Skip to main content

Biocatalysis: A sustainable approach to chemical synthesis

Download: Biocatalysis applications with rotating bed reactors (RBR)

Biocatalysis is the use of enzymes and occasionally other biological molecules to catalyze chemical reactions. It is used in a wide range of applications, including the production of chemicals, pharmaceuticals, flavoring agents, or food and beverages.

One of the main advantages of biocatalysis is its ability to highly selectively catalyze reactions under mild conditions, such as at moderate temperatures and pH values. This makes it a more environmentally friendly and intrinsically safer alternative than traditional chemical synthesis.

In addition to its environmental benefits, biocatalysis can also offer economic advantages, such as lower production costs and the ability to synthesize complex molecules that are difficult to access by other methods. These factors make biocatalysis an attractive option for many industries.

Some specific examples for applications of biocatalysis include the production of enzymes for laundry detergents, the synthesis of pharmaceuticals, and the production of biofuels.

Biocatalysis, the future of sustainable chemistry

Enzymes display remarkable chemo-, regio-, and stereoselectivity. The identification of a suitable enzyme that converts the mandated substrate to the desired product isomer, allows to significantly shorten reaction pathways compared to traditional multistep synthesis. Notably, protection and deprotection strategies can often be omitted, and difficult isomer separation may be avoided.

The mild conditions and modest temperatures employed in enzymatic reactions, in combination with the highly selective catalysis, typically result in few to no significant side reactions.

Additionally, environmental and toxicological benefits can be reaped by avoiding pathways that employ metal catalysts and hazardous reagents.

 

Exploring enzymes types and their applications

Enzymes are divided into seven classes according to the type of reaction they catalyze.

EC 1 - Oxidoreductases catalyze oxidation-reduction reactions, hence involving the transfer of electrons from one molecule to another.

EC 2 - Transferases catalyze the transfer of certain groups from one molecule to another.

EC 3 - Hydrolases catalyze the hydrolysis of various bonds.

EC 4 - Lyases catalyze the cleavage of various bonds by means other than hydrolysis, often forming a double bond or a new ring structure.

EC 5 - Isomerases catalyze the rearrangement of atoms within a molecule to form a structural isomer.

EC 6 - Ligases catalyze the formation of a new chemical bond, facilitated by the concommitant consumption of a high-energy cosubstrate.

EC 7 - Translocases facilitate the movement of ions or molecules across membranes or their separation within membranes.

 

Reaction optimization: Factors that influence the activity and stability of enzyme and improves your reaction

The activity and stability of enzymes are governed by several factors, including temperature, pH, solvent type or buffer conditions, water activity, immobilization, stirring, and reaction parameters. Understanding these factors allows us to optimize enzyme-catalyzed reactions and to improve their efficiency and effectiveness.

Temperature
Enzymes are subject to two competing processes: On the one hand an increase in temperature raises the catalytic turnover according to Arrhenius, and on the other hand it accelerates the breakdown of the enzyme. The combined result is a bell-shaped temperature-activity curve, i.e., enzymes have a specific optimal temperature with peak productivity flanked by diminishing returns at both higher and lower temperatures.

Enzymes are frequently engineered to shift the temperature range of optimal activity and to thereby make them more resistant to denaturation. The desired shift in temperature can be both to higher and lower temperatures to either allow for reactions at elevated temperatures or to ensure high activity even at low temperatures. Enzymes can also be engineered to allow for a broadened substrate scope or non-natural substrates and products. Finally, engineering may confer stability in non-conventional media.

pH
Similar to temperature dependence, enzymes show peak activity within a narrow pH range. When moving away from the optimal pH, the activity is diminished and finally lost. Consequently, some form of pH control is often necessary.

Solvent/buffer
Choice of buffer and buffer strength may provide pH control and stability in aqueous systems and consequently also determine activity and stability. In non-conventional solvents, pH effects are defined by the interplay of physicochemical properties of substrates, products, and the reaction medium. This may go so far as to render these effects completely void. However, solvents themselves may have a strong impact on enzyme stability and activity. If necessary, process analytical technology (PAT) and titration allow for active pH control in any case. Choice of solvent also strongly affects the enzymatic activity.

