry

by Andrew Mansfield | Sep 27, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

My first introduction to practical flow chemistry was as a Research Chemist at Pfizer and my first thought was: “why on earth would I want to conduct my chemistry in tiny tubes?” A few years later I was the biggest advocate for it. This blog post explains why…

What is flow chemistry and how does it work?

by Andrew Mansfield | Apr 17, 2018 | Batch chemistry, Flow chemistry, Scale-up, The Flow Chemistry Collection

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

Why perform your chemistry in continuous flow?

by Andrew Mansfield | May 15, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

So why should your lab consider performing your chemistry using continuous flow chemistry techniques? Discover several reasons including faster and reactions, and accessing novel chemistries not possible in batch

The post Electrochemistry made easy with continuous flow chemistry techniques appeared first on Syrris chemistry blog.

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Dr. Stephen Heffernan, Batch Chemistry Technical Applications Specialist, Syrris

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Going beyond the round-bottom flask: how to automate your chemistry
By Dr. Stephen Heffernan on October 8th, 2018 in Batch chemistry, Scale-up

From my very first introduction to chemistry at primary school, I have associated chemistry with conical flasks, Bunsen burners, and the ever-present round-bottom flask.

Speaking from experience, chemists tend to be creatures of habit – myself included – requiring a relatively high level of activation energy to make changes to methodology and/or technology. This is highlighted by the fact that synthetic methods and tools have remained largely unchanged over the last 200 years, meaning nearly every chemistry lab in the world has an extensive collection of round-bottom flasks.

The problems with traditional chemistry and round-bottom flasks – and their solutions

This reliance on traditional methods has placed restrictions on synthetic chemistry; limited temperature ranges, lack of repeatability, and the need for constant experiment supervision. These difficulties fly in the face of the ever-growing pressure on synthetic organic chemists to develop innovative chemical reactions and compounds quickly and efficiently.

This post aims to introduce how modern laboratory technology – such as jacketed reactors and software automation – can enable you to perform more reliable, consistent, and reproducible chemistry, even when you’re away from the lab bench or fume hood.

If you already know how automated chemistry systems work, check out our “5 benefits of automated lab chemistry systems” blog post

The challenge: Difficulty in accurately maintaining reaction temperatures

During my Ph.D. I worked almost exclusively at 4 temperatures: reflux, room temperature, 0 °C, and -78 °C. This limited temperature range was selected purely for the relative ease of maintaining reactions at each of these temperatures, something I’m sure many chemists can identify with.

  • Reflux – just heat until your reaction boils
  • Room temperature, although variable, speaks for itself
  • 0 °C can be achieved with an ice bath
  • -78 °C is the result of a mixture of acetone and dry ice

Accurately controlling these temperatures is still tricky, despite being “relatively easy” to maintain. I once, foolishly, attempted to carry out a 4-hour reaction at -40 °C, which involved adding dry ice to an acetone bath piece by piece until I reached the desired temperature. Needless to say, my temperature control was less than ideal, as each piece of dry ice added to the bath would cause the temperature to drop by a few degrees before slowly returning to -40 °C.

In reality, chemistry can be carried out across a far wider spectrum of temperatures, offering the possibility of better selectivity, improved yield, or the avoidance of unwanted side-products; but it’s hard to achieve and/or maintain temperatures other than the “big 4” mentioned above with traditional lab glassware.

The solution: Pinpoint accuracy in temperature control with jacketed reactor vessels and circulators

Advancements in laboratory glassware have led to the creation and widespread use of the jacketed reactor – double-walled glass vessels that allow for a “jacket” of oil to surround the reaction. This oil is constantly circulated by an external circulator and provides pinpoint accuracy in temperature control down to fractions of degrees. Not only does this enable much more consistent reaction temperatures, but it also provides easy temperature “ramping” – something that’s virtually impossible with round-bottom flasks.

Jacketed reactors are available in a huge range of sizes, from as low as 50 mL through to 50 L (or more), depending on your chemistry and scale.

The challenge: The need for constant reaction supervision

The second challenge facing chemists is freeing themselves from having to constantly interact with and monitor their reactions. My story above is just one example of when I had to stand in front of a lab bench, slowly feeding dry ice into my round-bottom flasks for 4 hours.

Constantly supervising your reactions is time-consuming, and, frankly, boring. I love performing chemistry, but it’s hard to deny that some parts of it are frustrating. It prevents you from performing other chemistry at the same time or can get in the way of taking the time to expand your knowledge by reading interesting papers.

The solution: Software automation and monitoring

Jacketed reactors, when combined with software automation, enable truly automated, walk-away chemical synthesis and have revolutionized the chemistry lab.

Automated jacketed reactors and automation add-ons for manual jacketed reactors use intelligent software that can control and constantly monitor your reaction through a number of probes (temperature, stirring speed, pH, turbidity, etc.). Working in conjunction with a circulator and temperature probe, the software can automatically compensate for any temperature fluctuations (exotherms/endotherms) by heating or cooling the oil flowing through the jacket. Combined with intelligent pumps you can also set up automated temperature-dependent and pH controlled dosing into your reaction.

Taking the intelligent automation further, you can set up entire complex recipes for your chemistry. Set-up your complete reaction prep, including all temperature set-points and reagent dosing and then walk away, allowing reactions to run autonomously, even when you have gone home for the evening/weekend! Smart safety features monitor your reaction and can shut it down in the event of reaching user-defined limits.

The ability to set and forget your chemistry frees up your time to analyze data from previous experiments, design your next reaction, or catch up on interesting publications you’ve been eager to read.

The challenge: Issues with reaction repeatability and reproducibility of results

Nearly all chemists will at some point have scratched their head when two apparently identical experiments produce significantly different results. This is all the more frustrating when you’ve had to supervise a reaction for hours on end.

A perfect example of this comes from my time supervising an undergraduate student during his final year research project. We were carrying out a rearrangement reaction using a weak base and had to keep the temperature at -90 °C to avoid unwanted side-products. No matter what we did, his reactions would not provide the desired product while mine would. As much as I would like to think it came down to my superior laboratory technique, even when we did the experiments side-by-side, we still had significant differences in success.

The solution: Software automation and data logging

Automation software automatically collects and logs all data from your reaction in real time. No reaction events escape detection, allowing your reactions to be compared side-by-side. This enables you to identify any differences in reaction conditions between experiments – particularly useful when things haven’t gone quite to plan! When combined with a preconfigured recipe, researchers can be confident that their experimental conditions will be the same every time – it’s just a matter of pressing “Start” and letting the system perform the reaction with no room for human error.

Atlas HD - Automated Chemical Synthesis System from Syrris - YouTube
Top 5 benefits of automated jacketed reactor systems

We’ve put a whole blog post together covering the top 5 benefits of automated chemistry systems, but you can see the short version in the infographic below.

