One of my great enthusiasms is the topic of small scale continuous synthesis. There has been some new thinking in this area recently. I don’t mean the use of robots to move material around- I mean continuous flow reactions. Our refinery friends have been doing this for a long time. It’s the reason gasoline isn’t $25/gallon.
Many, if not most, supplies of bulk raw materials come from continuous process equipment. The economies of large scale may require custom reaction equipment dedicated to a given product. The problem for small scale production is the cost of custom designed equipmet is often large compared to the value of the production run. It is usually best to develop processes to operate in conventional, off-the-shelf pots & pans.
The availability of stirred tank reactors and their ease of use for small scale production has dominated the mode of specialty chemical process technology to the present day. Generations of chemists and engineers in fine and specialty chemicals know nothing other than batch reactor chemistry.
Easy, inexpensive continuous processing isn’t automaticaly suitable for every process. Transformations that are suitable for continuous flow processing may still be disqualitied by virtue of upstream or downstream processes that feed from or into transformations that must be done batchwise. There is the question of feed rates to and from the continuous transformative step and the extent to which non-continuous operations are compatible.
But back to basics. Why have continuous synthesizers at all in the small scale? Why not just run the semi-batch process as may times as you need at the largest scale possible? Well, there is no reason not to. This is a tried and true business plan. But what small scale continuous processing allows is the possibility of multiple parallel operations run by fewer staff. At the small scale, batch chemical production typically has a larger labor component than bulk or commodity scale production. Improvements to small scale process economics rests to a large extent on reducing the labor cost contribution.
By it’s nature, continuous processing is an intensified activity. The idea is to construct a minimum reactive volume and flow materials through the reaction or processing zone under intensified conditions for as short of a residence time as possible. At any given moment, there is a minimum mass of hazardous materials undergoing a potentially hazardous transformation. Or, intensification may mean the use of smaller ancillary equipment continuously, as in the case of continuous filtration vs batch filtration.
There are those who are making progress in this field. Recently I ran into a number of websites and files of Ashe Morris in the UK. These folks are operating a productive engine of development in regard to reactor design and innovative process chemistry improvemets. They have focused on process efficency and intensification. The question is, what shape will the IP take? Will users pay a royalty on their production or will it be limited to the purchase cost ofthe equipmet. How they do this will make all of the difference to the extent and rate of acceptance in the market.
Lamentations on Chemistry 
The operative word here is “continuous”. We run batch-to-continuous conversions all the time for plastics and other rheologically “interesting” materials, but we really shine for our customers when we start up and don’t shut down or changeover to a new color or…-all part of the reasons gas is not $25/gal. Shutting down the refineries for hurricanes and restarting them is not as simple as shutting down and restarting a light bulb.
So then it is all a matter of getting the right-sized equipment. Too small and you can’t make enough, too big and you have excess capacity that you wasted your capital on.
Steve Ley at Cambridge seems to be one of the “pioneers” of the continuous approach in the academic world.
I built a benchtop continuous reactive distillation unit about 12 years ago for the preparation of lactide. That is how I got interested in this technology. This esterification reaction was well suited to continuous flow methods.
What is between the lines in this post is that there is a manufacturing sector that is in need of some new thinking. The domination of the current ACS curriculum sets up fixed occupational boundaries and restrains undergrads and college faculty from exploring or devising whole new cross disciplinary fields of endeavor. Instead, chemists all start with the same limited world view. Unless, of course, a dead millionaire bequeaths a big wad of money.
At Crop King we thought of it as a pipeline reaction. This approach was used for the continuous synthesis and formulation to a water suspension of Ziram (zinc dimethyldithiocarbamate) and Sulfalate. The big problem was to accurately meter in the reactants. The zinc oxide problem was only solved by prebatching as a liquid formulation and pumping that.
The EPA stopped this kind of work by making it so expensive to bring a new pesticide synthesis to market – $2,000,000.
Wow. Haven’t heard of that in a while. Ziram. I used that compound in grad school for some kind of transformation.
I would think that the preparation of API’s in the pharmaceutical industry would be a problem, in terms of generating validation data and production quality data. What is considered a “batch” in a continuous reactor system? How would the FDA handle this? I would assume that they need a lot of analytical paperwork to ensure quality control over the material being made.
Perhaps some sort of in-line or in-process analytical methods could be developed so that there could be real time data delivery to the operators for any adjustments in the process needed? I am not in the pharmaceutical industry, so I am unfamiliar if this is even being looked at.
Ifert there are a few APIs currently out there made by continous processes and there are ways around the issues. I don’t think the analytical is any more stringent than batch mode. There is plenty of in-line PAT now but again Pharma is way behind Petrolium and other Chemical applications. One problem is that often need multifunctional manufacturing units that can switch to making many different products whereas (I think) continous systems best designed/suited for making same/similar product lines.
IMO it does comes down to training/education as most classically synthesis people are only taught to run experiments as single reaction at a time. Occasionally might do one-pot telescoping of 2-3 transformations, but fairly simple steps combined. There are rare exceptions of labs who have devised small scale contious flow systems but again few people get exposed to this early before frame of mind established toward batch mode thinking. ChemEs on the other hand get taught this almost from beginning. They likewise typically have a better handle on the P-chem related aspects of both Thermodynamica and Kinetics that are vital to conducting continous reactions.
Blessedly, I am not in the pharma business, so I can only speak as one in the specialty chemical field. We are in need of a paradigm shift to spark innovation to mainstream fine chemical manufacturing. We need more engineering and economic savvy from chemists entering the business. We need more creative process engineering from our engineers.
For the US to remain competitive in specialty and fine chemicals, we must improve the economics, particularly in the area of labor productivity. This market sector (10 kg to 100 MT) produces products that tend to be heavy in labor costs. This is one of the major factors driving business to Asia.
One fix is to move from serial to parallel or convergent syntheses. Most good process people try to do this anyway. But we need more engineering solutions. Process intensification in its various forms must become the topic of conferences and elective courses.
All of this happy talk about increased innovation will require that chemists and engineers are able to mix professionally to a greater extent. More chemists should attend AIChE talks and more engineers attend ACS meetings … for starters.
I agree with you 100% about more interaction with ChemE’s. I was involved with a few projects that involved a vapor phase continuous chlorodenitration of an aromatic through a heated pipe reactor. Trust me, I was very glad that we had some capable ChemE’s (PhD’s) on hand to help with this.
Let me also say that I once took the ACS course on chemical engineering for chemists and basically slept through most of the two day presentation. I still can’t grasp teh concept of Reynolds numbers, etc…