Pharmaceuticals and Cosmetics

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 Today, biocatalysts have superseded chemocatalysts as the most used heterogeneous catalyst in RBR:s in Pharmaceutical industry.

From lab to production

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.

In the vessel

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.

Biocatalysis

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.

Chemocatalysis

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.

Stoichiometric reagents

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.

Solid phase peptide synthesis

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.

Downstream processing

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.

Application L1701
A novel hierarchically structured siliceous packing to boost the performance of rotating bed enzymatic reactors

Katarzyna Szymańska, Klaudia Odrozek, Aurelia Zniszczoł, Wojciech Pudło, Andrzej B. JarzębskiChemical Engineering Journal, 315 (2017) 18-24 Keywords: Biotransformatio, Immobilized enzymes, Organic molecules, Scientific literature

Application 1008
Activated carbon decolourization comparing rotating bed reactor and stirred tank reactor

Accelerated video showing the enhanced adsorption rates of methylene blue onto activated carbon using a rotating bed reactor (RBR) compared to a stirred tank reactor (STR). The RBR decolourized the solution almost twice as fast, did not create any visible fines and required no filtration.  Keywords: Activated carbon, Decolouration, Fast reaction, Organic molecules, Simple cleanup, Technology 

Application L1801
Advanced oxidation process for the removal of ibuprofen from aqueous solution: A non-catalytic and catalytic ozonation study in a semi-batch reactor

Degradation of the pharmaceutical compound ibuprofen by ozone, was optimized in batch type reactors with and without zeolite based heterogeneous catalysts. The rotating bed reactor technology increased the concentrations of dissolved gas compared to traditional stirred tank reactors and allowed convenient handling of the catalyst particles without any filtration.  Keywords: Fast reaction, Gas-distribution, Organic molecules, Scientific literature, Zeolite

Application 1012
An externally connected system for large scale heterogeneous downstream processing

Time lapse video illustrating how an externally connected rotating bed reactor (RBR) can pump and process large liquid volumes by the convective flow created by the spinning RBR. The concept enables handling of volumes at least 10-100 times larger than the external vessel, thus facilitating installation of RBR technology into existing plant equipment.  Keywords: Activated carbon, Continuous flow, Decolouration, Organic molecules, Seamless scaleup, Technology

Application 1007
Automated semi-continuous batch processing system with rotating bed reactor

Video showing the principle of an automated rotating bed reactor system capable of filling a solution, neutralizing it by ion exchange and draining it. By microcomputer control, unattended semi-continuous batch processing was accomplished for many cycles until the ion exchanger was completely saturated.  Keywords: Automation, Ion exchange, Seamless scaleup, Technology

Application 1014
Biocatalysis by immobilized enzymes in a rotating bed reactor

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.

Application L1704
Biocatalysis engineering: the big picture

A tutoral review taking a holistic approach to the engineering of biotransformations utilising isolated enzymes. The authors highlighted SpinChem® RBR technology benefits and wrote; “… in addition to protecting the biocatalyst from shear forces caused by the stirrer, it greatly accelerates mass transfer, thus affording substantially higher reaction rates and creating the possibility to use much smaller reactors”.   Keywords: Biotransformation, Immobilized enzymes, Organic molecules, Review, Scientific literature

Application 1023
Biocatalysis in rotating bed reactors – from screening to production

Poster describing the screening of resins with immobilized enzymes for esterification reactions. The screening was performed with prepacked cartridges inside a SpinChem® rotating bed reactor (RBR) and compared to parallel screening with prototype disposable magnetic RBR (MagRBR) in 10 mL volume. Both approaches were very quick, required minimum preparation and no filtration. Up-scaled processes enabled quick enzyme recycling, opening for the possibility of semi-continuous processes with attractive production economy.

