The importance of modern medicine and pharmaceuticals is hard to overestimate. During the history of humankind, save for the last blink of an eye, one could expect a 50/50 chance of dying from an infection - grim odds. The situation with infections changed dramatically for the better from World War I and onwards. The major killers today: circulatory diseases, cancer, and respiratory diseases were of minimal concern for our hunter-gatherer ancestors due to a different lifestyle and life expectancy. However, modern medicine has made fantastic accomplishments to keep up with today’s need, and more effort and progress will be needed over the foreseeable future.
SpinChem can trace its roots back to the fine chemical and pharmaceutical space - starting out with transition metal catalysts before pivoting to develop the rotating bed reactor (RBR). Pharmaceutical industry was then the primary business area. And continues to be a very important area when developing the RBR. Today, biocatalysts have superseded chemocatalysts as the most used heterogeneous catalyst in RBR:s in Pharmaceutical industry.
In the last few years, SpinChem has developed larger and larger RBR:s. As of today, there is nothing to indicate that there is an upper limit in size for the rotating bed reactor principle, consequently we will continue to develop even larger models as time and demand permits. Currently, the range of RBR models goes from 28 ml to 100 L solid phase. The corresponding liquid phase volume is completely application dependent and thus not listed for the RBR models larger than lab scale. The desired solid-to-liquid ratio will govern what size RBR is suitable, anywhere from tenths of percent to fractions of one percent has been used. When using heterogeneous catalysts, the activity of the catalyst and allowed reaction time will determine the loading. Similarly, when using adsorbents, allowed time is a factor as well as the capacity of the adsorbent in relation to the amount of solutes.
Most of the organic chemistry reactions and processes that are known may be relevant tools in the toolbox for the development and production of small-molecule pharmaceuticals. RBR technology may be used in the production of biomolecule-based therapeutics, but it will be discussed elsewhere. Briefly, an RBR can be used in these categories of processes: biocatalysis, chemocatalysis, non-catalytic reactions including solid-phase peptide synthesis, and work-up/ downstream processing.
The selection of commercially available enzymes and possibilities to acquire custom-developed enzymes has exploded in the last few years. Enzymes from many classes are available in immobilized form, e.g. peptidases/amidases, lipases/ esterases, oxidoreductases, and aminotransferases. The activity and stability under non-physiological conditions is remarkable in many cases, which has allowed to make them a relevant or even superior alternative to classical chemical catalysis in commercial processes. In Pharma, perhaps the high regio- and stereoselectivity that enzymes may offer are even more interesting properties allowing cleaner reaction steps or alternative routes relative to chemical synthesis.
Classical chemical catalysis has not stood still either. Saying that the emergence of transition metal catalysis has revolutionized the field is probably not overstating it. Named reactions such as Suzuki, Stille, Grubbs, Heck, Negishi, Sonogashira, and Grignard to name a few have been around long enough to be considered parts of an organic chemist’s basic toolbox. With immobilized transition metal complexes, these reactions are available in RBR, e.g. our partner Reaxa offers alternatives in their EnCat line.
A more recent development is seen with organocatalysis, which was awarded the Nobel Prize in chemistry in 2021. Organocatalysts are available in immobilized form, we look forward to the first application in an RBR.
Perhaps the most straight-forward heterogeneous chemocatalyst is ion-exchange beads for acidic and basic catalysis.
The final example of chemocatalysis here, and also the most requested is palladium-catalyzed hydrogenation. Regular Pd/C is in powder-form and too fine for an RBR. However, there are Pd(0)-catalyst and granulated Pd/C to use from different suppliers. SpinChem currently does not offer pressurized hydrogenation vessels, which does not prevent a customer from installing an RBR in such a vessel. Also, transfer hydrogenation has been proven to work in RBR, offering a convenient and safe alternative to hydrogen gas.