Water activity
Enzymes require a minimum amount of water to sustain their catalytic function. This is typically due to the need for structurally-bound water and becomes important for reactions in non-aqueous media. However, the share of water required is frequently less than 1% of the total reaction medium. As a consequence - and perhaps counter-intuitively - a small amount of water is also added to reactions that from a thermodynamic perspective should ideally be 'water-free' (i.e., condensation reactions).

Immobilization
Immobilization of free enzymes onto solid materials (enzyme carriers) often provides stabilization and thereby prolonged lifetime of the enzyme. However, it also affects enzymatic activity whereby an increase is the more desirable yet less prevalent result. The success of the immobilization is strongly defined by the compatibility between enzyme and enzyme carrier material, and trials with several different materials are advisable. Arguably, the most common enzyme carrier materials are synthetic polymers (resins), but inorganic materials such as glass, natural fibers, etc. are also used and bio-based organic alternatives gain traction as well. The final choice is typically based on overall catalytic productivity.

Inherently connected to the enzyme carrier material is the method of attachment. While some enzymes, notably lipases, may be attached non-covalently by hydrophobic interactions, covalent attachment is often needed. The chemistries used hereby are versatile and frequently react nucleophilic free amines or thiols from the enzyme surface with electrophilic reactive groups (epoxides, aldehydes) on the carrier surface. The exact choice of attachment strategy will definitely affect the catalytic properties of the obtained heterogenous biocatalyst preparation.

Read more in our insight 'Introduction to Enzyme Immobilization'.

Mixing
In the case of industrially preferred immobilized enzymes, the method of mixing determines the longevity of the heterogeneous catalyst. For batch reactors, the rotating bed reactor offers almost complete protection against the grinding effects that standard stirred tank reactors suffer from. As a result, extended recycling becomes feasible and convenient.

 

 

A rotating bed reactor (RBR) is designed to prevent disintegration of solid phase particles by retaining them inside a rotating cylinder during the reaction. This minimizes solid phase debris even at high speeds, which would normally occur due to mechanical forces when using stirred tank reactors. Due to this characteristic of the RBR, reaction rates can be improved by increasing the stirring speed without simultaneously shortening the lifespan of the solid particles. This ensures easy in-line monitoring of the process, as well as a more efficient recycling of the solid phase, making the RBR a cost and time efficient alternative to conventional methods for immobilized enzyme biocatalysis.

Reaction parameters
Perhaps more related to the efficiency of the enzymatic reaction than the stability of the enzyme are parameters such as reagent stoichiometry, gas introduction method, and the minimization of temperature or concentration gradients. Proper mixing ensures the necessary mass transfer of all substrates to the enzyme and is crucial especially in three-phase reactions where saturation with gaseous reagents has to be considered as well. Here too, the RBR provides important advantages over stirred tank reactors.

Key biocatalysis applications and challenges

Common Challenges with Biocatalysis

Biocatalysis, while offering numerous advantages over traditional chemical catalysis, presents several significant challenges that researchers and industry professionals must address. These include enzyme stability issues (temperature, pH, and storage sensitivity), mass transfer limitations, economic constraints (high costs and limited recyclability), process integration challenges (compatibility with chemical processes and product separation difficulties), substrate/product inhibition effects and scalability. Overcoming these challenges requires innovative approaches in enzyme engineering, reactor design, and process development.

Application Key Challenge
API synthesis (Pharma) Enhancing enzyme stability and reusability while ensuring high enantioselectivity
Fine chemical production Overcoming mass transfer limitations to improve reaction rates
Food & beverage processing Achieving cost-effective enzyme immobilization for high-volume production
Industrial liquid remediation Designing reactors for efficient throughput and operational simplicity

 

Process Scale-Up and Industrial Applications of Enzymes

How to scale up a biocatalytic process?

Scaling up biocatalytic processes involves several key considerations, including optimizing reaction conditions, selecting appropriate reactor technologies, while ensuring that the process is feasible to transfer to the larger scale.

This requires technology that preserves enzyme efficiency and stability as the production volume increases. Unlike other reactor types, the the Rotating Bed Reactor (RBR) specifically addresses scale-up challenges by:

  • Protecting immobilized enzymes from mechanical damage
  • Delivering enhanced mass transfer across all scales
  • Maintaining consistent reaction parameters from lab to production

Read about successfully scaled biocatalytic processes from 300 mL to 750 L (a 2,500× increase) while maintaining identical reaction conditions and preserving enzyme activity.