Application L1604
Catalytic hydrogenation of d-xylose over Ru decorated carbon foam catalyst in a SpinChem® rotating bed reactor

Tung Ngoc Pham, Ajaikumar Samikannu, Anne-Riikka Rautio, Koppany L. Juhasz, Zoltan Konya, Johan Wärnå, Krisztian Kordas, Jyri-Pekka MikkolaTopics in Catalysis, 59 (2016) 1165-1177

Application 9005
Chemical Catalysis with MagRBR and EasyMax – Quick and Convenient Suzuki couplings

This application note demonstrates how the combination of a SpinChem MagRBR custom-filled with heterogenous Pd(II)-catalyst and the controlled conditions in a Mettler-Toledo EasyMax™ 102 Advanced Synthesis Workstation allows for quick and convenient generation of C-C coupled products.  Keywords: Chemical catalysis, Easy handling, Mettler-Toledo

Application 1035
Column vs RBR

A performance comparison between a column (fixed bed reactor) and rotating bed reactor (RBR) for de-ionizing 1000 L of tap water. Using best-in-class standard protocols for both technologies, we tested which technology could de-ionize to a desired endpoint conductivity value the quickest. The result show that the RBR is significantly faster, reaching 3.7 times faster a conductivity level of 0.15 µS/cm compared to the column.  Keywords: Cleantech, Deionization, Fast reaction, Technology  

Application 1024
Comparing rotating bed reactor and fixed bed reactor for adsorption purification

Comparison of rotating bed reactor (RBR) technology and fixed bed reactor (FBR) column during activated carbon decolourization. The more efficient use of the adsorbent with a SpinChem® RBR enabled completion of the process within 40% of the time at the same material amount or allowed reduction to 50% material while still being able to finish the process within the same time as the FBR.  Keywords: Activated carbon, Decolouration, Fast reaction, Organic molecules, Purification, Technology  

Application 1006
Comparison of reaction speed with rotating bed reactor and stirred tank reactor

Video revealing the efficient mass transfer and resulting shorter reaction time with a rotating bed reactor (RBR) during ion-exchange neutralization of a base. The reaction with the RBR finished 30% faster and left a completely clear solution without any particles. Keywords: Fast reaction, Ion exchange, Technology

Application 1004
Consequences of viscous solutions on the reaction rate with rotating bed reactors

Log-log plot of how viscosity affects the reaction time for a mass transfer limited reaction at a fixed rotational speed of a rotating bed reactor (RBR). The RBR behaved very predictably and delivered reaction times that increased linearly with reaction media viscosity up to at least 500 mPa·s.  Keywords: Ion exchange, Organic molecules, Technology, Viscous solutions  

Application 1030
Decolourization of highly viscous solutions using a rotating bed reactor and a stirred tank reactor

The performance of a SpinChem® rotating bed reactor (RBR) in the treatment of highly viscous solutions was compared to that of a conventional stirred tank reactor (STR). Both reactor set-ups were used for the extraction of Allura red dye from a glycerol-dye mixture using an ion exchange resin. The RBR removed 10 times the amount of dye in just over 40 % of the time, compared to the STR. This comparison underlines the efficient mixing and clever design of the SpinChem® RBR, as well as the broad spectrum of applications for which this technology is highly relevant.  Keywords: Decolouration, Fast reaction, Ion exchange, Technology, Viscous solutions    

Application 1031
Decolourization in an IBC tank using the ProRBR IBC add-on

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.  

Application 1034
Decolourization using 79 L of activated carbon in a 7000 L vessel

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.  Keywords: Activated carbon, Cleantech, Decolouration, Fast reaction

Application 1033
Deionizing 7000 L of tap water using the SpinChem® RBR S100

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.  Keywords: Ion exchange, Seamless scaleup, Technology  

Application 1021
Demonstration of loading, reaction and unloading in a production scale rotating bed reactor

Video showing how a SpinChem® rotating bed reactor (RBR) for use in 20-300 L vessels was charged with solid particles, used for pH neutralization, drained from reaction liquid and finally emptied from solid phase without opening the RBR. This procedure illustrates one approach to using RBR in production scale equipment without opening the reaction vessel.  Keywords: Easy handling, Ion exchange, Seamless scaleup, Technology

Application 1003
Effective phase-transfer between immiscible liquids and an ion exchange resin

Illustrative video showing how a phenolic colourant is deprotonated and extracted from an organic to an aqueous solvent. Using SpinChem® RBR in a flower-baffled reaction vessel created fine emulsion droplets resulting in effective phase-transfer between the two liquids and the solid phase. Keywords: Immiscible liquids, Ion exchange, Organic molecules, Technology

