Laboratory automation strategies have vast potential for accelerating discovery processes. They enable higher efficiency and throughput for time-consuming screening procedures and reduce error-prone manual steps. Automating repetitive procedures can for instance support chemists in optimizing chemical reactions. Particularly, the technology of DNA-encoded libraries (DELs) may benefit from automation techniques, since translation of chemical reactions to DNA-tagged reactants often requires screening of multiple reaction parameters and evaluation of large numbers of reactants. Here, we describe a portable, automated system for reagent dispensing that was designed from open source materials. The system was validated by performing amide coupling of carboxylic acids to DNA-linked amine and a micelle-mediated Povarov reaction to DNA-tagged hexahydropyrroloquinolines. The latter reaction required accurate pipetting of multiple components including different solvents and a surface-active reagent. Analysis of reactions demonstrated that the robotic system achieved high accuracy comparable to experimentation by an experienced chemist with the potential of higher throughput.
The transfer of batch processes to continuous flow is a major driver for the application of microreactors. Here, we present a methodology for the transfer of (bio)chemical reactions in batch mode to two-phase continuous flow. For our purposes, the coiled flow inverter (CFI) is a promising reactor design providing enhanced heat and mass transfer, narrow residence time distribution, and rapid mixing. First, this methodology is used for current development of a droplet-based reaction screening system, which was first tested with a Paal−Knorr pyrrole synthesis as model reaction. The reaction was successfully performed in the automated screening system. The yields compared to the batch mode revealed enhanced mass transfer of the product into the continuous phase. Second, we investigated the biocatalyzed oxidation of ABTS by the enzyme laccase in a straight capillary for process development in a CFI. Because of its high flexibility regarding substrate specificity, laccase oxidizes many substrates with a colored product. Hence, an optical evaluation method for determination of reaction rate is used. We compare the Michaelis−Menten kinetic of the batch reaction and the continuous reaction in a capillary. The results show that the batch reaction can be mapped to the capillary setup. However, the capillary in continuous operation enables higher screening capacity of different reaction conditions and simple scale-up procedure.
Limited applicability and scarce availability of analytical equipment for micro- and millifluidic applications, which are of high interest in research and development, complicate process development, control, and monitoring. The low-cost sensor presented in this work is a modular, fast, non-invasive, multi-purpose, and easy to apply solution for detecting phase changes and concentrations of optically absorbing substances in single and multi-phase capillary flow. It aims at generating deeper insight into existing processes in fields of (bio-)chemical and reaction engineering. The scope of this work includes the application of the sensor to residence time measurements in a heat exchanger, a tubular reactor for concentration measurements, a tubular crystallizer for suspension detection, and a pipetting robot for flow automation purposes. In all presented applications either the level of automation has been increased or more information on the investigated system has been gained. Further applications are explained to be realized in the near future. Article highlights • An affordable multipurpose sensor for phase differentiation, concentration measurements, and process automation has been developed and characterized • The sensor is easily modified and can be applied to various tubular reaction/process units for analytical and automation purposes • Simple integration into existing process control systems is possible Graphical abstract
Model-assisted prediction methods depict an important tool in the development of digital bioprocess twins. However, this requires reliable predictions as informative as possible to support process design, development of process strategies, and decision making during running processes. Challenges in this context are large time steps between measurements, measurement deviations, and biological variabilities, leading to difficulties in parameter estimation and prediction of reliable outcomes.
The combination of lab automation and design of experiments for the execution of screening experiments increases productivity and reduces error-prone manual work. A self-developed software tool allows for creating fractional-factorial experimental design (FFED). Application of FFED on the screening of a Suzuki-Miyaura cross-coupling leads to a 93 % reduced design compared to full-factorial design. The resulting regression model qualitatively shows the positive effect of educt concentrations, time, and temperature and reveals the decrease in conversion at high base concentrations.
Miniaturization and modularization are fast growing fields in chemical engineering in recent years. Fast and flexible production processes for microstructured devices are desirable to meet the requirements of rapid prototyping and flexible chip manufacturing. Reactive ion etching provides a structuring process which leads to a highly precise and anisotropic etching behavior. A new manufacturing process for polyimide-based microstructured devices with low surface roughness was developed and applied on reactor geometry for liquid-liquid two-phase-flow. The fabricated chip geometry is designed for creating droplets via flow focusing as the dispersed phase is incised by two continuous phase inlet streams. The droplets are created in the widening channel. In order to keep the pressure loss for the developed reactor geometry and the production time as small as possible, the manufacturing process was optimized with a view to minimize surface roughness and maximizing the etching rate by using Design of Experiments. The corresponding pressure drop was measured for flow rates from 0.05 ml min−1 to 0.5 ml min−1.
Microfluidic devices intensify transport phenomena and can improve chemical processes. New manufacturing processes and materials are perpetually developed due to constantly growing interest in process intensification. In this contribution, the authors present the design and application of polyimide‐foil‐based microfluidic mixing devices manufactured by reactive ion etching. As appropriate model reaction system, acid‐catalyzed 2,2‐dimethoxypropane (DMP) hydrolysis was chosen and investigated in three different mixing structure with varying flow rate. Energy dissipation rates were calculated to estimate mixing performances. The results show good mixing quality for Reynolds numbers between 10 and 100 and similar mixing times scales for all investigated microstructured mixers.
Besides the common benefits of micro-structured reactors such as enhanced mass and heat transfer caused by a high specific surface and enhanced mixing, they have also drawbacks due to their tiny dimensions. Non-invasive temperature measurement is an important issue for micro process engineering regarding to process control and safety issues. High resolution and robustness are requirements which should be met by the temperature measuring method. Thin film technology combines the possibility to manufacture micro scaled structures with great flexibility in choosing material and geometry of the structures. Layers of aluminum with a thickness in nanometer range are deposited on flexible polyimide foil and structured lithographically to obtain electrical conductor tracks which are used as temperature sensors based on their electrical resistance. The produced temperature sensors were calibrated in the range from 20 to 70 °C and the accuracy of the sensors was checked.
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