But wait! What about continuous flow chemistry?

I’d be remiss if I failed to mention continuous flow chemistry techniques when talking about “modern chemistry technology” and improving upon traditional chemistry. Continuous flow is a radically different approach to performing chemistry and involves pumping reagents through tubes or pipes – but it is far too big a subject to cover in this blog post. See all the blog posts covering the ins and outs of flow chemistry.

Enjoy chemistry automation in your lab

Whether you’re working with round-bottomed flasks and are looking to step into the world of jacketed reactors, or you’re already using one, speak to Syrris today to find out how you can enjoy the benefits of lab automation.

About Dr. Stephen Heffernan

As a Batch Chemistry Applications Specialist for Syrris, Stephen is responsible for many technical pre-sales inquiries, producing applications notes, and performing feasibility studies for potential customers. Stephen is also the Product Manager for the Atlas HD family of automated chemical reactors at Syrris. Read Stephen’s bio here.

Related posts:
Continuous flow chemistry in the pharmaceutical industry

by Andrew Mansfield | Sep 27, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

My first introduction to practical flow chemistry was as a Research Chemist at Pfizer and my first thought was: “why on earth would I want to conduct my chemistry in tiny tubes?” A few years later I was the biggest advocate for it. This blog post explains why…

What is flow chemistry and how does it work?

by Andrew Mansfield | Apr 17, 2018 | Batch chemistry, Flow chemistry, Scale-up, The Flow Chemistry Collection

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

Why perform your chemistry in continuous flow?

by Andrew Mansfield | May 15, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

So why should your lab consider performing your chemistry using continuous flow chemistry techniques? Discover several reasons including faster and reactions, and accessing novel chemistries not possible in batch

Solid phase catalysis in continuous flow

by Neal Munyebvu | Jun 22, 2018 | Batch chemistry, Flow chemistry

What is catalysis? What is a catalyst? How does catalysis work? And why would you want to perform catalysis in continuous flow? Flow Chemistry Applications Specialist, Neal, explains why chemists like to incorporate catalysts into their chemistry and the benefits they bring…

The post Going beyond the round-bottom flask: how to automate your chemistry appeared first on Syrris chemistry blog.

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Neal Munyebvu, Technical Support Specialist, Syrris

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7 things to keep in mind when adopting flow chemistry

Sometimes the biggest hurdle for chemists adopting flow chemistry is the time it takes to convert a batch process into a seamless flow set-up – but it doesn’t have to be!

Whether you want gradual or immediate adoption, this post covers the 7 main things you should consider when you are looking to convert your batch process into continuous flow.

We know chemists are inquisitive creatures and love to discover things for themselves, but we’ve been helping chemists implement flow chemistry since 2001. We’d love to discuss your applications and whether they’re possible in continuous flow; don’t hesitate to contact us to chat to an expert!

1. What is your application and is it suitable for continuous flow?

There’s a library of publications from chemists using continuous flow techniques to perform a wide range of different chemical reactions. If it can be done using traditional chemistry, it can often also be achieved using flow chemistry.

While many chemists are performing their entire process in continuous flow, It’s worth bearing in mind that some reactions may benefit from a combination of continuous flow chemistry techniques and traditional batch techniques. This combined approach may offer the best of both worlds, enabling you to perform specific portions of a reaction pathway in flow, rather than the entire process. Synthesis to and from intermediates to be used in batch processes downstream for example is common.

Some applications that may seem inaccessible can reliably be performed in continuous flow, such as;

Reactions reliant on heterogenous solid-liquid phase chemistry

Using solids may not seem immediately intuitive as part of ‘flow’ chemistry, however, a lot of work has been done using packed bed columns and flowing reagents over a packed bed solid catalyst/substrate. It’s worth noting that many chemists are able to remove the need for solids in their chemistry due to the benefits flow chemistry  when they adapt it to continuous flow

Reactions using extremely sensitive or dangerous reagents

Compared to the traditional methods of dosing dangerous reagents into the entire contents of a round-bottomed flask or jacketed reactor, the nature of flow chemistry – reacting small quantities continuously – means hazardous reagents and intermediates are much more accessible using small volume reactors which limit risk.

Just the mention of an incredibly explosive reagent such as diazomethane is enough to grab the rapt attention of most chemists – but continuous flow makes it incredibly safe as you create tiny quantities of it continuously as demonstrated by Oliver Kappe and his team at the University of Graz – access the fascinating paper here. (If you’re unaware of just how much diazomethane makes chemists quiver, read this blog post!).

2. What would you like to achieve using continuous flow chemistry? Product synthesis

Are you looking to synthesize product(s) anywhere from small scale to pilot to manufacturing scale quantities? All possible in continuous flow.

Imagine flow chemistry as a tap; turn it on and you can fill a cup, but leave it running and you can fill a bath. Of course, the equipment required as you step-up or down each scale will vary – for example, manufacturing-scale synthesis will require pumps that can handle very high flow rates to achieve more product in smaller amounts of time – but the principle remains the same.

A common misconception is that continuous flow chemistry is inherently slower than performing a batch reaction because the quantity of reagents reacting at any one time is small. In reality, the increased pressures and temperatures flow enables can significantly reduce the time required for each reaction, as well as enabling much faster reaction optimization (as explained below).

Reaction optimization

Batch chemistry reactions can be laborious to optimize, often requiring several vials/round-bottomed flasks/jacketed reactors, each with changes in the reaction conditions. In continuous flow, you use automated liquid handling modules, such as the Asia Automated Reagent Injector, along with automation software, to automatically run 10s-100s of reactions on one system.

Inline sample analysis

Would you like to analyze a sample immediately after it is produced to ensure you are creating the right product? Continuous flow systems offer the capability to perform inline sample collection, dilution, and injection directly into your preferred online analysis method.

Depending on your set-up you are not limited to just one. There are many application areas to explore around and within these areas including flow electrochemistry, photochemistry, or In-line workup.

3. Don’t reinvent the wheel: read relevant papers that are related to the chemistry you would like to perform

Thanks to the huge library of papers now available using flow chemistry across a wide range of applications, there’s a good chance that similar chemistry (whether it’s direct application, methodology, or both) has already been performed. Browse as much literature as you can, and use this wealth of information to help improve the initial idea and design of your experiment going forward.

Download a list of recent continuous flow publications using the Syrris Asia Flow Chemistry System.

4. Design your initial experiment

Flow chemistry pumps, pressure, the reactor(s), and some form of manual or automated collection, are the main components of a flow chemistry reactor system.

Each parameter of your chemistry that requires precise control is important in considering which components you will need to add to this and ultimately the final design; view the full list of the available flow chemistry components here.

