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Item type:Publication, Access status: with files , Development of an experimental setup and a validated model for a highly integrated biocatalytic process(American Chemical Society (ACS), 2026-07-23); ; ; ; The development and validation of a mathematical model for a highly integrated biocatalytic process are presented. A multienzymatic cascade comprising three parallel and sequential reaction steps was implemented in a miniplant setup, integrating an enzyme membrane reactor (EMR) and a reactive extraction centrifuge (REC) to enable intensified biotransformations. Laboratory-scale experiments were conducted to obtain the kinetic and thermodynamic data necessary for model development. The resulting process model captures both the enzymatic reaction kinetics and the dynamic behavior of the integrated unit operations. Model validation was performed under representative process conditions in the miniplant system. The results demonstrate good agreement between the model and experimental data, confirming the predictive power of the model and supporting its use in future process design, scale-up, and optimization. This work underscores the importance of model-based development for advancing sustainable and efficient biocatalytic processes.Publicationtype: Journal Article27 9 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: with files , Debottlenecking a 2-phase multi-enzymatic cascade by an enzyme membrane reactor – Modelling and experimental validation(Elsevier, 2025-08-08); ; ; ; Biotechnological processes have a high potential to make industrial processes more sustainable. However, biotechnological processes often have low product concentrations and production rates. This is where process intensification can help to make these processes competitive. Using the example of the multi-enzymatic synthesis of natural cinnamyl cinnamate, it is shown how an existing multi-enzymatic process can be intensified by using an enzyme membrane reactor. The individual enzymatic reactions are first characterised in laboratory scale and then combined in a mini plant. In addition, a process model of the mini plant is developed. It is shown that the use of an enzyme membrane reactor can increase the production rate of the multi-enzymatic process by a factor of 10 compared to a previously investigated set-up.Publicationtype: Journal Article57 21 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: with files , Analytical and numerical approaches to the analysis of progress curves: a methodological comparisonAccurate models of the reaction kinetics of enzymatic reactions are essential for the design of biocatalytic processes. While many experimental studies still build on initial slope analysis, progress curve analysis offers the potential for modelling enzymatic reactions with a significantly lower experimental effort in terms of time and costs, but requires the solution of a dynamic nonlinear optimization problem. There are many different approaches for solving this problem for parameter regression, building on the experimental progress curve data. In order to provide some guidance for selecting an appropriate approach, this study presents a detailed comparison of two analytical and two numerical approaches analysing their strengths and weaknesses on the basis of three case studies. The analytical approaches build on the implicit and explicit integrals of the respective reaction rate equations, while the numerical approaches consider the direct numerical integration of the differential mass balance equations as well as the transformation of the dynamic problem to an algebraic problem by means of spline interpolation of the reaction data. In particular, the dependence of the results on the initial parameter estimates is evaluated, showcasing that the numerical solution with spline interpolation shows a lower dependence on the initial values providing parameter estimates comparable to the analytical approaches, which are however limited in applicability.Publicationtype: Journal Article47 17 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Multifunctional reactor for process intensification of a multi-enzymatic cascade(American Institute of Chemical Engineers (AIChE), 2023-11-08); ; ; ; Introduction Biocatalysis plays a crucial role in the sustainable production of bulk chemicals, specialty chemicals, and high-value products. The use of enzymes, can reduce investment and operational costs and decreases the risk of accidents by enabling milder reaction conditions compared to chemical processes [1]. Enzyme-catalyzed reactions also have high selectivity, increasing yields, and reducing the complexity and costs of downstream processing. However, several challenges still exist, such as high enzyme costs, reactant or product inhibition, and low conversion rates. In order to overcome these, multi-enzymatic cascades can be a sufficient option. They allow the production of tailored products with flexible synthesis routes and can be operated without the separation of the intermediate [2]. In addition to the use of enzymes, process intensification is a key factor in improving biocatalytic processes for sustainable production. As stated by Stankiewicz process intensification “consists in the development of innovative apparatuses and techniques that offer drastic improvements in chemical manufacturing and processing, substantially decreasing equipment [..] and ultimately leading to cheaper, safer, technologics” [3]. In biocatalytic processes, this can be achieved through the use of multifunctional reactors, as e.g. achieved in reactive separations. Multifunctional reactors can be designed to overcome limitations such as enzyme instability or low conversion rates by providing suitable reaction conditions for biocatalysts [4]. Furthermore, a membrane bioreactor can be combined with a packed bed reactor to improve mass transfer and minimize substrate inhibition [4,5]. This contribution investigates the intensification of a biocatalytic process for producing cinnamyl cinnamate, a natural flavor and fragrance. The process employs a multi-enzymatic cascade, as depicted in Figure 1. The first step of the cascade converts cinnamyl aldehyde into cinnamyl alcohol. However, the alcohol dehydrogenase (ADH) used in this reaction requires the costly co-factor NADH. To