Industrial applications of immobilized enzymes

Pharmaceutical Industry

Immobilized enzymes have revolutionized pharmaceutical manufacturing by enabling more efficient, sustainable, and cost-effective production processes. From API synthesis to chiral resolution and peptide manufacturing, immobilized enzymes offer pharmaceutical companies significant advantages over traditional chemical methods.

Food & Beverage Industry

Immobilized enzymes are essential in food processing due to their stability, reusability, and control benefits. They enhance the production efficiency of food ingredients while minimizing waste and costs. Key uses include lactose-free milk, high-fructose corn syrup, clarified fruit juices, flavor synthesis, and food analysis.

Industrial Waste Remediation

Biocatalysis offers innovative solutions for environmental remediation and liquid waste treatment challenges. Enzymes can effectively break down pollutants, transform hazardous compounds into benign substances, and operate under mild conditions that minimize energy consumption. 

Download a brochure

Biocatalysis applications with SpinChem Rotating Bed Reactors (RBR)

Industrial enzyme systems

Choosing the right immobilization method, carrier material, and reactor to deploy them in is critical for maximizing enzyme performance and process economics.

Unlike other common reactor types such as batch or flow reactors, SpinChem's rotating bed reactor (RBR) specifically addresses several of these issues by providing enhanced mass transfer while protecting immobilized enzymes from mechanical damage, even at industrial scales. The RBR technology integrates smoothly into existing processes to simplify the adoption of immobilized enzymes in your operations.

Read more about SpinChem reactor design and scale up possibility.

Reactor technology solutions for immobilized enzymes

Get in-depth Insights on biocatalysis

How to avoid grinding of immobilized biocatalysts?

To avoid grinding of immobilized biocatalysts, use rotating bed reactors that protect immobilized enzymes while maintaining excellent mass transfer at industrial scales.

Preventing mechanical damage is essential for maintaining enzyme activity, extending catalyst lifespan, and improving process economics.

Learn how SpinChem RBR helps to avoid grinding of molecular sieves

 

How to filter solid phase particles from reaction media?

Traditional methods like vacuum filtration or centrifugation can be time-consuming and often result in product loss.

SpinChem's Rotating Bed Reactor (RBR) technology offers a superior solution by containing solid phase particles within a porous rotating cylinder, eliminating the need for filtration altogether. This innovative approach:

  • Keeps solid catalysts confined while allowing reactants and products to flow freely
  • Prevents filter clogging issues common with fine particles
  • Enables continuous operation without interruption for filtration steps
  • Simplifies downstream processing by keeping reaction media free of particulates

How to improve mass transfer and process efficiency in biocatalysis?⁠

Improving mass transfer and process efficiency in biocatalysis requires innovative reactor design that addresses fundamental limitations. SpinChem's Rotating Bed Reactor (RBR) technology specifically enhances mass transfer while protecting immobilized enzymes from mechanical damage, resulting in higher reaction rates and improved catalyst longevity.

Read more about detailed strategies on optimizing mass transfer in biocatalytic processes

Learn how this innovative reactor design outperforms stirred tank reactors by enhancing mass transfer and minimizing process limitations.

Download a Brochure about Biocatalysis Applications

What are the advantages of immobilized enzymes?

Immobilized enzymes offer numerous advantages over traditional free enzymes in biocatalysis processes. They provide enhanced stability, easier recovery and reuse, improved resistance to environmental changes, and better process control. This significantly reduces enzyme costs while increasing efficiency in industrial applications across pharmaceutical, food processing, and fine chemical production.

For more detailed information on enzyme immobilization techniques visit our comprehensive guide: Introduction to Enzyme Immobilization

How to recycle and reuse immobilized enzymes

Effectively recycling immobilized enzymes is crucial for sustainable and cost-efficient biocatalysis. Rotating Bed Reactor (RBR) technology offers a superior solution by protecting immobilized enzymes from mechanical damage while providing enhanced mass transfer, enabling multiple reaction cycles without significant activity loss.

Read how catalyst recycling can be performed for more than 10 consecutive reactions with preserved reaction rates using the SpinChem Rotating Bed Reactor.

How to exploit immobilized enzymes in a heterogeneous system? How to overcome challenges during the reaction work up?