The various reaction parameters (and the technology that enables them) are explained below;

Pumping and flow rates

What flow rates will you need to obtain the residence times your chemistry requires? The Asia Flow Chemistry Syringe Pump offers highly accurate flow rates from 1 μL to 10 mL/min, enabling both extremely long and extremely fast residence and times.

The design of the pump plays a role as well; syringe pumps provide significantly smoother flow at ultra-slow and fast flow rates and no cavitation compared to peristaltic pumps, for example.

Temperature

What temperature extremes do you need to go to? Will one heating/cooling module be enough or will you need multiple for your various chemistries? Most commercial lab-scale flow chemistry systems offer various heating/cooling modules and the ability to heat/cool different types of reactors, depending on your needs. For the Syrris Asia Flow Chemistry System, chemists can choose from the following;

  • The Asia Heater provides heating for all types of Asia reactors due to an interchangeable adapter. Glass microreactors can be heated to 250 ºC, tube reactors can be heated to 125 ºC (fluoropolymer) or 250 ºC (stainless steel), and solid phase column reactors can be heated to 150 ºC
  • The Asia Chip Climate Controller enables a range of glass microreactors to be cooled or heated from -15 ºC to +150 ºC without the need for an external circulator or cold water supply
  • The Asia Cryo Controller rapidly cools fluoropolymer or stainless steel tube reactors to -70 °C or glass or quartz microreactors to -100 °C
  • The Asia Tube Cooler rapidly cools fluoropolymer or stainless steel tube reactors to -68 °C
Residence time (reaction time) and type of chemistry

How long does your chemistry need to fully react? Glass microreactors offer very high temperatures but relatively short residence times, whereas tube reactors offer much longer residence times but generally lower temperatures (unless stainless steel is used). Column reactors enable the use of solid phase catalysts in your chemistry if required.

Pressure

Operating at pressure enables far higher solvent boiling points, enabling faster reactions and opening up novel chemistry spaces. What pressure(s) will your chemistry require? Will you be working with gases, and/or air and moisture sensitive reagents?

The Asia Pressure Controller enables you to pressurize the system up to 20 bar. The Pressurized Input Store enables the use of air and moisture sensitive reagents but also assists in delivering an extremely smooth flow by minimizing input cavitation and gas bubble formation during pumping at high flow rates

Inline work-up

What kind of in-line work-up or analysis will you be performing? Many continuous flow chemistry systems enable the use of in-line work-up and analytics. For example, the Asia FLLEX (Flow Liquid-Liquid EXtraction) Separator Module is the flow chemistry equivalent of a separatory funnel. Operating continuously, this aqueous workup/extraction module initially mixes the organic product stream with an aqueous phase, then allows time for diffusion to occur before finally splitting the flow back to its constituent parts. It also enables you to separate two-phase mixtures that would be extremely difficult by typical techniques e.g. THF and an aqueous phase, thanks to the use of advanced membrane technology instead of gravity.

The Asia Sampler and Dilutor (SAD) Module enables on-line reaction analysis by offering automated sample extraction, dilution, and transfer to virtually any LCMS, GCMS, UPLC, etc. without stopping the experiment.

5. Perform your first experiments

Once you’ve decided which components you need for your chemistry, it’s time to build your system. Simply set-up each of your separate components and connect them using tubes, and then you’re ready to go.

Like all scientists know too well, it is unlikely you will achieve perfect results after your very first experiment. There are a few tips that can help to make your initial experiments smoother and avoid early frustration:

Prime your flow system and ensure you avoid leaks!

Leaks result in losing solvents or worse, precious reagents, lowering the pressure of your system and introducing air/contaminants. Any of these are detrimental to the smooth running of any flow system.

Run initial experiments at low concentrations

The effectiveness of reactions can be surprising for first-time continuous flow chemists. If your product is susceptible to crashing out of solution, this can happen inside the reactor and blockages can occur. Clearing a blockage isn’t particularly difficult but can be annoying so is best avoided. Increasing concentration is something that can be done during optimization, and it is better to start too low than too high.

Avoid running using the most extreme parameters immediately

Now you have an exciting new set-up available, for the most eager users out there it is tempting to test the maximum performance of your system straight away.

You may come out with less than ideal results, but it is good to become comfortable with the processes that occur and ensure that reactions are safe. (Although, I have yet to meet anyone running at 250 °C and 20 bar who wasn’t a little bit cautious regardless of experience).

6. Change your experiments to help optimize your reaction

Have you finished your initial experiments and noticed the yield of your product is not as high as you would like?

Now begins the optimization stage: concentrations, temperatures, pressures, residence times, and many more variables can be adjusted. All parameters will have an effect, so based on the initial chemistry and your system’s capabilities you can decide which are the best to change. Many flow chemists choose to change one parameter at a time to analyze the effect of each.

Using Design of Experiment (DoE) software allows you to create a matrix of experiments which can alter specific parameters automatically and allow easier observation into the effect of each change.

7. Develop experience, gain confidence (and maybe even get published!)

From the initial stages, you’ll quickly gain experience and confidence in:

  • Setting up flow experiments
  • Expected results versus the actual results
  • Optimizing experiments to help achieve their aims

With time and experience comes confidence, and with confidence comes great chemistry (and with great chemistry comes the chance to be published!).

Speak to Syrris about your chemistry

We’ve been helping chemists to implement continuous flow chemistry into their labs since 2001. If you’re considering implementing continuous flow techniques into your lab, or even if you’re already working in flow but looking to improve your results, simply fill in the contact form and an expert will get back to you.

About Neal Munyebvu (MChem)

As a Flow Chemistry Technical Specialist for the Syrris Support Team, Neal is responsible for installing Asia Flow Chemistry Systems in client sites around the world, helping chemists overcome issues, and enabling chemists to get the most out of their flow chemistry equipment.

Related posts:
Continuous flow chemistry in the pharmaceutical industry

by Andrew Mansfield | Sep 27, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

My first introduction to practical flow chemistry was as a Research Chemist at Pfizer and my first thought was: “why on earth would I want to conduct my chemistry in tiny tubes?” A few years later I was the biggest advocate for it. This blog post explains why…

What is flow chemistry and how does it work?

by Andrew Mansfield | Apr 17, 2018 | Batch chemistry, Flow chemistry, Scale-up, The Flow Chemistry Collection

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

Why perform your chemistry in continuous flow?

by Andrew Mansfield | May 15, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

So why should your lab consider performing your chemistry using continuous flow chemistry techniques? Discover several reasons including faster and reactions, and accessing..

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This is Part #3 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Andrew Mansfield Head of Flow Chemistry, Syrris

Minute read

This is Part #3 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Minute read
Continuous flow chemistry in the pharmaceutical industry

By Andrew Mansfield on September 27th, 2018 in Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

My personal experience with continuous flow in the pharmaceutical industry

Having worked at Pfizer for over 10 years (2001 to 2011), I witnessed the first attempt at introducing continuous flow techniques into the drug discovery and drug development processes.  My first introduction to practical flow chemistry was on a Syrris Africa system – one of the very first systems to be used on the market.  My first thought was: why on earth would I want to conduct my chemistry in tiny tubes?