Application L1301
Efficient biocatalysis with immobilized enzymes or encapsulated whole cell microorganism by using the SpinChem reactor system

Hendrik Mallin, Jan Muschiol, Dr. Emil Byström, Prof. Dr. Uwe T. BornscheuerChemCatChem, 5 (2013) 3529-3532   "...the immobilized transaminase was better protected from mechanical forces in the SpinChem device."    Keywords: Alginate, Biotransformation, Encapsulated cells, Immobilized enzymes, Organic molecules, Scientific literature

Application 1002
Efficient synthesis of chiral lactones by encapsulated cells in a rotating bed reactor

Comparison of SpinChem® rotating bed reactor (RBR) with traditional reaction set-ups for a demanding biotransformation. SpinChem® RBR matched or outperformed the other systems and gave a 10 to 25-fold more time-efficient recycling of the encapsulated cells.   Keywords: Alginate, Biotransformation, Encapsulated cells, Gas-distribution, Organic molecules, Quick recycling

Application 1028
Enzyme immobilization screening using magnetic rotating bed reactors

The SpinChem® MagRBR ECR screening kit, pre-packed with Purolite® Lifetech™ resins, was used to screen six different enzyme carrier resins in parallel for the immobilization of lipase CalB. Easy sampling and monitoring of the process, together with effortless handling, established the MagRBR as a time and labour efficient screening device. Keywords: Biotransformation, Easy handling, Immobilized enzymes, Rapid screening

Application L1402
Lipase catalyzed regioselective lactamization as a key step in the synthesis of N-Boc (2R)-1,4-oxazepane-2-carboxylic acid

A synthesis of N-Boc (2R)-1,4-oxazepane-2-carboxylic acid was developed in 39% yield over seven steps starting from methyl (2R)-glycidate. The key step was a lipase-catalyzed regioselective lactamization performed using SpinChem® rotating bed reactor that simplified work up and recycling of the enzyme. Carl-Johan Aurell*, Staffan Karlsson, Fritiof Pontén, and Søren M. Andersen Keywords: Biotransformation, Immobilized enzymes, Organic molecules, Quick recycling, Scientific literature

Brochure
Mass transfer revolutionized

Learn how SpinChem rotating bed reactors (RBR) can eliminate poor mass transfer in heterogeneous reactions during chemical synthesis and biotransformations. Preserve activity and facilitate recycling of solid phases with the RBR. This brochure shows technology and applications.  Keywords: Biotransformation, Brochure, Fast reaction, Immobilized enzymes, Molecular sieve, Preserved activity, Simple cleanup, Synthesis, Technology

Application L1602
Modularized biocatalysis: Immobilization of whole cells for preparative applications in microaqueous organic solvents

Jochen Wachtmeister, Philip Mennicken, Andreas Hunold, Dörte RotherChemCatChem, 8 (2016) 607-614   Keywords: Biotransformation, Encapsulated cells, Organic molecules, Scientific literature

Application L1703
Reaction engineering of biocatalytic (S)-naproxen synthesis integrating in-line process monitoring by Raman spectroscopy

A traditional stirred tank reactor setup was compared to a rotating bed reactor (RBR) for the biocatalytic synthesis of the anti-inflammatory drug (S)-naproxen. Both setups performed well during five repetitive bathes giving an enantiomeric excess of 99% and an isolated yield of 92%, but the RBR was easier to handle and the authors concluded that “… the rotating bed reactor concept can be regarded as a promising option for industrial applications”. Keywords: Biotransformation, Immobilized enzymes, Organic molecules, Scientific literature

Application 1019
Recycling of immobilized enzymes using rotating bed reactor technology

Poster on study of catalyst recycling during esterification and transesterification reactions with immobilized lipases in rotating bed reactors. Data from several laboratories showed that no attrition or grinding occurred and that no filtration was necessary between reaction cycles. The production capacity was estimated to 50 kilograms per gram of catalyst thanks to the high catalyst stability. Keywords: Biotransformation, Immobilized enzymes, Organic molecules, Preserved activity, Quick recycling

Application 9001
Recycling of Immobilized Enzymes – Simple and Streamlined Biocatalysis

