Design Software for Application-Specific Microfluidic Devices | Clinical Chemistry

Leave a comment

Microfluidics-based lab-on-a-chip systems, which feature miniaturization of biological separation and assay techniques, are rapidly transforming biochemical analysis and high-throughput screening. Microfluidic system design requires expertise in materials, chemistry, biology, and engineering, and understanding the complex interplay between variables that influence and limit system performance is difficult without computational assistance. Modeling approaches based on 3-dimensional numerical simulations provide detailed information regarding spatiotemporal variations of the field variables but are computationally very expensive for system-level analysis. Design-modeling tools are needed that rapidly simulate the complex underlying phenomena such as electroosmosis, electrophoresis, sample dispersion, mixing, and biochemical reactions without significantly compromising accuracy (1)(2)(3)(4)(5). In addition, these design tools must be easily usable by the microfluidic community, which comprises scientists and engineers from a variety of disciplines. To meet these challenges, we developed integrated design software that allows rapid layout of microfluidic channel networks, fast system performance simulation using a system solver, and the ability to easily reconfigure chip layout to meet specifications. We illustrate the application of the software to improve the design for an electrokinetic immunoassay chip.

The software design follows a modified form of the traditional client-server architecture. The user interacts with a graphical user interface (GUI) front-end (client). Fig. 1 shows a screenshot of the GUI. The microfluidic lab-on-a-chip system is represented as a network of interconnected components that can be assembled from a component library. The sequence of operations required for the creation of the microfluidic network, analysis, and visualization of results using the GUI is as follows:

(1) Creation of the microfluidic network: The components (such as sample reservoirs, straight channels, bends, biosensors, and interconnects such as Y-, T-, and cross junctions) are selected from the component library and assembled into a network using a drag-and-drop method.

(2) Problem specification: Geometric properties for components (channel length, breadth, and depth, turn radius and angle, well diameter) and operating conditions (applied voltage and pressure, flow rate, and injected analyte concentrations, as appropriate for the problem under consideration) are specified for the components. The property database contains physicochemical property data for commonly used buffers, reagents, and analytes (density and viscosity of buffers; electrical conductivity, and electrokinetic mobility and molecular diffusivity of analytes) and is fully integrated with the GUI.

(3) Solution and visualization: The performance is simulated using the system solver, and the results are analyzed using the visualization toolkit, which allows the results from the simulation to be displayed in a variety of tabular and graphical formats.

The GUI employs the hierarchical model-view-controller (MVC) architecture (6) to achieve the user-friendliness, flexibility, and extensibility needed. MVC programming uses 3-way factoring, whereby objects of different software classes take over the operations related to the application domain (model), the display of the application’s state (view), and the user interaction with the model and the view (controller). The MVC architecture is aimed at exploiting the benefits associated with modular components in the software. The GUI has been developed with the Java™ programming language using standard Java libraries and the included Swing toolkit(7).

(4) System solver: The system solver uses a combination of various modeling approaches for a rapid simulation of the microfluidic chip performance. This mixed-methodology approach uses an integral method to simulate fluid flow and electric field, a method of moments-based analytical solution to compute analyte dispersion, and a Fourier series–based analytical solution to compute microfluidic mixing based on laminar diffusion. These disparate models have been integrated in the system solver and validated against both experimental data and detailed 3-dimensional numerical models. The system solver shows a substantial improvement in computational speed (2–4 orders of magnitude) over the 3-dimensional models without appreciably compromising accuracy (error <10%). Details of the models and validation studies have been described elsewhere (4)(8)(9)(10). A brief explanation of these models is given below:

  • Fluid flow: Pressure-driven flow is calculated by solving the Navier-Stokes and continuity conservation equations in their integral forms. An implicit iterative numerical solution scheme based on the SIMPLE (semiimplicit method for pressure-linked equations) algorithm (11) is used. Details of the implementation are discussed elsewhere(8).

  • Electric field: The electric current conservation law is solved at every component with a constitutive equation to compute currents and voltages. These equations are used to compute the electroosmotic and electrophoretic flow velocity.

  • Analyte transport: An analytical model based on the method of moments approach has been developed to characterize the dispersion induced by combined pressure and electrokinetic-driven flow. In addition, the system solver uses a combination of numerical schemes and analytical approaches to simulate mixing due to laminar diffusion and biochemical reactions; specifically, the method of lines (MOL) and 2-compartment models for biochemical reactions, and a Fourier series-based model for analyte mixing.

We present the use of the microfluidic design software to improve the design of an electrokinetic microfluidic device for an on-chip assay of the drug theophylline (Th) in serum samples. The assay involves on-chip mixing of serum samples with a labeled tracer compound and reaction with a selective antibody. This reaction is followed by an electrophoresis-based separation step to isolate and quantify the reactants and products. This immunoassay method is appropriate for incorporation into a microfluidic format and allows for rapid separation, because of the short separation distances. Starting with the microfluidic device previously demonstrated (12), we applied the software to rapidly explore alternative design concepts to improve device performance and demonstrate the ability to create a lab-on-a-chip for a real clinical analysis using a simulation-based design approach. Similar analysis using an analog hardware description language (Verilog-A) has been previously reported(13).