reduce the use of NADH, a second reaction is introduced for co-factor regeneration using a formate dehydrogenase (FDH). Both reactions take place in the aqueous phase The third reaction in the cascade takes place in the organic phase, where an esterification reaction using an immobilized lipase forms the final product, cinnamyl cinnamate. To ensure optimal reaction conditions, two phases are utilized. The esterification reaction cannot occur in the aqueous phase, as water is produced as a byproduct. The ADH and FDH enzymes are highly sensitive to the organic medium, necessitating the use of an aqueous medium. This reaction system offers an opportunity to produce a natural flavor and fragrance sustainably. However, its technical implementation is challenging as it requires controlling three reactions in two phases. This contribution explores the realization of the process in a miniplant scale and the potential for improving the process using multifunctional reactors. The shown reaction system was operated in a former project in a miniplant. the previous setup of the process, which comprised a reactor for the two aqueous-phase reactions, an extractive centrifuge for facilitating mass transfer between the phases, and a reactor for the organic-phase reaction [6]. Recent simulation studies identified two primary, independent bottlenecks in this setup: the immobilized enzymes in the aqueous phase and the reflux stream of the organic phase from the fixed bed reactor back into the centrifuge during continuous operation. Set-up The integrated process with modifications for both bottlenecks is shown in Figure 2. When immobilized on a silica carrier, ADH and FDH exhibited only 4% residual activity. Consequently, an alternative to immobilization that keeps the enzymes in place had to be found. An enzyme membrane reactor was suitable for this purpose since it allowed the reaction medium, substrates, and products to pass through while retaining the native enzymes. This can significantly enhance enzyme activity and reaction velocity. The second part for improving the process was to reduce the reflux rate from the organic reactor into the centrifuge during continuous operation. According to Baldea [7], high reflux rates indicated the need for further process integration, such as the integration of the reactor and the extractive centrifuge as a reactive extraction centrifuge. In order to store the organic volume that was not inside the centrifuge, a tank for the organic phase was added. The subsequent sections will describe the implementation of the enzyme membrane reactor, the reactive extraction centrifuge, and the simulations in a miniplant. Investigation of membrane reactor and reactive extractive centrifuge Prior to their integration into the process, both the enzyme membrane reactor and the reactive extraction centrifuge were investigated individually. To establish the feasibility of the enzyme membrane reactor, a solvent resistant membrane that offers a high permeate flux, and provides a suitable cut-off between the enzyme and the product size was required. A screening of seven membranes identified an ultrafiltration Pebax® membrane that met these requirements. This membrane was then integrated into an enzyme membrane reactor, which was used to investigate ADH-catalyzed synthesis. Figure 3 illustrates the experimental results of the enzyme membrane reactor, which reveals a sharp increase in alcohol concentration after a dead time of around four hours. The dead time can be explained by the high volume of the membrane plant compared to the volume flow in and out of the plant. The effects of the enzyme membrane reactor were being compared to those of the previous setup, in which immobilized enzymes were used. The experimental results show that the enzyme membrane reactor produced an intermediate alcohol yield that is about 4 times higher than that achieved using the previous setup in the same time span. Adjusting the startup and operation procedures to reduce the system's dead time is expected to increase this effect further. To study the reactive extraction centrifuge, a modified extractive centrifuge was used as there are no reactive extraction centrifuges commercially available. The reactive zone was integrated into the rotor of the centrifuge, and operation conditions that allow for clear phase separation were determined without conducting a reaction. The volume flow into the reactive extraction centrifuge and the rotational speed were found to be the key factors that influence phase separation, with a rotational speed of 500 rpm and a total volume flow of 500 mL/min being suitable parameters [8]. The whole reactive extraction centrifuge was then studied, with exemplary results presented in Figure 4. These results demonstrate a clear increase in the final product concentration during the operation time, indicating that the novel, internally constructed apparatus is operational. Simulation of the integrated process To gain a deeper understanding of the process, it is beneficial to create a mathematical model. In this study, a dynamic model will be implemented in Python with time discretized in one-minute steps. The developed model includes both phases, as well as the concentrations of all substrates, intermediates, and products. To create the model, the reaction kinetics of all three reactions were determined on a laboratory scale, and physical properties and substance-related data, such as the partition coefficient, were used to describe the process [6]. Solubilities were taken into consideration as well. The concentrations, volumes, and temperatures are limited to be zero or higher as a boundary condition. This model can be used to conduct case studies, particularly to determine the initial substrate concentrations and operational conditions, such as the temperature. Conclusion To summarize, this contribution explores how the use of multi-enzymatic cascades and process intensification can help reduce the effect of challenges such as high enzyme costs and low conversion rates. Specifically, the intensification of a biocatalytic process for producing cinnamyl cinnamate and the potential for improving the process using multifunctional reactors is investigated. The study proposes the use of enzyme membrane reactors and reactive extraction centrifuges in the process to increase the