Immobilized catalyst recycling using a SpinChem® rotating bed reactor (RBR) and a Mettler-Toledo EasyMax™ 102 Advanced synthesis workstation. The process proved very time efficient as no filtration steps were needed between cycles, or for the samples extracted for analysis during each run. Washing of the resin between runs was fast, simple and robust, without running the risk of material loss. Keywords: Biotransformation, Immobilized enzymes, Mettler-Toledo, Organic molecules, Preserved activity, Quick recycling

Application L1705
Role of biocatalysis in sustainable chemistry

A comprehensive review of biocatalysis covering how the recent advances in engineering of enzymes, substrates, media and reactor design contributes to a sustainable chemistry development. The authors wrote that SpinChem® RBR technology “combines the advantages of a stirred tank with those of a packed bed” thus giving benefits by “circumventing mechanical attrition of the biocatalyst” while “mass transfer is greatly accelerated”.   Keywords: Biotransformation, Immobilized enzymes, Organic molecules, Review, Scientific literature

Application 1032
Rotating bed reactor for immobilized enzymatic reactions

Poster on a case study of applying the rotating bed reactor for the lipase-mediated stereoselective acetylation of a racemate amine as a model reaction for the manufacturing of pharmaceutical building blocks. The results showed that enzyme recycling and synthesis scale up was easy to achieve with preserved yield, enantioselectivity and catalytic activity.   Keywords: Biotransformation, Easy handling, Immobilized enzymes, Quick recycling, Seamless scaleup

Application 1025
Rotating bed reactor setup for in situ formation, loading and handling of alginate beads and whole cell encapsulation

Video showing the formation of alginate beads under conditions mimicking whole cell encapsulation. The use of a SpinChem® rotating bed reactor (RBR) allowed easy collection, maturing and washing of the alginate beads. With the RBR setup, it was possible to immediately continue with filling of the reaction substrate into the same vessel, thus reducing the number of handling steps and facilitating bead recycling. The beads showed no signs of physical wear after use in the RBR.   Keywords: Alginate, Biotransformation, Easy handling, One-pot multistep, Technology

Application 1010
Rotating bed reactors completely avoid grinding of molecular sieves

Photos showing how grinding caused by stirring of molecular sieves can be completely avoided by using a rotating bed reactor (RBR). Molecular sieves contained in a RBR for a 200 mL vessel can theoretically hold 0.23 moles of water. This allows synthesis of product in the range of 100 gram by ester condensation or drying of 25 litres of analytical grade organic solvent. Keywords: Easy handling, Molecular sieve, Purification, Simple cleanup, Synthesis, Technology, Water

Application 1036
Screening of activated carbon using the SpinChem® RBR S2

In co-operation with ZHAW, two students screened various types and sizes of activated carbon using the SpinChem® RBR S2. Five different carbons were screened by decolorizing solutions of methylene blue in distilled water. The decolorization process was monitored using inline UV-Vis spectrometry (PAT). The results show the importance of choosing the correct media for your application. In this case of activated carbon, the source and type of the activation was shown to have a major impact on performance.  Keywords: Activated carbon, Decolouration, Fast reaction, Rapid screening, Technology

Application 9002
Screening of Immobilized Enzymes – Fast and Convenient Reaction Optimization

The stable reaction environment in the EasyMax™ 102 Advanced synthesis workstation and the high flow rates through the SpinChem® RBR allowed for quick and convenient screening of different immobilized lipases to find the enzyme most suitable for further reaction optimization.   Keywords: Biotransformation, Immobilized enzymes, Mettler-Toledo, Organic molecules, Rapid screening

Application 1027
Screening of immobilized lipases using magnetic rotating bed reactors

Six different immobilized lipases were screened in parallel for the esterification of lauric acid into propyl laurate using the pre-packed SpinChem® MagRBR Lipase screening kit. The process proved fast and simple, as efficient sampling and monitoring of the process was achieved without filtration steps, by keeping the immobilized catalyst confined inside the MagRBR.   Keywords: Biotransformation, Easy handling, Immobilized enzymes, Organic molecules, Rapid screening

Application 1009
Simultaneous extraction of two dyes selectively onto different resins

