We asked 6 questions to our Flow Chemistry experts : Jean-Baptiste Rouchet, Synthetic technologies expert for Continuous flow and Jean-Yves Lenoir, R&D Manager for Flow Chemistry. They share their insights on this valuable tool to develop safe and competitive processes.
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Jean-Baptiste Rouchet: Flow chemistry has gained renewed interest over the past two decades as an alternative to the traditional batch process. This method can handle reactions and conditions that are challenging or difficult to implement at large scale in batch (such as exothermic process, high pressure or photochemical processes), making it a valuable tool for optimizing the synthesis of compounds, including active pharmaceutical ingredients (APIs). Plurality of commercially equipment give the opportunity to design and use modular and flexible equipment for custom synthesis. These assets are enabling the development of small, agile production plants that can be used for the manufacture of multiple products — with easy re-configuration allowing for rapid product changeover.
These elaborate processes can be performed under safer conditions and with competitive economics for the reshoring of processes previously only performed overseas. Furthermore, the environmental footprint can be reduced not only through lower energy and solvent consumption, but also through a significantly smaller floor space footprint. The infrastructure needed varies greatly and depends on the available chemistry, cost of goods, volumes required and the hazard profile of a transformation. Most of CDMO player’s have identify this key technology to as cutting-edge.
What has made this technology so successful is also from a regulatory point of view. The US Food and Drug Administration (FDA) committed to encourage the adoption of continuous manufacturing processes. Leveraging quality improvement using precise control strategy and the advantage of continuous analysis (in-line analysis) to avoid out of specification process as far as possible. This driving force from the FDA is supported by the publication of the ICH Q13 guideline recommendation for adoption and implementation of continuous manufacturing for drug substance, API, or pharmaceutical product release in . These quality aspects are often at the root of drug shortages and recalls.
Jean-Baptiste Rouchet : Flow chemistry offers a broad scope of capabilities. The key advantages are enhanced mass and heat transfer, reduce the risk and severity of adverse events, improved reaction efficiency, reduced waste, easier scalability, and improved reproducibility.
Used adequately, continuous flow chemistry can offer greater control of process parameters such as pressure and temperature, the involvement of highly reactive intermediates, thus extending the safe operating range of chemical processes and enabling companies to develop APIs to their full potential.
Overall, flow chemistry offers greater flexibility and agility in the manufacturing of APIs. The time-to-market of new APIs can be significantly reduced along with improved supply chain resilience. Supply chain security and improvements in process sustainability are strong emerging drivers for the adoption of such technology.
Flow chemistry will not replace batch chemistry. It has certain advantages that batch chemistry is difficult to implement, but has limitations in the implementation of certain processes especially with the use of solids. Although solutions do exist, their use on a pilot or commercial scale remains very limited. Flow chemistry will complement batch chemistry in the search for the most efficient and cost-effective way to deliver the drugs of the future.
At SEQENS, we rely on our dedicated and highly experienced flow chemists team who can deliver successful projects from the laboratory scale to hazard evaluation, to the engineering expertise to implement flow synthesis on higher scale (such as commercial scale), and understanding where flow chemistry can fit in and complement the batch chemistry, and deliver an expertise to our customers for supplying a product that is a high quality and high yielding.
Jean-Yves Lenoir : First of all, I would prefer avoiding the term “flow chemistry”. Actually, the chemistry is always the same whether it occurs in continuous or batch reactor. The term continuous flow process is more appropriate.
One of the main features of Plug Flow Reactors (PFR) is their enhanced heat transfer performance. It allows a very fine control of the temperature which is mandatory with unstable reaction mixtures like those of nitration or diazotization reactions for example. The high heat transfer performance conjugated with the small volume of PFRs make the process safer. A runaway reaction due to overheating is very unlikely. Thus, a continuous flow process must be considered each time a thermal event may occur.
A strict temperature control also has a beneficial effect on the product quality. Formation of by-products from thermal degradation is avoided.
