Multiphasic continuous Reactors

That’s an excellent question and post. I have experience working with packed bed reactors for fine chemical production and air purification applications, dealing with both solid-liquid-gas and solid-gas phases. One of the main challenges we faced was coke formation, primarily because most reactions occur at high temperatures. This coke formation led to the deactivation of catalysts, significantly affecting their performance. To address this issue, we focused on enhancing the properties of the catalysts. We attempted to increase the porosity and decrease the size of the catalyst particles, which resulted in a higher surface area and improved reaction efficiency. Another challenge was the limited surface area for the catalysts; by decreasing particle size and making it more uniform, we were able to improve reaction yield. Additionally, we worked on increasing the acidity of the catalysts and providing more acidic sites for reactions to further delay coke formation.

For the gaseous reagents in packed bed reactor, the main issue was efficiently removing the gaseous by-products from the reactor to enhance the overall yield, moreover these by-products, if not effectively managed, can lead to rapid catalyst deactivation. I highly recommend reading this article "Multiphasic Continuous-Flow Reactors for Handling Gaseous Reagents in Organic Synthesis: Enhancing Efficiency and Safety in Chemical Processes "This article provides an overview of the development of gas-handling continuous-flow technology from 2016 onwards, highlighting the benefits such as increased interfacial area, improved mass and heat transfer, and seamless scale-up. It discusses the use of gaseous reagents in the production of active pharmaceutical ingredients (APIs) and the advancements in ensuring efficiency and safety in these processes.I am interested to learn more about the approaches and solutions others have employed for packed bed, membrane, wall-coated, and Taylor flow reactors. If anyone has insights or experiences to share, I also would like to hear about your strategies and results.

Thanks Farshid for sharing your experience.

And that is an invaluable lesson, which I would like to frame it in a new question for the community to contribute, as “transferable knowledge”.

What transferable knowledge you could bring from other industries to CM in Pharma? The equipment, process, PAT, models, SCADA,… and so many other aspects of the continuous manufacturing are being used in food, petrochemical, oil and gas,…. What can be learned, adopted, modified, and deployed from other industries?

I am personally coming from petrochemical industry (more than 20 years ago). All processes, equipment, control systems, PAT, and everything designed for CM and being work fine for over 80 years. Although, petrochemical industry is not a “regulated” industry as pharma, but many processes and products could be as challenging (or more) as pharma. An example for impurity control in the Petrochemical industry is Trimethylamine (TMA) in methanol production that should be in kept in PPB level (yes B for Billion), and the plant production capacity is up to 1.8 million tons per year.

Getting back to our discussion here on the gas-liquid reactors, most of the polymerization reactions are in multiphase systems with gas (feedstock) and liquid (solvent and product) and solid (catalysts). Liquid phase is non-Newtonian and change by time or location of the reactor. (in pharma, for change of viscosity over time and location I’d refer to Peptide synthesis. And yes, there are pharmaceutical companies, who make peptides in CM).

So, all, what transferable knowledge you could bring from other industries to the pharma CM?

Here, in Farshid's comment, the coke formation is a side reaction, an impurity, and then process deviates, because the by-product poisoned the catalyst. 

Thank you Farshid for sharing this article and important conclusions. I am curious to read this published work and would like to confirm authors and citation information: 

Angew. Chem. Int. Ed. 2024, 63, e202316108

Annechien A. H. Laporte, Tom M. Masson, Stefan D. A. Zondag, Timothy Noël

Thank you in advance for your help!

The reactor platforms in the continuous manufacturing in the pharmaceutical or fine chemical industries are typically Plug Flow Reactor (PFR) or Continuous Stirred Tank Reactors (CSTR). Both have their own advantages and disadvantages, applications, reason to avoid, or to love!

I started a table here to kick-off the discussion. Could you add more characteristic aspects?

Comparison of two Main Continuous Reactor Platforms (PFR and CSTR)

Both tubular and CSTR's are great for specific reactions. I would also consider reactors such as the OFBR, the Autichem Dart reactor, the Nottingham university vortex photochemical reactor, the tube in tube reactor, the spinning disc reactor, the Stoli reactor, Scheibel Column, Spinid reactor to name a few. They all have their strengths and weaknesses, but they all need to be fed by pumps.

What type of pump is required? what materials of construction? what flow rate range is required? and what pressure rating is required. Suddenly there are a lot of different options to apply to both the pumping system, reactor system, and heat exchanger systems. 

Traditional bulk chemistry is performed in dedicated flow processing systems that have been refined over many years for the specific purpose of manufacturing a single product. 

I truly believe that continuous reactor technology, when optimised, will result in higher yields, lower waste, lower cost processing, but the compromise is multi-purpose operation. When you optimise the engineering for a particular synthetic route to deliver a product, this engineered system will not be optimised for anything else. This is especially true for highly enabling steps such as photochemistry and electrochemistry.

I think that there is a place for modularity, but only in the research domain. For full scale manufacturing a dedicated continuous process will be required in all cases to deliver an optimised solution. 

While there will be opportunities to carry out problematic (low yielding) chemical transformations in large scale flow chemistry skids to deploy targeted improvements in existing processes, going forward, there will be greater gains to be had in the development of fully continuous systems for specific products.

I feel there remains a significant amount of exciting flow development to explore!

Thanks Oliver, great points. Thanks for mentioning some reactor examples. I think they are falling in either categories of CSTR/PFR or a combined characteristic, in terms of flow, mixing, RTD, …

I was wondering if you could elaborate more on each of the Reactors you mentioned. Attached is an Excel spreadsheet, would you please fill that out and re-post?

Also, anyone who is interested in contributing to the table content, you could post along or email me an offline version, so I’d consolidate all comments and post back (nima@procegence.com) .