Fast forward to 2007 and my full-time job was helping Pfizer medicinal chemists adopt flow technologies to solve issues faced in drug discovery.  It was a hugely exciting time where I felt the group were really pushing the boundaries of chemical technology and we were producing some excellent chemistry that was not achievable in batch and solving some extremely problematic synthetic steps.

Flow chemistry systems and techniques have come on a long way since then, and recent years have seen academia around the world publish a wealth of papers on accessing new chemistries and improving existing reactions with continuous flow chemistry techniques. My current position as Head of Flow Chemistry at Syrris enables me to help chemists across a range of industries introduce and perfect their flow chemistry techniques.  As with most new technologies, uptake in industry is usually led by the pharmaceutical industry but many other industries have adopted continuous flow due to the large number of benefits continuous flow exhibits.

Why pharmaceutical chemists are adopting continuous flow

This article covers my thoughts on why the pharmaceutical industry has led the industrial uptake of flow chemistry with a particular focus on drug discovery.  Of course, the most important aspect of adopting flow chemistry in a pharmaceutical industry is to ensure that all departments adopt the technology.  This will allow seamless discovery, rapid development, and optimization through to scaling up of potential drug compounds – rapidly reducing attrition and time to market.  That’s the theory so let’s hope this pans out like this!

Access new chemistries not previously possible

A big draw for a lot of chemists is doing something new, something no other chemist has managed yet. The nature of flow chemistry allows for better control of reaction parameters whether this is mixing, addition, temperature or reaction time. This means that chemists can often benefit from better yielding, more selective and cleaner reactions. Smaller reaction inventory (small flow reactors) means less reaction occurring at any point which reduces the inherent risks of performing certain chemistries. If we add the ability to carry out telescoped reactions where multiple reactions can be carried out in sequence then this technique opens up exciting opportunities for the design of drug candidates.

The ability to synthesize unstable intermediates and hazardous reagents in-situ allows for the exploration of novel synthetic routes potentially reducing reaction steps and work-up and opening up novel areas of chemical space.

More control: better results and improved safety

The capability of very fast heating and cooling of flow reactors due to this high surface area/volume ratio means that exotherms generated during the reaction are dissipated very quickly. This is beneficial as these exothermic reaction pathways are often difficult to control under batch conditions have are often avoided due to the inherent risk.

Thanks to the small volume reactors used in flow chemistry systems, it’s easy to pressurize reactions which significantly increases the boiling point of solvents (typically by 100-150 ºC depending on the solvent). Not only does this result in faster reactions (thank you, Arrhenius rate law!), it also enables chemistry otherwise impossible or incredibly difficult and dangerous to achieve – try pressurizing a glass vessel to 20 bar and see what happens! (That’s a joke, please don’t try that!)

Solvent boiling point
Solvent 1 bar 7 bar 17 bar
 Dichloromethane 41 °C 109 °C 153 °C
 Methanol 65 °C 138 °C 185 °C
 Water 100 °C 181 °C 231 °C

Take the example of Dr. György Túrós, a Research Scientist at the innovative pharmaceutical company, Gedeon Richter, who, along with his team, is using flow chemistry techniques to improve the design and synthesis of original central nervous system (CNS) drugs by performing new chemistry.

“We purchased an Asia flow chemistry reactor in June 2012 and are reaping the benefits of using flow chemistry techniques. The system has extended the range of chemistries available to us, allowing us to work at much higher pressures and temperatures – sometimes above a solvent’s boiling point – to create completely new heterocyclic scaffolds.”

Efficient reaction optimization

The use of flow chemistry for reaction optimization allows a much more efficient process. The precise control of reaction parameters such as time, temperature, molar ratios of reagents etc. can readily be screened with the use of automation allowing the chemist to step away and get on with something else. Compared to common traditional time-consuming methods where multiple vials/flasks are used for each iteration, flow chemistry uses only the one reactor for as many conditions the chemist wants to see. The addition of simple liquid handles also allows for the screening of reagents and reactants adding further benefit. (This is explained in more detail with an example in the “why perform chemistry in continuous flow” blog post).

Fast library synthesis

Due to the benefits flow chemistry can offer chemists – e.g. better reaction control, greater selectivity, access to increased chemical space – it is an excellent method for the rapid synthesis of vast compound libraries and has been adopted in some form by all of the top pharmaceutical companies in the world. Drug compound Libraries can be synthesized and screened quickly with the use of an autosampler to avoid manual loading of reagents between experiments, and one flow chemistry reactor can automatically run 100s of experiments with minimal set-up time. Furthermore once a hit is found it’s extremely easy to resynthesize that compound for further study.

Take the example of Antimo Gioiello, Associate Professor in Organic Synthesis and Medicinal Chemistry at the Department of Pharmaceutical Sciences at the University of Perugia. His laboratory is focused on the discovery and characterization of synthetic and natural bioactive compounds, and the development of pharmaceutical formulations to improve the pharmacokinetics and pharmacodynamics of lead compounds. His laboratory is particularly interested in steroid chemistry and receptors and has experience in the implementation of enabling technologies – such as flow chemistry – to assist complex syntheses, generation of lead-like compound libraries and large-scale compound preparation. After implementing continuous flow techniques, he said:

“… it is also really useful for compound library generation, screening reactions and optimization studies, as it is easy to work with small amounts of compound, which is important when you work with costly materials, such as enzymes”

Bi-phasic and heterogeneous reactions

Liquid-liquid and gas-liquid bi-phasic reactions are common in drug synthesis. The use of static mixers and microreactors to create very large surface interactions in these systems can help accelerate these processes.

Many heterogeneous reaction conditions are used in the drug development process whether these are catalysts, enzymes or simpler reactants. Using packed bed flow reactors allow these heterogenous liquid-solid reactions by enabling solids or supported solids to be packed into a rigid column. The liquid phase is then pumped through this packed column and the reaction occurs. Often the ratio of substrate to reagent is such that reaction rates are increased.

Easy access to electrochemistry for rapid drug metabolism testing

Electrochemistry is a very underused synthetic technique and is notoriously difficult chemistry to access, but, has become simple through flow chemistry. Current research has shown that flow electrochemistry can mimic certain oxidative pathways generated in the human liver, enabling chemists to quickly and easily synthesize metabolites, positively impacting the drug discovery process in time and money.

Reaction calorimetry for drug discovery scale-up safety studies

By utilizing reaction calorimeters to identify the reaction enthalpy at the laboratory scale (and at an early stage), process chemists can gain valuable information in the selection of robust, safe, and scalable routes to drug candidates, saving development costs further through the process.