But there is also in many cases another impact of the use of PFR on the quality. Stoichiometry of the reagents is controlled by the flowrate of the feeding pumps at the inlet of the reactor. The reaction occurs along the reactor and the formed product is collected at the outlet. So, the product never meets neat reagents. This feature of PFRs allows limiting over-reaction.
Some reactions only occur at high temperature because of a high activation energy. Heating big batch reactors to these high temperatures is time and energy consuming. Furthermore, heating in a reasonable time a large volume of material induces a high temperature difference between the reactor wall and its content. The high wall temperature is often a source of thermal degradation. Considering the huge heat transfer capacity of PFRs, the heating can be very fast and as only a small amount of material is heated at once, the energy consumption is reduced. For harsh reaction conditions, continuous flow process must also be considered.
Generally, high temperature reactions are carried out in high boiling point solvents which are often toxic and difficult to eliminate. Thanks to the pressure resistance of PFR due to their small volume, reactions can be run in lower boiling point solvents under pressure. Greener solvents can be chosen regardless of their boiling point. The high temperature and pressure achievable also allow minimizing the excess of reagents necessary to complete the conversion under milder conditions.
Jean-Yves Lenoir : Since , we have worked on more than 20 projects, so we have many examples.
The first that comes to my mind is a decarboxylation reaction. It is not a dangerous reaction with huge heat release nor unstable reaction mixture. The reaction was first developed in batch. Heating to 140°C was necessary to reach the activation energy and make the reaction occur. At that temperature, 5 hours heating were necessary to reach completion. As the solvent chosen was water, a high-pressure vessel was needed at that temperature. By switching to a PFR, it became easy to heat to 200°C under 17 bar (vapor pressure of water at this temperature) and the conversion was completed within 10 minutes.
Another general example is cryogenic conditions. Reaction that involves organometallics are commonly carried out at very low temperatures in batch due to the instability of the metalated species over the long addition times necessary to keep the mixture at this temperature. In continuous flow process, they can generally be run at 0°C or even 20°C. With residence times as short as few seconds for the metalation reaction and reaction with electrophiles, unstable intermediates do not have time to undergo degradation. A significant energy saving can be achieved by avoiding cryogenic cooling.
Jean-Baptiste Rouchet : At SEQENS, we have the expertise and assets for conducting multipurpose flow chemistry from lab scale to commercial scale. We can produce at ton scale within cGMP domain on our pilot unit. Taking advantage of the homothetic character offered by continuous technology, we have laboratory equipment that enables easy transfer to production scale.
If you are looking for more details, kindly visit Lianhe Aigen.
Our modules can afford high pressure (up to 20 bar) and a range of temperature (-20°C to 200°C). The resistance of our equipment material can allow us to deal with a large panel of reaction conditions, using corrosive or oxidative media such as nitration , but also handling gas reagent to perform processes. We have integrated process analytical technology (PAT) tools to monitor the process involved and this unit is connected to continuous work-up system.
We know that each process is unique, and that in order to offer the most appropriate solution, I can only recommend to our customer to come to us and visit our assets and meet our teams in our flagship R&D center near Paris!
Jean-Yves Lenoir : The process development and process parameters optimization may be somewhat longer for a continuous flow process compared to batch. In a batch process you can implement an “in-process-control” and plan action to reach conformity like adding some more reagent or maintain heating longer. In a continuous flow process, you need to be compliant when the steady state is reached. So, you need to define an operating set of parameters that gives you the expected result all the time. This requires in-depth study of each parameter based on “Design of Experiments”. Then you have to ensure that heat and mass transfer are equivalent on your production reactor. This work done, the scale-up is seamless.
For many, a journey into flow chemistry has just begun; therefore, understanding the key aspects of this process is extremely important.