As for non-catalytic applications of RBR, the most common are ion-exchange beads and drying by molecular sieves. There are, however, a large selection of commercially available immobilized reagents. As far as we know, immobilized reagents are yet to be utilized in an RBR. Presumably, the relatively high cost per capacity offered is preventing widespread use. For the right application, the cost may be recouped in easier downstream processing.
Carrier beads, such as Merrifield, Wang, and more recent developments, for solid-phase peptide synthesis may be considered a case of stoichiometric reagents suitable for RBR. The possibility to save solvent in these processes are obvious by the improved liquid flow rates through the packed bed compared to other technologies.
Transition-metal catalysis was mentioned above. There is a risk that a small amount of the immobilized metal catalyst has leached into the solution during reaction. A good method to remove the often toxic heavy metal ions from the reaction product is a metal scavenging resin. The selection of heterogeneous scavengers is good, ranging from neutral to IEX-based, organic to inorganic backbone, and more general to more specific.
Perhaps less common in use, there are scavengers for selected organic compounds based on complementary electrophilic-nucleophilic reactivity, e.g. aldehyde-amine and Michael acceptor-thiol.
Adjusting pH during workup is a very common procedure and IEX resins are an option for doing this, also offering a way to produce less salt in the vessels during workup.
We would like to include treatment of waste streams in the context of downstream processing. It may make environmental and/or economical sense to treat your own waste streams locally before discharge or destruction. At the production site, the waste streams are contained, concentrated, and this is likely where the most knowledge about the content is found. Where large, costly, or specialized treatment equipment is needed, it may make more sense to transport to a common waste treatment site. Whether the waste stream contains excess dye from clothing manufacture or API precursors from pharmaceuticals production, a simple activated carbon treatment may be sufficient to make the waste stream acceptable for discharge. Best case scenario environmentally and financially, successfully treating the waste stream whether it is water or organic solvent, will allow it to be re-used in the process.
Ideally, the waste streams can be turned into a resource by extracting residual amounts of valuable components. Two examples comes from the pharmaceutical industry: scavenging and re-use of transition metals (e.g. palladium, iridium) from reaction waste after chemical TM-catalysis and recovery of API:s and precursors to API:s in small, residual concentrations from reaction waste or purification step waste. In both examples, the transition metal and API precursor is likely to be toxic in the wrong place (e.g. aquatic life) but valuable when recovered in pure form.
Katarzyna Szymańska, Klaudia Odrozek, Aurelia Zniszczoł, Wojciech Pudło, and Andrzej B. Jarzębski Chem. Eng. J., 2017, 315, pp. 18-24.
Activated carbon is a common choice for removing impurities or capturing compounds from a product batch. However, the carbon may itself foul the product and be difficult to separate. The rotating bed reactor offers a clean way to deploy activated carbon that removes the need for time-consuming filtration and extends the lifetime of the solid phase.
Soudabeh Saeid, Pasi Tolvanen, Narendra Kumar, Kari Eränen, Janne Peltonen, Markus Peurla, Jyri-Pekka Mikkola, Andreas Franz, and Tapio Salmi Appl. Catal. B, 2018, 230, pp. 77-90.
The rotating bed reactor (RBR) is a combined tool for chemical transformations and liquid transfer operations, reducing or eliminating the need for external pumps. Filled with a catalyst or adsorbent, and rotated by a motor, the RBR brings the liquid to be processed in contact with the solid-phase at high flow rates. Due to the high flow rate generated, the RBR can not only treat the liquid in the reaction vessel, but also transfer it into the vessel for processing.
Automation of large-scale processes is often a requirement for economically viable chemical processes. The benefits of scale are best harvested at high throughputs and 24/7 operation. This leads to the demand for process automation, and the elimination of hands-on work.
Time lapse video showing how straightforward it is to use immobilized enzymes in a rotating bed reactor. A substrate giving a yellow coloured product was used to follow the reaction progress of an ester hydrolysis by an immobilized lipase. This substrate is commonly used to screen and characterize lipases.