Oliver Kappe and his research group at the University of Graz, have recently published a paper on performing reaction calorimetry in continuous flow (using a Chemisens Calorimeter and an Asia Flow Chemistry System). Access the paper here.

Continuous work-up

After the synthesis, it is more often than not necessary to work-up the reaction to isolate the compound of choice. Flow chemistry not only allows us to perform our reaction continuously but also this purification. In-line extraction using porous membrane separators create continuous separating funnels allowing pharmaceutical chemists to perform laborious process saving time and often solvent. In fact, this technique can be used for work-up at any step of the synthesis route enabling chemists to clean intermediates en route.

The use of packed bed reactors are not confined to reactions but can be also be used for in-line work-up and sequestering of unwanted reactants and by-products from the reaction mixture.

In-line monitoring and analysis

By incorporating in-line analysis into a flow system, real-time monitoring of a reaction is possible. Analytical techniques such as IR, Ramen, UV, and even NMR can be used for in-line analysis and LC and MS techniques for off-line analysis. This approach enables drug discovery chemists to analyze their chemistry without the need for product collection.

Significant developments in this area also mean that software can be designed to link to and automatically control flow systems, obtain results and edit reaction parameters in real time; Enabling flow systems to become self-optimizing.

Scale-up to continuous manufacturing

Once a compound has been thoroughly screened, tested and assessed to be a suitable drug candidate, chemists are required to produce larger quantities of this material and develop suitable scale-up processes hopefully all the way to production scales. Flow chemistry lends itself very well to this scaling up the process. Many Pharmaceutical companies are applying this knowledge to quickly transition research/discovery through Development and into the Continuous Manufacturing of API.

The future of continuous flow chemistry in the pharmaceutical industry

With the extremely challenging process of bringing a new medicine to market costing an average of $2.6B and taking up to 12 years, it is vital that pharmaceutical companies optimize the drug discovery and development process, to maximize the lifetime of the medicine before patents expire. The clear benefits continuous flow chemistry offers will likely reduce costs and reduce the time it takes to bring new drugs to market.

Recent FDA approval has opened the path for pharmaceutical companies to use flow chemistry for the entire process of drug discovery, drug development, and drug manufacture, enabling all areas of the drug process to enjoy the benefits continuous flow process offer.

With clear benefits and a rapidly-growing database of papers for chemists to draw from, the future of continuous flow in the pharmaceutical industry will be an interesting one – watch this space!

Speak to me about your chemistry

To discuss how flow chemistry techniques could improve your chemistry, .

About Andrew Mansfield

Andrew was formerly a Research Chemist at Pfizer and spent much of his career focusing on introducing flow chemistry technologies, meaning Andrew is well placed to lead Syrris’ flow chemistry offering. Read Andrew’s bio here.

Related posts:
Continuous flow chemistry in the pharmaceutical industry

by Andrew Mansfield Sep 27, 2018 Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

My first introduction to practical flow chemistry was as a Research Chemist at Pfizer and my first thought was: “why on earth would I want to conduct my chemistry in tiny tubes?” A few years later I was the biggest advocate for it. This blog post explains why…

What is flow chemistry and how does it work?

by Andrew Mansfield Apr 17, 2018 Batch chemistry, Flow chemistry, Scale-up, The Flow Chemistry Collection

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

Why perform your chemistry in continuous flow?

by Andrew Mansfield May 15, 2018 Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

So why should your lab consider performing your chemistry using continuous flow chemistry techniques? Discover several reasons including faster and reactions, and accessing novel chemistries not possible in..

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This is Part #1 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Andrew Mansfield Head of Flow Chemistry, Syrris

Minute read

This is Part #1 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Minute read
What is flow chemistry? How do flow chemistry systems work?

By Andrew Mansfield on April 17th, 2018 in Batch chemistry, Flow chemistry, Scale-up, The Flow Chemistry Collection

Famous chemistry professors are doing it. Magazines are writing about it. Students are focusing on it. Research and development chemists are perfecting reactions with it, and scale-up chemists are producing products with it.

You’ve undoubtedly heard about flow chemistry, but unless you’ve used our R&D100 Award-winning Asia Flow Chemistry System, you might still be wondering – what, exactly, is flow chemistry?

The basics of flow chemistry

Though it goes by a number of names – “plug flow chemistry”, “microchemistry”, and “continuous flow chemistry” – the principles of flow chemistry are the same.

Flow chemistry is the process of performing chemical reactions in a tube, capillary or micro structured device (a flow reactor).

What this means is that reactive components are pumped first through a mixing device, either a t-junction or a static mixer and then flowed down a temperature-controlled flow reactor; a radically different approach from the traditional chemistry method of performing reactions in glass flasks or jacketed reactors.

Further to maintaining a fixed temperature to promote a reaction flow chemistry lends itself perfectly to using photon or electron flux to mediate continuous reactions.

The differences between plug flow and continuous flow chemistry
Though often used interchangeably, there is a small difference between “plug flow chemistry” and “continuous flow chemistry”.

Continuous flow chemistry is just that – continuous. The reactive materials are continuously pumped with no breaks, resulting in a continuous stream of chemicals, and therefore a continuous stream of end product.

Plug flow chemistry is where alternating “plugs” of reactive materials and solvent are pumped, where each plug is considered as a separate entity (a discrete reaction mixture). These plugs never meet – they are separated by the system solvent – so the conditions in which they go through the flow chemistry system (i.e. temperature, stoichiometry, residence time etc.) can be changed to observe how the reaction changes.

Plug flow lends itself well for method development, reaction optimization, and library synthesis, where smaller amounts of material are required.

Intelligent systems, such as the Asia Flow Chemistry System, can automate these processes. Automation enables a range of reaction conditions, reagents or analogs to be explored with the automated collection of individual plugs, sending the product into one collection vial and the solvent to waste.

What is a mixing junction?

So what do we mean by a “mixing junction”? A mixing junction is where our reagent streams meet before flowing into our flow reactor. Often this is a simple t-piece but if faster more efficient mixing is required, e.g. for reactions needing fast mass transfer, a static mixer can be used. The two types of mixing junctions contribute to different mixing regimes, diffusive and turbulent.

When a fluid is flowing through a closed channel such as a flow reactor, either of two types of flow may occur depending on the velocity and viscosity of the fluid: laminar flow or turbulent flow. Laminar flow tends to occur at lower velocities, below a threshold at which it becomes turbulent. Turbulent flow is a less orderly flow regime that is characterized by eddies or small packets of fluid particles, which result in lateral mixing. In non-scientific terms, laminar flow is smooth, while turbulent flow is rough.