Video illustrating how a mixture of red and blue dyes with different chemical properties can be selectively extracted onto different adsorbents within the same run using a rotating bed reactor (RBR). The dyes were separated based on ionic and hydrophobic interactions, respectively.  Keywords: Cleantech, Decolouration, Extraction, Ion exchange, One-pot multistep, Organic molecules, Polymeric resin, Technology

Application 9003
Simultaneous Selective Decolouration – Illustrating a Concept for Cascade Reactions

Two dyes were selectively extracted onto different adsorbents within the same run using a SpinChem® rotating bed reactor (RBR) and an EasyMax™ 102 Advanced synthesis workstation. This experiment illustrates performing cascade reaction for one-pot multi-step synthesis.  Keywords: Cleantech, Decolouration, Extraction, Ion exchange, One-pot multistep, Organic molecules, Polymeric resin, Technology

Application 1022
Transfer hydrogenation with catalyst recycling in a rotating bed reactor

Convenient transfer hydrogenation catalysed by palladium-containing beads was performed using a SpinChem® rotating bed reactor (RBR). The set-up resulted in high product conversions throughout more than 10 consecutive batches without any need for filtration to recycle the catalyst.  Keywords: Easy handling, Organic molecules, Palladium on carbon, Quick recycling, Synthesis

Application 9004
Treatment of Viscous Solutions – Simple Extraction and In-line Monitoring

Blue dye was removed from a highly viscous liquid using a SpinChem® RBR S2 in an EasyMax™ 102 Advanced Synthesis Workstation. Monitoring of the reaction was easily recorded as no freely suspended ion exchange resin beads or resin debris interfered with the readings. This demonstrates that the RBR technology is extremely well suited for in-line monitoring. The viscosity of the solution was determined to ca 230 cP at 25°C, showing that it is possible to absorb dye even from a highly viscous solution.  Keywords: Decolouration, Extraction, Ion exchange, Mettler-Toledo, Viscous solutions

Application L2001
Using Spinchem Rotating Bed Reactor Technology for Immobilized Enzymatic Reactions: A Case Study

Subhash Pithani, Staffan Karlsson, Hans Emtenäs, and Christopher T. ÖbergOrganic Process Research & Development 2019 23 (9), 1926-1931 "By using SpiChem RBR technology, we found that recycling of the immobilized enzyme was easy with preserved enantioselectivity and catalytic activity. The final optimized process was successfully demonstrated on a 1 kg scale with 39% isolated yield and 98.8% enantiomeric purity."     Keywords: Scientific literature

Application L1706
Whole-cell cascade biotransformations for one-pot multistep organic synthesis

This scientific minireview highlights that “one-pot multi-catalysis reactions is a revolutionary tool for multistep synthesis” and that “reaction engineering is indispensable to further advance biotransformation processes”. The authors concluded that “advanced reactor design such as … the SpinChem reactor, could also enhance cascade biotransformation processes”.   Keywords: Biotransformation, Encapsulated cells, One-pot multistep, Review, Scientific literature

Application 1037
In-tank deployment of large scale rotating bed reactor

To further demonstrate the use of RBR:s at process scale, a decolorization using ion exchange resin was performed at 7500 L scale. An RBR S14 was filled with strongly acidic cationic resin NRW1160 from Purolite and used to remove blue dye from an aqueous solution in a stainless steel tank of 7500 L volume. The solid-to-liquid ratio is a fraction of percent, showing the efficiency of the RBR technique for convectional mass-transfer and global mixing. The RBR was spun at 340 rpm while the transmittance at 663 nm was monitored for ca 4 h at which point the transmittance had recovered the baseline value for colorless de-ionized water.   Keywords: Ion exchange, Cleantech, Nuclear, Scale-up  

Application L2110
Process design of a continuous biotransformation with in situ product removal by cloud point extraction

In biotransformations, obstacles commonly encountered are product inhibition, product toxicity, and reaction equilibria that prevents complete conversion. Enzyme engineering has made tremendous progress in alleviating these problems. The concept of in situ product removal (ISPR) may still be an attractive alternative or complement. The authors have demonstrated concurrent enzymatic reaction and ISPR, referred to as 'extractive biocatalysis'. For the ISPR, the authors evaluated the use of aqueous micellar two-phase systems (ATPMS) as an extraction medium. For the model reaction, Penicillin G hydrolysis by CalB lipase, the demonstrated process was thus a continuous, heterogeneous extractive biocatalysis with cloud point extraction. An RBR was used during the process development work to determine the Michaelis-Menten kinetics of the CalB immobilized in gel coatings on column packing material. Also, the particles were easily re-used in stability experiments.