Roger A. Sheldon and Pedro C. Pereira Chem. Soc. Rev., 2017, 46(10), pp. 2678-2691.
Enzyme screening is an important step in the development of a biocatalytic application. The behaviour of the biocatalyst is often hard to predict, meaning that different combinations of materials and reaction conditions need to be tested.
Tung Ngoc Pham, Ajaikumar Samikannu, Anne-Riikka Rautio, Koppany L. Juhasz, Zoltan Konya, Johan Wärnå, Krisztian Kordas, and Jyri-Pekka Mikkola Top. Catal., 2016, 59, pp. 1165-1177.
Hilde Larsson, Patrick Alexander Schjøtt Andersen, Emil Byström, Krist V. Gernaey, and Ulrich Krühne Ind. Eng. Chem. Res., 2017, 56, 14, pp. 3853-3865.
Heterogeneous catalysis can be an effective tool for chemical synthesis, particularly in the discovery and development of pharmaceutical ingredients. The handling of these solid catalysts is sometimes challenging as it leads to more unit operations in the factory scale, as well as introduces additional work-up in the laboratory.
Removing ions from liquids is common in industry and society. Ions are remediated in applications ranging from the production of pharmaceuticals to the treatment of communal waste streams. Likewise, the nuclear energy sector deals with the removal of ionic radioactive substances from water on a daily basis.
A fixed bed reactor (FBR), also known as a packed bed reactor or column, is a traditional technology for processes such as adsorption or heterogeneous catalysis. Achieving the required level of purification or conversion means running the liquid through the reactor at a sufficiently low flow rate, and the throughput of a fixed bed reactor is therefore often limited.
Mass transfer limited reactions can create problems for applications like the synthesis of chemical products or the manufacture of active pharmaceutical ingredients. Poor yields, high side-product formation or impractically long reactions are potential issues. Efficient reactor design can greatly improve the mass transfer and remove the limitation to a minimum.
Liquids with high viscosity create problems for heterogeneous applications in traditional reactors. Packed bed reactors (columns) suffer from huge back pressures, and stirred tank reactors (STR) exhibit reduced reaction rates due to poor mixing. Both issues lead to longer processing times and expensive operations.
Adsorption of methylene blue (3 g, 5 mg/L) onto Purolite® NRW1160 (4.2 L) placed in a SpinChem® S5 RBR operated at 147 rpm. The SpinChem® S5 RBR was placed within a 600 L IBC tank, using the ProRBR IBC add-on, where the tank was filled with water. The data was acquired using a UV-VIS spectrophotometer.
Decolorization, pesticide remediation, catalysis, and many other applications involve dealing with viscous liquid that needs to be modified in some way. The rotating bed reactor presents an efficient way to treat viscous liquids, without the challenges of conventional reactors.
A large scale decolourization experiment using the SpinChem® rotating bed reactor (RBR) S100, packed with 79 L of activated carbon. The vessel contained 7000 L of water with added methylene blue dye. In under 40 minutes, 95% of the initial concentration of methylene blue was removed from the water, which shows that the RBR S100 can achieve fast reaction times in large scale processes.
The SpinChem® rotating bed reactor (RBR) S100, with a solid phase capacity of 100 L, was used to deionize 7000 L of tap water. The RBR S100 was operating at 160 rpm and filled with 36.5 L of mixed bed ion exchange resin. The results show that the RBR S100 can efficiently process large liquid volumes. As shown by the successful deionization, the performance of the RBR remains high even when it is partially filled, which proves the extreme robustness of the RBR technology.
The separation of a heterogeneous catalyst, an adsorbent, or an ion-exchange resin from a liquid product is a time-consuming unit operation that often makes the use of these materials impractical. The rotating bed reactor is a more efficient technology for deploying catalysts for manufacturing or adsorbents for purification.