Mixing in laboratory scale flow systems such as Asia mixing will occur through the lateral mixing regime of laminar flow. Diffusion mixing can be slow however the diameter of the tubing used on these scales is small and diffusive mixing is very significant, and more notably reproducible. 

When rapid mixing is required, e.g. in reactions that require fast mass transfer, turbulent flow is necessary. Turbulent mixing is generated in flow generally by a micromixer (static mixer) of some type.


What types of flow reactors are available?

A flow reactor is essentially the equivalent of a round-bottomed flask or a jacketed reactor – it’s where the reaction occurs in a flow chemistry system.

As described earlier two (or more) separate solutions of reactive compounds are brought together, mixed and flowed through a single, temperature-controlled channel in order to react them.

Flow reactors come in a variety of shapes and sizes, but they all perform the same role: to allow chemical reactions to take place continuously. There are a few characteristics that flow reactors should aim to provide:

  • Flexibility in volume to allow a large range of residence (reaction) times
  • Excellent mixing
  • Excellent heat transfer
  • Good visibility where possible
  • Ability to perform different types of chemistry (i.e. Homogeneous and heterogeneous)

The common types of flow reactor are outlined below and are all available with the Syrris Asia Flow Chemistry System.

Glass microreactor chips

Glass microreactor chips are the most commonly known type of reactor used in a flow chemistry system. A piece of glass is “etched” with a particular design (depending on the application); the design helps determines how wide the mixing channel is and how the mixing occurs. A longer channel enables a longer residence time than a shorter channel (assuming the pump flow rate is the same).

Glass microreactor chips are inserted into chip climate controllers which maintain a set temperature throughout the entire chip and are the perfect system for chemists just starting out in flow chemistry.

Tube reactors

Tube reactors are effectively long tubes wrapped around a heated or cooled coil. The large length of the coil offers far longer residence times than glass microreactor chips (or much faster pump flow rate) if the application requires it.

Tube reactors are available in different materials, depending on the application. Material such as PTFE allows good visibility of the flow reaction but are limited for high-temperature reactions. Stainless Steel and Hastelloy enable higher temperatures and pressures to be achieved.

Column reactors

Column reactors are typically glass columns and allow heterogeneous chemistry to be performed, small diameter tubes don’t like having solids passed through them. Solid-supported reagents, catalysts, enzymes, and scavengers can be employed – this will be explored in further blog posts.

So why are chemists adopting flow chemistry into their reactions?

By saying flow chemistry is essentially one more tool to add to the chemist’s tool-box does not do this synthetic technique the justice it deserves. Flow chemistry techniques allow the precise control of reaction conditions such as stoichiometry, mixing, temperature control, and reaction time. Controlling these factors gives excellent reaction control often leading to greater yields and better selectivity.

FYI – We’ve put a whole blog post and infographic together to explain the 9 main benefits flow chemistry offers. Read it here.

There are a number of reasons chemists across all industries are introducing or switching to, continuous flow chemistry, but in short, the main benefits are;

Conclusion

So now you know what flow chemistry is, how it works, and the different types of mixing junctions available. But if you’re performing chemistry in batch at the moment, why would you bother switching to continuous flow? The “why perform your chemistry in continuous flow?” blog post explains the 9 main reasons chemists in various industries are adopting flow chemistry into their labs.

About Dr. Andrew Mansfield

Andrew was formerly a Research Chemist at Pfizer and spent much of his career focusing on introducing flow chemistry technologies, meaning Andrew is well placed to lead Syrris’ flow chemistry offering. Read Andrew’s bio here.

Related posts:
Continuous flow chemistry in the pharmaceutical industry

by Andrew Mansfield | Sep 27, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

My first introduction to practical flow chemistry was as a Research Chemist at Pfizer and my first thought was: “why on earth would I want to conduct my chemistry in tiny tubes?” A few years later I was the biggest advocate for it. This blog post explains why…

What is flow chemistry and how does it work?

by Andrew Mansfield | Apr 17, 2018 | Batch chemistry, Flow chemistry, Scale-up, The Flow Chemistry Collection

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

Why perform your chemistry in continuous flow?

by Andrew Mansfield | May 15, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

So why should your lab consider performing your chemistry using continuous flow chemistry..

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Dr. Omar Jina, CCO, Syrris

minute read
Continuous flow microreactors in nanoparticle synthesis
By Dr. Omar Jina on August 31st, 2018 in Flow chemistry

Although the pharmaceuticals industry has been the main driving force behind the rise of flow chemistry since early 2000, other chemicals-related industries have now taken an interest in this new laboratory technique. For years, organic synthesis has been the main focus of all research work conducted on flow chemistry equipment and the advantages offered by flow chemistry are now well established and documented. Other fields – such as biofuels, petrochemistry, and nanoparticle synthesis – can also benefit from these same advantages.

Syrris has seen growing demand for the Asia Flow Chemistry System since its launch in 2012, from companies and universities specializing in nanoparticle synthesis. In addition, there has been an increasing number of publications on the subject of the continuous formation of nanoparticles, quantum dots, and colloidal metals.

Nowadays, nanoparticles are used in a wide range of fields because of their physical and chemical properties, resulting in a growing demand that challenges chemists to provide a reliable supply of large amounts of good quality nanoparticles.

Various chemical methods have been applied to produce nanoparticles in batch, but these all present problems: non-homogeneity in mixing, the importance of aging, the difficulty of accurate temperature control and questionable reproducibility from batch to batch. Often a batch process relies as much on the skill of the chemist as on the chemistry itself.

All of these issues become even more difficult to address when scaling up the manufacturing. Flow chemistry offers a number of advantages that help to overcome these challenges, notably fast and reproducible mixing, excellent temperature control, the ability to carry out pressurized reactions, modularity and easy scale-up.

Accurate reaction control in nanoparticle synthesis

One of the key characteristics of a flow chemistry system is the very small diameter of its internal wetted channels, which are typically in the range of 0.3-1 mm. This has a huge impact on both the quality of mixing and temperature control in microreactors.

The flow conditions in a system are defined by the Reynolds number (Re), i.e. the mean viscosity of fluid multiplied by characteristic dimension and divided by kinematic viscosity. For a low Reynolds number (below 4,000), flow conditions are laminar; for a high Reynolds number, they are turbulent. In a continuous flow chemistry system, the channel dimension results in the Reynolds number always being small (usually <100), therefore flow conditions are always laminar.

Microreactor size (µL) Total flow rate (µL/min) Estimated mixing volume (µL) Estimated mixing time (secs) Residence time (mins)
1 62.5 60 3.3 3.30 1.04
2 62.5 240 6.6 1.65 0.26
3 250 240 12.6 3.15 1.04
4 250 1000 5.6 0.34 0.25
5 250 5000 5.6 0.07 0.05
6 1000 240 19.8 4.95 4.17
7 1000 1000 19.8 1.19 1.00
8 1000 5000 19.8 0.24 0.20

Under laminar flow conditions, mixing is diffusion-limited and extremely fast. Typically, in a Syrris microreactor, the mixing is in the order of 1-5 seconds. It is also very reproducible, as the shape of the microreactor does not change and no physical stirrer is involved.