Application 1040
The importance of baffles in a reactor vessels

baffle (noun) : a device (such as a plate, wall, or screen) to deflect, check, or regulate flow or passage (as of a fluid, light, or sound) Can you use a rotating bed reactor (RBR) in any type of vessel? Absolutely. Would the performance be higher with baffles in the vessel? Definitively. A vortex, which forms due to the rotation of an agitator, is detrimental to the mixing in a reactor vessel. If the agitator is a rotating bed reactor, it also disrupts the flow through the RBR. Baffles are features in the reactor vessel that break the circulating flow pattern, preventing vortex formation and improving overall mixing. The importance of baffles has long been established for stirred tank reactors with agitation by impellers, and baffling is equally important for vessels with an RBR installed. You don't need to take our word for it; customers that have investigated the effect of baffling on their mass-transfer limited reactions have found the same result. The most recent data comes from research at the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB. They started out with the RBR S3 in a smooth glass vessel. After observing a deep vortex, drawn down into the RBR, and the resulting disappointing performance, one simple flat-blade baffle was installed. The performance for the enzymatic reaction was quantified with and without the flat-blade baffle, and the result is presented in the figure below. As seen in the data, installing one simple baffle resulted in a doubled yield at each time point on average. The double-walled glass vessels (V2 and V3) that SpinChem offer are custom-made to fit the RBR S2 and S3 respectively. The vessels have structured inner glass walls that serve as "flower-shaped" baffles, which do not take up the same space as traditional flat-blade baffles. This minimizes the required volume of reaction medium, and maximizes mixing performance.   Some non-baffled vessels perform as if they had flow breakers installed, just through the shape of their vessel walls. For instance, any non-round geometry such as rectangular IBC-tanks may provide satisfactory mixing and prevention of a deep vortex forming. On benchtop scale, the round beaker is appealing with its simplicity, but a baffled reaction vessel will yield much better performance. If you have more questions about this contact us.

Application L2117
Multi‐enzyme cascade reaction in a miniplant two‐phase‐system : Model validation and mathematical optimization

In the American Institute of Chemical Engineers, AIChE Journal, the authors of this paper highlights the use of Rotating Bed Reactor (RBR) with two different immobilized enzymes at the same time in a cascade reaction. In the flow chart above of the miniplant consisting of a continuously stirred tank reactor (CSTR) equipped with an RBR (highlighted in orange) (a), a buffer tank (b), an extractive centrifuge (c) and a fixed bed reactor (d)  In the reaction scheme the complete multi-enzyme cascade is shown with the two enzymes placed in the RBR is highlighted. If you would like to get in contact with us give us a call or fill in the form.

Application L2112
Production of hydroxytyrosol rich extract from Olea europaea leaf with enhanced biological activity using immobilized enzyme reactors

The paper describes work to valorize olive leaves, the major by-product in olive oil production. Aqueous olive leaf extract is rich in oleuropein that was enzymatically hydrolyzed by beta-glucosidase to hydroxytyrosol and other products. Compared to the non-modified extract, the modified one demonstrated 20% higher antioxidant activity, seven-fold higher antibacterial activity, and enhanced cytotoxicity against leiomyosarcoma cells. The beta-glucoside was immobilized in chitosan-coated magnetic beads and used in both stirred tank reactor (STR) and rotating bed reactor (RBR). The immobilized enzyme showed good stability over time and the activity was good in both STR and RBR settings. However, the enzyme beads were damaged mechanically in the STR and could not be re-used. The RBR solved the problem of bead attrition allowing the immobilized enzyme to be re-used and thus giving superior total turnover number to the STR.