The transition from traditional batch processes to flow chemistry can be quite daunting, especially when you are a first-timer. Our previous blog explains why flow chemistry is more beneficial in the industry than batch reactions. Before using flow processes for your applications, there are so many different aspects to consider. Whether you want to produce large quantities of APIs (active pharmaceutical ingredients) or are looking to test different catalysts, this blog will be your quick guide to flow chemistry.
The flow process involves reactants continuously traveling through a reactor vessel to form the desired product (Figure 1). In comparison, multi-step reactions require thorough step-by-step transformations of the initial reactants to achieve the final product. After the isolation step, purification is necessary to remove undesired materials that may disrupt further steps. A significant benefit of flow chemistry is that it allows researchers to bypass the isolation step.
In flow processes, pumps are used to flow the reaction liquid into the reactor, and this can be achieved using semi-continuous or continuous pumps. Semi-continuous pumps may need a syringe to be refilled; however, continuous pumps do allow for an indefinite flow of solution [1]
A typical flow setup consists of six zones (Figure 2): reagent delivery, mixing, reactor, quenching, pressure regulation, and collection. Purification and further analysis are often also included when the end product is collected.
Figure 2. A breakdown of the six main components within a basic flow system with a coil reactor. Other stages in the system can include purification and analysis of the final product.
Before you start your flow journey, a number one consideration is the type of reactor that is suitable for your application. These reactor vessels are divided into four main groups: coil, packed bed, chip reactors, and continuous stirred tank reactors [2]. The most used of the three are the packed bed and coil reactors (Figure 3).
Figure 3. Common reactors used in flow chemical process i) coil ii) packed -bed iii) continuous stirred tank reactor (CSTR) iv) continuous flow reactor chip
Coil reactors are mainly used for single-phase chemistry, where the mixing of reagents relies on diffusion rates. Due to the higher cost of chip reactors, coil reactors have become a suitable alternative for synthetic reactions. These reactors tend to be made from fluoropolymers such as PTFE, PFA, and FEP but can also be stainless steel with a range of internal diameters [3].
Packed bed reactors work best for heterogeneous reactions. These reactors are generally tubular and are often stainless steel or Hastelloy to facilitate working at pressure, with a filter frit to ensure particulates do not escape the reactor. Inside the reactor are the catalysts, typically transitional metals, which are coated onto a support material. The support material is then spaced out with some inert packing material, such as glass beads. Fixed bed reactors are highly advantageous for heterogeneous reactions, as the reactants have a greater retention time and thus have a long contact time with the catalyst. Secondly, these reactors achieve a higher effective molarity of catalyst to reagents, decreasing the reaction time.
Mixing is a significant component in flow chemistry; flow conditions allow for enhanced mixing and control of reactant residence time. Mixing is influential in the conversion of reactions in flow chemistry. The two main mixing methods are passive and active mixing. Active mixing involves using an agitator to mix the reactants, which can be seen in continuous stirred tank reactors (CSTRs) [3]. Passive mixing, the main form of mixing in our FlowCAT, utilizes pressure that forces fluids to move through the reactor at a constant rate.
Temperature and pressure play a significant role in flow chemistry. Along with the flow rate of reactants, temperature and pressure are controlled parameters for the desired reactions to occur. With flow chemistry, heat transfer increases due to the larger surface areas compared with batch methods, allowing for better temperature control.
Pressure control is essential for reaction speeds. In liquid/gas reactions, the reactant gas must efficiently dissolve into the liquid reactant. Increasing pressure allows for increased gas solubility, which will increase the reaction speed. Flow reactions are pressurized using back-pressure regulators, usually found towards the end of the flow system. Back-pressure regulators prevent the liquid and gas flow from the reactor unless the process pressure exceeds a specific threshold.
For many, a journey into flow chemistry has just begun; therefore, understanding the key aspects of this process is extremely important.
Flow chemistry can provide excellent solutions to the chemical industry when utilizing the best and most appropriate technologies to meet demands.
This blog has covered some of these critical points, and we hope it can be the guide you need to start your journey.