When working with an emulsion (and particularly with a heterogeneous catalyst) the mass transfer between the phases is critical. Insufficient mixing leads to lower interfacial area per volume, and in turn to poor mass transfer across the phases.
Hendrik Mallin, Jan Muschiol, Emil Byström, and Uwe T. Bornscheuer ChemCatChem, 2013, 5, pp. 3529-3532.
Whole cell biocatalysis is powerful, but not straightforward. One way of utilizing whole cells is to encapsulate them in a matrix such as alginate to make them easier to separate from a reaction mixture. However, alginate beads are not mechanically stable enough to be packed into columns and are easily destroyed in stirred tank reactors (STR). This makes enzyme recycling ineffective, at the same time as mass transfer limitations may prevail.
Finding the optimal chemistry and solid-phase material for immobilization of enzymes relies heavily on trial and error. The right resin will ensure satisfactory immobilization yield, as well as high activity and stability of the enzyme.
Ariana Causevic, Eimantas Gladkauskas, Kim Olofsson, Patrick Adlercreutz, and Carl Grey Biochem. Eng. J., 2022, 187, 108610.
How can this process be scaled up? This is perhaps the most important question to consider when developing a chemical process. If it cannot be done on large scale, all the time and resources invested in laboratory work will be unrewarded. Pumping liquids through massive columns or separating solids from a large batch can be unsurmountable challenges that bring a halt to a new project before it has even left the starting blocks.
Anup Ashok and Santhosh Kumar Devarai 3 Biotech, 2019, 9(9), 349.
Carl-Johan Aurell, Staffan Karlsson, Fritiof Pontén, and Søren M. Andersen Org. Process Res. Dev., 2014, 18(9), pp. 1116-1119.
The SpinChem rotating bed reactor (RBR) can eliminate poor mass transfer in heterogeneous reactions during chemical syntheses and biotransformations, preserve catalyst activity, and facilitate recycling of solid phases. This brochure presents our technology and its applications.
Jochen Wachtmeister, Philip Mennicken, Andreas Hunold, and Dörte Rother ChemCatChem, 2016, 8, pp. 607-614.
Jens Johannsen, Francesca Meyer, Claudia Engelmann, Andreas Liese, Georg Fieg, Paul Bubenheim, and Thomas Waluga AIChE J., 2021, 67(4), e17158.
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Jochen Wachtmeister and Dörte Rother Curr. Opin. Biotechnol., 2016, 42, pp. 169-177.
Biocatalysis is a useful method for the synthesis of small chiral molecules, offering new possibilities for the synthesis of active pharmaceutical ingredients and other compounds. The rotating bed reactor has been established as an efficient way to deploy enzymes in production as well as research and development.
Investigating reactions can easily grow from an idea into very time-consuming projects, but the upside of properly understanding the reaction is great. The choice of equipment has a very large impact on the efforts required. The rotating bed reactor is a tool that unlocks the full potential of your Mettler-Toledo EasyMax™ 102 Advanced synthesis workstation for this development.
Roger A. Sheldon and John M. Woodley Chem. Rev., 2018, 118(2), pp. 801-838.
This case study presents a lipase-mediated stereoselective acetylation of a racemic amine in a rotating bed reactor.
Stirred vessels tend to damage soft heterogeneous catalysts, like enzymes immobilized in agarose or alginate beads, with activity loss and tedious workup as consequence. In a fixed bed reactor, these materials are easily compressed by the pressure gradient, leading to a loss of flow rate. Overcoming these challenges opens up the possibility to use biocatalysis as a tool for greener processes and more sustainable manufacturing.
When using of solid-phase catalysts or adsorbents in reactors, the physical degradation of the materials is a common problem. The traditional stirred tank reactor inflicts mechanical damage to the particles, which causes attrition, fines that are difficult to separate, and loss of the functionality of the solid-phase.