Effectively utilizing immobilized enzymes in heterogeneous systems requires specialized technology that addresses mass transfer limitations while protecting catalyst integrity. Rotating Bed Reactor (RBR) technology provides an optimal solution by containing immobilized enzymes within a protective rotating cylinder while ensuring excellent mass transfer, even at high speeds. This approach significantly improves reaction efficiency and simplifies work-up procedures by eliminating filtration steps and reducing mechanical damage to enzyme carriers.

Is there a more cost-effective and time-efficient method for immobilized enzyme biocatalysis than traditional methods?

Traditional immobilized enzyme methods often struggle with mechanical damage, poor mass transfer, and high costs. SpinChem's Rotating Bed Reactor (RBR) technology offers a superior alternative by protecting immobilized enzymes while enhancing mass transfer efficiency—even at industrial scales. This innovative approach significantly improves enzyme longevity and process economics, making biocatalysis more commercially viable.

What lab equipment is best for solid-liquid interaction experiments?

SpinChem's Rotating Bed Reactor (RBR) technology is specifically designed for optimal solid-liquid interactions in laboratory settings. This innovative system addresses the most common challenges researchers face in these experiments.

Key benefits for your solid-liquid interaction work:

  • Superior mass transfer between solid and liquid phases
  • Protection of valuable solid materials from mechanical damage
  • No filtration needed - solid particles remain contained in the rotating bed
  • Eliminates filter clogging problems common with fine particles
  • Cleaner reaction media for simplified downstream processing

RBR technology offers exceptional scalability, enabling you to seamlessly transfer your lab protocols to larger volumes. Customers have successfully scaled processes from 300 mL to 750 L while maintaining identical reaction conditions. You can start your biocatalysis experiments in a lab with a complete starter kit and scale up seamlessly to production

Explore practical biocatalysis applications – case studies & application notes

Biocatalysis by immobilized enzymes in a rotating bed reactor

Immobilized biocatalysis is the application of enzymes bound to solid supports, where they act as catalysts facilitating a chemical reaction. Traditionally, this process has been performed in stirred tank reactors or fixed bed reactors. The stirred tank will quickly destroy the solid support, leading to loss of catalysts and fouling of the product. Although the fixed bed (also known as column) circumvents this problem, it still suffers the challenge of severe pressure buildup which often makes deployment impossible at scale.

Improving reactions in emulsions using a rotating bed reactor

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.

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

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.

Enzyme immobilization screening using rotating bed reactors

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.

Recycling Novozym® 435 with a rotating bed reactor in the EasyMax™ 102

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.

Rotating bed reactor for immobilized enzymatic reactions

In pharmaceutical manufacturing and other industries, traditional methods are burdened by unsustainable use of solvents and transition metal catalysts. The use of enzymes is pursued as an alternative, offering greener synthetic routes and better results due to improved specificity. However, enzymes are costly and reusing them for many cycles is practically a requirement for process economy. This essentially means that the enzymes must be immobilized on a solid support so that they can be separated from the product.

Soft alginate beads used 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.

Screening of Immobilized Enzymes in an EasyMax™ 102

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.

Screening of immobilized lipases using rotating bed reactors

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.

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.

A glass beaker containing clear liquid where orange and blue dyes are being separately introduced through two tubes, creating distinct streams of color in the solution. The dyes maintain separation, demonstrating selective extraction.

Cascade reactions with a rotating bed reactor in an EasyMax™ 102

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.

Lipase-catalyzed hydrolysis in 750 L using a rotating bed reactor

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.

How the loading of solids influences reaction speed

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?

Amination of a green solvent via immobilized biocatalysis for the synthesis of Nemtabrutinib

Christopher K. Prier, Karla Camacho Soto, Jacob H. Forstater, Nadine Kuhl, Jeffrey T. Kuethe, Wai Ling Cheung-Lee, Michael J. Di Maso, Claire M. Eberle, Shane T. Grosser, Hsing-I Ho, Erik Hoyt, Anne Maguire, Kevin M. Maloney, Amanda Makarewicz, Jonathan P. McMullen, Jeffrey C. Moore, Grant S. Murphy, Karthik Narsimhan, Weilan Pan, Nelo R. Rivera, Anumita Saha-Shah, David A. Thaisrivongs, Deeptak Verma, Adeya Wyatt, and Daniel Zewge ACS Catal., 2023, 13(12), pp. 7707-7714.

A molecular structure representation symbolizing biocatalysis and heterogeneous chemical reactions in industrial enzyme systems.

Cellulose-bead immobilized enzymes as biodegradable and renewable catalysts

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.