The mixing time can be reduced even further to below one second, by using specially designed microreactors called micromixer chips. This makes the micromixer chip a reactor of choice for nanoparticle synthesis protocols, where mixing is a critical parameter.

The small diameter of the microreactor channels also means that its surface-to-volume ratio is extremely high. This results in excellent heat transfer and fast, efficient temperature control and response. Not only is there no temperature gradient – as seen in a batch reactor – but any exotherm or endotherm is very quickly absorbed, maintaining a homogeneous temperature throughout the microreactor.

Prof. Seeberger and co-workers at the Max Planck Institute of Colloids & Interfaces noted the key role played by precise control over experimental conditions in a paper describing a process for continuous quantum dot synthesis in a glass microreactor. The quantum dots synthesized in continuous flow by Seeberger’s group have a much narrower particle distribution than those obtained using a similar batch protocol. This trend has also been shown by Fitzner and co-workers for the preparation of colloidal gold in a flow microreactor.5

More recently, a continuous synthesis protocol for the synthesis of iron nanoparticles has been developed in Syrris’s laboratory. Here, the size of the particle is critical, as it determines its paramagnetic characteristics. Performing the synthesis in microreactors allowed ultra-fast mixing and, subsequently, the formation of fine magnetic iron nanoparticles with better quality and reproducibility than in batch synthesis.

Process flexibility in continuous flow

Other advantages of using a continuous flow chemistry system for making nanoparticles include easy scalability, the modularity of the system, and the ability to carry out high-pressure reactions and multi-step processes.

A flow chemistry system consisting of a syringe pump, a microreactor, and a pressure controller is a good starting point for nanoparticle synthesis. This system will allow the user to run a series of experiments to determine the best reaction conditions. Once the optimized reaction conditions have been established, the same set-up is used to synthesize multi-gram quantities of nanoparticles continuously in suspension.

By adding an autosampler and automating the system via software, the system’s capabilities are expanded and it becomes ideal for process optimization and the study of reaction parameters. A series of experiments can quickly be set up, run automatically and all the samples collected separately for analysis. Fitzner and co-workers used this kind of set-up to study the effect of reaction temperature on the particle size distribution of colloidal gold.

Flow chemistry systems are also very easily and safely pressurized using a back pressure regulator. This allows solvents to be heated above their boiling point, which is commonly called ‘superheating’, thus increasing the reaction kinetics and creating ultra-fast reaction conditions. On top of this, pressurizing the system minimizes any degassing effect that might occur when a reaction produces gas as a by-product.

Finally, microreactors and flow chemistry are ideal for multi-step processes, commonly called ‘telescoping synthesis’. By simply connecting the output of the first reactor to the input of a second, a two-step reaction can be set up. Seeberger’s group used this flow chemistry benefit in their quantum dot process. First, cadmium-selenium nanoparticles were formed in a microreactor, then the nanoparticles were covered with zinc sulfide in a second microreactor connected in series. This two-step reaction was run as one continuous process, therefore saving time and manual effort.

Conclusion

Flow chemistry is as an effective technology for the optimisation of nanoparticle reactions and their large-scale synthesis. Among the key advantages of flow chemistry which can assist the nanoparticle industry are excellent reaction control, flexibility and easy scale-up. These benefits are of such importance that, in the near future, continuous-flow is likely to become the method of choice for nanoparticle synthesis.

Watch the experiment in the video below.

Iron Magnetic Nanoparticle Synthesis - Flow Chemistry by Syrris - YouTube
References:

M. Drobot, Speciality Chemicals Magazine 2011, 31(6)
C. Wiles & P. Watts, Green Chemistry 2012, 14, 38-54
L. Malet-Sanz & F. Susanne, J. Med. Chem., forthcoming
P. Laurino, R. Kikkeri & P.H. Seeberger, Nature 2011, 6, 1209-1220
M. Wojnicki, K. Paclawski, M. Lutyblocho, K. Fitzner, P. Oakley & A. Stretton, Rudy I Metale Niezelane 2009, 12

About Dr. Omar Jina

Omar’s role as Chief Commercial Officer includes overseeing Marketing, Sales, Product Management, Application & Support of all Blacktrace brands (Syrris is one of 5 Blacktrace brands). Read Omar’s bio here.

Related posts:
What is flow chemistry and how does it work?

by Andrew Mansfield | Apr 17, 2018 | Flow chemistry, The Flow Chemistry Collection

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

Why perform your chemistry in continuous flow?

by Andrew Mansfield | May 15, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

So why should your lab consider performing your chemistry using continuous flow chemistry techniques? Discover several reasons including faster and reactions, and accessing novel chemistries not possible in batch

Solid phase catalysis in continuous flow

by Neal Munyebvu | Jun 22, 2018 | Batch chemistry, Flow chemistry

What is catalysis? What is a catalyst? How does catalysis work? And why would you want to perform catalysis in continuous flow? Flow Chemistry Applications Specialist, Neal, explains why chemists like to incorporate catalysts into their chemistry and the benefits they bring…

Continuous flow microreactors in nanoparticle synthesis

by Dr. Omar Jina | Aug 31, 2018 | Flow chemistry

We’ve seen rapidly increasing interest in flow chemistry systems from companies and universities specializing in nanoparticle synthesis. Offering greatly improved reaction control, mixing, process flexibility, and reproducibility, it’s easy to see why many chemists are switching to continuous flow. Read more here…

The post Continuous flow microreactors in nanoparticle synthesis appeared first on Syrris chemistry blog.

Read Full Article
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This is Part #1 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Andrew Mansfield Head of Flow Chemistry, Syrris

Minute read

This is Part #1 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.

Minute read
What is flow chemistry? How do flow chemistry systems work?

By Andrew Mansfield on April 17th, 2018 in Flow chemistry, The Flow Chemistry Collection

Famous chemistry professors are doing it. Magazines are writing about it. Students are focusing on it. Research and development chemists are perfecting reactions with it, and scale-up chemists are producing products with it.

You’ve undoubtedly heard about flow chemistry, but unless you’ve used our R&D100 Award-winning Asia Flow Chemistry System, you might still be wondering – what, exactly, is flow chemistry?

The basics of flow chemistry

Though it goes by a number of names – “plug flow chemistry”, “microchemistry”, and “continuous flow chemistry” – the principles of flow chemistry are the same.

Flow chemistry is the process of performing chemical reactions in a tube, capillary or micro structured device (a flow reactor).