efficiency of the reaction and to successfully operate the novel apparatus. In addition to that the process is successfully modeled and simulated in order to gain a better understanding of the complex process. This model can be used for further studies to determine bottlenecks and possibilities for further improvement of the process. References Green biocatalysis; Wiley Blackwell: Chichester, West Sussex, 2016, ISBN 9781118822296 Ricca, E.; Brucher, B.; Schrittwieser, J.H. Multi-Enzymatic Cascade Reactions: Overview and Perspectives, 2011. Stankiewicz, A. Reactive separations for process intensification: an industrial perspective. Chemical Engineering and Processing: Process Intensification 2003, 42, 137–144, doi:10.1016/S0255-2701(02)00084-3 The fabrication of a high performance enzymatic hybrid membrane reactor (EHMR) containing immobilized Candida rugosa lipase (CRL) onto graphene oxide ..., 2020. Rodríguez-Hernández, L.; Esteban-García, A.L.; Tejero, I. Comparison between a fixed bed hybrid membrane bioreactor and a conventional membrane bioreactor for municipal wastewater treatment: a pilot-scale study. Bioresour. Technol. 2014, 152, 212–219, doi:10.1016/j.biortech.2013.10.081 Johannsen, J.; Meyer, F.; Engelmann, C.; Liese, A.; Fieg, G.; Bubenheim, P.; Waluga, T. Multi‐enzyme cascade reaction in a miniplant two‐phase‐system : Model validation and mathematical optimization. AIChE J 2021, 67, doi:10.1002/aic.17158 [In Citavi anzeigen] . Baldea, M. From process integration to process intensification. Computers & Chemical Engineering 2015, 81, 104–114, doi:10.1016/j.compchemeng.2015.03.011 Meyer, F.; Gasimov, N.; Bubenheim, P.; Waluga, T. Concept of an Enzymatic Reactive Extraction Centrifuge. Processes 2022, 10, 2137, doi:10.3390/pr10102137Publicationtype: Conference Presentation78 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Debottlenecking a multi-enzymatic cascade reaction in a 2-phase system(2023-09-19); ; ; ; Publicationtype: Conference Presentation53 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: with files , Concept of an enzymatic reactive extraction centrifuge(Multidisciplinary Digital Publishing Institute (MDPI), 2022-10-20); ; ; Biocatalytic processes often provide an ecological alternative to many chemical processes. However, further improvements in terms of the economic efficiency are required. In order to achieve that, the concept of process integration is a promising option. Applying this within a biocatalytic process, a highly integrated apparatus working as a reactive extraction centrifuge was developed and operated. For this purpose, a commercially available extraction centrifuge was modified to implement a biocatalytic reaction. The novel apparatus was used within a multi-enzyme cascade for the production of a natural flavor and fragrance, namely cinnamic ester. The characterization of the reactive extraction centrifuge and the suitable operation conditions for the inlet streams and the rotational speed for a stable operation were determined. Furthermore, different initial substrate concentrations were applied to prove the reaction. The results provide a successful proof of concept for the novel reactive extraction centrifuge.Publicationtype: Journal ArticleScopus© Citations 1 126 281 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: with files , Commissioning and operation of an enzymatic reactive extraction centrifuge.Publicationtype: Conference Poster not in Proceedings183 135 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Modeling of an enzymatic reactive extraction centrifuge as part of a multi-enzymatic cascadePublicationtype: Conference Presentation86 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Evaluation of process integration for the intensification of a biotechnological process(2021-10); ; ; ; Process intensification is a well-known and established method to improve ecological and economic efficiency of large-scale chemical processes. Process intensification in form of integrating an in-situ product or intermediate removal can also improve processes. In this study the effects of integrating an intermediate separation in form of an extraction centrifuge and a product separation in form of a pre-purification into a multi-enzyme cascade as well as the potential for further process integration in form of a reactive extraction centrifuge are analyzed for a biotechnological process. In order to evaluate the application of process integration, different process configurations are compared regarding to the efficiency using a model-based approach. Although the highly integrated process leads to lower space-time yields in some cases, an operating window can be identified in which the space-time yield is significantly higher compared to a sequential process. In order to distinguish both cases and thus choose a suitable operating point simulative studies are required. Moreover, a potential for further integration can be identified for the reference process studied in this work.Publicationtype: Journal Article97 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: with files , Multi-enzyme cascade reaction in a miniplant two-phase-system: model validation and mathematical optimization(Wiley, 2021-01-11); ; ; ; Biotechnological application of multiple enzymes in different phases for target compounds synthesis poses a significant challenge for industrial process development. At the same time, a growing demand for natural flavors and fragrances opens up possibilities for novel biotechnological processes to replace current chemical synthesis routes, with additional advantages such as avoiding harsh reaction conditions and toxic chemicals, and less by-products in the system. Within complex biotechnological processes, the key for unfolding their industrial application potential in bioprocess engineering lies in their mathematical modeling. In this contribution, a multi-enzyme cascade reaction in a two-phase system implemented in a miniplant-scale reactor setup is mathematically modeled for the example of the flavoring agent cinnamyl cinnamate. Using our validated model and a mathematical optimization tool based on a genetic algorithm, optimization runs are performed to demonstrate the potential of computer-aided process development for complex biotechnological processes.Publicationtype: Journal ArticleScopus© Citations 11 157 338