Contaminations in liquids can often be removed using an adsorbent, such as granular activated carbon (GAC). The best choice of adsorbent is unique for each contaminant, and the effectiveness depends on many parameters. Failing to investigate these can lead to unnecessarily high material costs and long processing times.
Screening immobilized enzymes to find the best match with the substrate and reaction conditions can be a time-consuming process. The introduction of the solids in a stirred tank reactor leads to damage to the immobilized biocatalysts and makes filtration necessary.
The SpinChem rotating bed reactor (RBR) has been proven to be a time and labor-efficient tool in the screening of biocatalysts. Here, we present the quick simultaneous screening of six different immobilized lipases for the esterification of lauric acid to propyl laurate using our pre-packed MagRBR lipase screening kit.
Research and development quickly takes new directions, and the requirements on a laboratory may vary with every new project. Limiting yourself to equipment with a narrow scope of conditions and applications may become expensive, since new equipment must be acquired for anything out of scope. With budgets quickly consumed by other projects, the need for new equipment may mean significant delays and a reduced capability to take on emerging opportunities.
The synthesis of products, such as active pharmaceutical ingredients (APIs), often involves multiple steps using heterogeneous catalysts or adsorbents. Thus, the simultaneous use of multiple solid phases either during synthesis or downstream processing is frequently highly advantageous.
Synthesis typically involves multiple reaction steps and the isolation of intermediate products. Any incomplete conversion at the end of each step will compound to an overall lower yield. To make things worse, the work-up of each intermediate can be very time-consuming. This has made one-pot cascade synthesis (the simultaneous execution of multiple steps in a single reactor) a desirable target for chemists. This approach aims to minimize intermediate work-up, reduce the risk of material loss, and enhance overall process efficiency.
Can you use a rotating bed reactor (RBR) in any type of vessel? - Absolutely! Would the performance be higher with baffles in the vessel? - Definitely!
Hydrogenation reactions using hydrogen gas are usually efficient and clean. Drawbacks are the safety issues of handling hydrogen gas, need for reactors made for pressurized reactions, and the necessity of vigorous stirring to make these solid-liquid-gaseous reactions work well.
Heterogeneous reactions involving viscous solutions put high demands on equipment and materials. Columns face high pressure drops and require powerful pumps and durable solid phase particles. Stirred tank reactors do not face the same problem, but the high liquid viscosity and low particle density will have a negative impact on reaction kinetics and require tedious filtration to separate the solids afterwards.
Subhash Pithani, Staffan Karlsson, Hans Emtenäs, and Christopher T. Öberg Org. Process Res. Dev., 2019, 23(9), pp. 1926-1931.
Shuke Wu and Zhi Li ChemCatChem, 2018, 10(10), pp. 2164-2178.
Biocatalysis offers many benefits in the production of chemicals and active pharmaceutical ingredients. One major challenge has been the deployment of immobilized enzymes in an efficient way on large scale. The rotating bed reactor offers a convenient way to scale a biocatalytic process.
Catalyst recovery is an important step in downstream processing. Using an appropriate scavenger resin and a rotating bed reactor to deploy it, the recovery is straightforward and effective.
Sometimes you don’t want to pack the entire rotating bed reactor full with your solid-phase material. Fully loading might simply be wasteful, or you may want to experiment with your reaction conditions. But how does the amount of solids in the rotating bed reactor influence the reaction performance? Can you use only 10% of the full capacity?
Scavenging of soluble undesirable compounds and substances onto solid phase is used in a wide range of applications. In this example, a rotating bed reactor (RBR) is used to capture low concentrations of a phenol onto readily available Strong Anion Exchange (SAX) resin as a scavenger.
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Environmentally benign and safe synthesis is enabled by highly active biocatalysts. To bolster economic and ecological aspects, catalyst reuse is essential and achieved by heterogenization of otherwise soluble enzymes onto solid supports. Here, this is demonstrated on novel renewable and non-polluting cellulose beads.
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