Application L1903
L-Asparaginase production in rotating bed reactor from Rhizopus microsporus IBBL-2 using immobilized Ca-alginate beads

The present work reports on the production of extracellular l-asparaginase from Rhizopus microsporus IBBL-2 using submerged fermentation (SmF) process free of glutaminase and urease activities. Scale-up studies involving 200-mL and 1-L rotating bed reactor (RBR) using immobilized beads were done and the results obtained are 20.21 U mL-1 and 19.13 U mL-1, respectively, the increased activity with immobilization accounts for reduced shear on cells due to increased stability as compared to the free-flowing cells.

Application L2115
Production of recombinant choline oxidase and its application in betaine production

The paper describes the author’s successful work to express and use recombinant choline oxidase. The gene for the choline oxidase was isolated from a Gram-positive soil bacterium, cloned into an expression vector, inserted into and overexpressed in a Rosetta expression system. The isolated recombinant choline oxidase was subsequently immobilized onto Ni-Sepharose beads, which were loaded in a rotating bed reactor (RBR). With the immobilized choline oxidase in the RBR, reaction conditions such as pH and temperature were optimized and the enzymatic activity measured for the reaction of choline to glycine betaine via betaine aldehyde.

Application L2213
Impact of critical parameters influencing enzymatic production of structured lipids using response surface methodology with water activity control

Water is an important factor in enzymatic reactions as it affects the enzyme activity and the equilibrium position of hydrolytic reactions. To study these effects, the authors first developed a system based on relatively simple and low-cost components that could continuously control the activity of water in organic media in a SpinChem® RBR. Structured lipids with desired properties can be produced by enzymatic transesterification. This is a multistep reaction with many factors influencing both the product yield and quality. In this study, the single and combined effects of water activity, temperature and substrate ratio were studied on the reaction between high oleic sunflower oil and ethyl stearate. The efficient mixing in the RBR also in viscous solutions such as oil, further improves the dispersion of nitrogen gas and the mass transfer rate. A system to control the thermodynamic water activity in the range of 0.05–0.92 in a 0.12–0.3 L RBR from SpinChem® (Umeå, Sweden) was developed. A schematic drawing of the system is presented in the figure above. The reactor is a jacketed glass reactor (SpinChem® V2) with a rotating bed (SpinChem® S2) for agitation and compartmentalization of immobilized enzymes.    

Application 1044
Simple scale-up using flexible reactors

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. Many heterogeneous processes (e.g. adsorption or catalysis) are made faster by increasing the solid-to-liquid ratio. Studying scale-up effects can also help to predict full-scale performance. For these reasons it’s wise to invest in equipment that can handle different operating conditions such as liquid volume, solids loading, pH and temperature. The RBR S3 Plus is the most modular rotating bed reactor for laboratory use. Made from two stacked rotating bed reactors, the S3 Plus quickly converts to a single RBR S3 for use with smaller liquid volumes. When used in the dedicated glass reactor system, this yields an operating range of 250 - 1500 mL of liquid and 0 - 140 mL of solids.   This application note investigates the effect of solids loading on the reaction rate of two applications: the adsorption of a dye and a biocatalytic esterification reaction. These two reactions are mass-transport limited and relatively fast. In the first case, an RBR S3 and an RBR S3 Plus were filled with 50 mL and 100 mL respectively of the ion-exchange resin Purolite® NRW1160. Methylene blue was dissolved in water, and the solution was decolorized by spinning an RBR at 600 RPM (reaction conditions in the details below). The results were clear; each case followed 1st order kinetics with a rate constant for the RBR S3 Plus that was twice that of the RBR S3. Note that the solid-to-liquid ratio for the RBR S3 Plus was also twice that of the RBR S3. For the enzymatic esterification, the same rotating bed reactors (RBR S3 and RBR S3 Plus) were filled with 40 mL and 80 mL respectively of the biocatalyst Purolite® immo PS. The rotating bed reactors were used in separate reactions in mixtures of lauric acid, 1-propanol and water. Also in this case the reaction rate was proportional to the solid-to-liquid ratio, yielding twice the productivity with the RBR S3 Plus compared to the RBR S3. The conclusion is that with a rotating bed reactor you are making the most out of the solid-phase. Doubling the amount of catalyst or adsorbent will generally double the reaction rate constant, which makes scaling up straightforward. Contact us today to discuss how we can scale your process.

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