What this means is that reactive components are pumped first through a mixing device, either a t-junction or a static mixer and then flowed down a temperature-controlled flow reactor; a radically different approach from the traditional chemistry method of performing reactions in glass flasks or jacketed reactors.

Further to maintaining a fixed temperature to promote a reaction flow chemistry lends itself perfectly to using photon or electron flux to mediate continuous reactions.

The differences between plug flow and continuous flow chemistry
Though often used interchangeably, there is a small difference between “plug flow chemistry” and “continuous flow chemistry”.

Continuous flow chemistry is just that – continuous. The reactive materials are continuously pumped with no breaks, resulting in a continuous stream of chemicals, and therefore a continuous stream of end product.

Plug flow chemistry is where alternating “plugs” of reactive materials and solvent are pumped, where each plug is considered as a separate entity (a discrete reaction mixture). These plugs never meet – they are separated by the system solvent – so the conditions in which they go through the flow chemistry system (i.e. temperature, stoichiometry, residence time etc.) can be changed to observe how the reaction changes.

Plug flow lends itself well for method development, reaction optimization, and library synthesis, where smaller amounts of material are required.

Intelligent systems, such as the Asia Flow Chemistry System, can automate these processes. Automation enables a range of reaction conditions, reagents or analogs to be explored with the automated collection of individual plugs, sending the product into one collection vial and the solvent to waste.

What is a mixing junction?

So what do we mean by a “mixing junction”? A mixing junction is where our reagent streams meet before flowing into our flow reactor. Often this is a simple t-piece but if faster more efficient mixing is required, e.g. for reactions needing fast mass transfer, a static mixer can be used. The two types of mixing junctions contribute to different mixing regimes, diffusive and turbulent.

When a fluid is flowing through a closed channel such as a flow reactor, either of two types of flow may occur depending on the velocity and viscosity of the fluid: laminar flow or turbulent flow. Laminar flow tends to occur at lower velocities, below a threshold at which it becomes turbulent. Turbulent flow is a less orderly flow regime that is characterized by eddies or small packets of fluid particles, which result in lateral mixing. In non-scientific terms, laminar flow is smooth, while turbulent flow is rough.

Mixing in laboratory scale flow systems such as Asia mixing will occur through the lateral mixing regime of laminar flow. Diffusion mixing can be slow however the diameter of the tubing used on these scales is small and diffusive mixing is very significant, and more notably reproducible. 

When rapid mixing is required, e.g. in reactions that require fast mass transfer, turbulent flow is necessary. Turbulent mixing is generated in flow generally by a micromixer (static mixer) of some type.


What types of flow reactors are available?

A flow reactor is essentially the equivalent of a round-bottomed flask or a jacketed reactor – it’s where the reaction occurs in a flow chemistry system.

As described earlier two (or more) separate solutions of reactive compounds are brought together, mixed and flowed through a single, temperature-controlled channel in order to react them.

Flow reactors come in a variety of shapes and sizes, but they all perform the same role: to allow chemical reactions to take place continuously. There are a few characteristics that flow reactors should aim to provide:

  • Flexibility in volume to allow a large range of residence (reaction) times
  • Excellent mixing
  • Excellent heat transfer
  • Good visibility where possible
  • Ability to perform different types of chemistry (i.e. Homogeneous and heterogeneous)

The common types of flow reactor are outlined below and are all available with the Syrris Asia Flow Chemistry System.

Glass microreactor chips

Glass microreactor chips are the most commonly known type of reactor used in a flow chemistry system. A piece of glass is “etched” with a particular design (depending on the application); the design helps determines how wide the mixing channel is and how the mixing occurs. A longer channel enables a longer residence time than a shorter channel (assuming the pump flow rate is the same).

Glass microreactor chips are inserted into chip climate controllers which maintain a set temperature throughout the entire chip and are the perfect system for chemists just starting out in flow chemistry.

Tube reactors

Tube reactors are effectively long tubes wrapped around a heated or cooled coil. The large length of the coil offers far longer residence times than glass microreactor chips (or much faster pump flow rate) if the application requires it.

Tube reactors are available in different materials, depending on the application. Material such as PTFE allows good visibility of the flow reaction but are limited for high-temperature reactions. Stainless Steel and Hastelloy enable higher temperatures and pressures to be achieved.

Column reactors

Column reactors are typically glass columns and allow heterogeneous chemistry to be performed, small diameter tubes don’t like having solids passed through them. Solid-supported reagents, catalysts, enzymes, and scavengers can be employed – this will be explored in further blog posts.

So why are chemists adopting flow chemistry into their reactions?

By saying flow chemistry is essentially one more tool to add to the chemist’s tool-box does not do this synthetic technique the justice it deserves. Flow chemistry techniques allow the precise control of reaction conditions such as stoichiometry, mixing, temperature control, and reaction time. Controlling these factors gives excellent reaction control often leading to greater yields and better selectivity.

FYI – We’ve put a whole blog post and infographic together to explain the 9 main benefits flow chemistry offers. Read it here.

There are a number of reasons chemists across all industries are introducing or switching to, continuous flow chemistry, but in short, the main benefits are;

Conclusion

So now you know what flow chemistry is, how it works, and the different types of mixing junctions available. But if you’re performing chemistry in batch at the moment, why would you bother switching to continuous flow? The “why perform your chemistry in continuous flow?” blog post explains the 9 main reasons chemists in various industries are adopting flow chemistry into their labs.

About Dr. Andrew Mansfield

Andrew was formerly a Research Chemist at Pfizer and spent much of his career focusing on introducing flow chemistry technologies, meaning Andrew is well placed to lead Syrris’ flow chemistry offering. Read Andrew’s bio here.

Related posts:
What is flow chemistry and how does it work?

by Andrew Mansfield | Apr 17, 2018 | Flow chemistry, The Flow Chemistry Collection

Let’s start with the basics and explain what flow chemistry actually is and talk a bit about why it’s so useful. Flow chemistry is the process of performing chemical reactions in a tube or pipe. Read on to learn more…

Why perform your chemistry in continuous flow?

by Andrew Mansfield | May 15, 2018 | Batch chemistry, Flow chemistry, Reaction calorimetry, Scale-up, The Flow Chemistry Collection

So why should your lab consider performing your chemistry using continuous flow chemistry techniques? Discover several reasons including faster and reactions, and accessing novel chemistries not possible in batch

Solid phase catalysis in continuous flow

by Neal Munyebvu | Jun 22, 2018 | Batch chemistry, Flow chemistry

What is catalysis? What is a catalyst? How does catalysis work? And why would you want to perform catalysis in continuous flow? Flow Chemistry Applications Specialist, Neal, explains why chemists like to incorporate catalysts into their chemistry and the benefits they bring…

Continuous flow microreactors in nanoparticle synthesis

by Dr. Omar Jina | Aug 31,..

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