The operation of the competitive immunoassay chip is a multistep process that includes (a) mixing of serum sample containing Th with fluorescein-labeled Th tracer (Th*), carried out in the microfluidic channel and based on laminar diffusion; (b) reaction of the resulting mixture with an anti-Th antibody (Ab), which allows Th and Th* to compete for a limited number of antibody-binding sites; (c) electrokinetic injection of the solution containing the Ab-Th* complex produced in the reaction, as well as the unreacted Th*, into the separation channel, where they are separated by electrophoresis; and (d) detection of the fluorescent species (Th* and Ab-Th*) by laser-induced fluorescence.

The chip layout was created in the layout editor, using the component library and the drag-and-drop methodology. The layout parameters (channel dimensions, connectivity) and operating conditions (voltages and concentrations) were specified, and the performance of the chip was simulated. All channels had a rectangular cross-section with a uniform depth of 20 microns. The original layout had channels with widths of 52–236 microns, and the same widths were used in the modified layout. Th and Th* in the sample were specified in the system design software as separate species with identical molecular diffusivity (3.3 × 10−10 m2/s) and electrokinetic mobility [2.84 × 10−8 m2/(V s)]. The corresponding properties for the antibody (Ab) were 4.0 × 10−11 m2/s (molecular diffusivity) and 4.45 × 10−8 m2/(V s) (electrokinetic mobility) (14). The binding between Th and Ab was assumed to be irreversible and complete. An electric field of 770 V/cm was used for electrophoretic separation. The performance was characterized by the extent of mixing/reaction and by the efficiency of separation, which is characterized by the separation resolution, peak height, variance, and time for separation. The layout was reconfigured using the layout editor to minimize the chip footprint. The modified layout (3.5 cm × 3.5 cm) occupies <25% of the area of the original chip (7.6 cm × 7.6 cm), and the time required for electrophoretic separation was decreased by more than 50% relative to the original design(12), thereby decreasing the overall assay time. This reconfiguration decreased the separation resolution, but the resulting resolution was still sufficient to resolve the species bands while limiting the band-broadening induced by dispersion. In addition, the signal amplitude increased by 11.5% and 5% for Ab-Th* and Th*, respectively. The degree of mixing for the antibody: Formula

where y is the widthwise coordinate, w is the channel width, c is the concentration profile along the channel width, and cavg is the average concentration along the width, was also improved to 100%. The entire analysis (including layout generation and problem setup) was completed in approximately 4 h, more than 2 orders of magnitude faster than currently available techniques. The improvements are summarized in Table 1 . In retrospect, the original system was substantially overdesigned, a problem that is common to several microfluidic systems currently available today and is attributable primarily to a lack of design tools.

In summary, the design software we describe is useful for estimating device performance and creating microfluidic chip layouts; these layouts can be rapidly modified to design chips that meet performance requirements. We used the software to improve the design of a microfluidic immunoassay chip. The resulting design occupied <25% of the area of the original chip, and the time required for electrophoretic separation was decreased by more than 50% relative to the original design, allowing for a faster assay. This process is more than 2 orders of magnitude faster than conventional design techniques and is ideally suited for design optimization of microfluidic lab-on-a-chip systems.



Microchannel reactors in fuel production | Digital Refining

Leave a comment


Biofuels produced entirely from waste such as agricultural by-products and municipal solid waste have attracted attention as a substitute for petroleum-based transport fuels. Since they do not contain aromatics or sulphur-containing contaminants, the liquid fuels produced via biomass to liquids (BTL) are typically of a higher quality, and they burn more cleanly than petroleum-based diesel and jet fuels. They could also prove to be valuable in the effort to reduce carbon emissions. A study carried out by the Southern Research Institute Carbon to Liquids Development Center 
in the US used the GREET (Greenhouse gases, Regulated Emissions & Energy use in Transportation) model to show that biomass-based FT diesel (biodiesel) production and use results in net greenhouse gas (GHG) emissions savings of 135% compared to petroleum-based diesel, and GHG savings of 129% compared to 
petroleum-based gasoline. This is largely because bio-derived synthetic diesel production relies on biomass, rather than fossil fuels, as a feedstock.

Despite their potential advantages, economic, environmental and technical obstacles remain to be overcome before biofuels produced from waste can achieve wider application. A major problem is that it takes roughly one tonne of biomass to produce one barrel of liquid fuel. As a result, to avoid the economic and environmental costs of transporting feedstock to central processing plants, BTL production facilities need to be relatively small and located near the source of the feedstock. Establishing small-scale distributed production of biofuels as a practical and economically feasible option requires, in turn, the development of relatively small facilities that can produce typically 500–2000 bpd of liquid fuels, efficiently and cost-effectively.

The Fischer-Tropsch (FT) process, in which synthesis gas (syngas), a mixture of carbon monoxide (CO) and hydrogen (H2), is converted into various liquid hydrocarbons using a catalyst at elevated temperatures, is a key process in BTL. However, fixed-bed or slurry-bed reactors, the two conventional reactor types currently used for FT processes, are designed to work at minimum capacities of 5000 bpd. They only function well and economically at capacities of 30 000 bpd or higher, and the technology does not scale down efficiently.

However, new reactor designs, such as microchannel reactors, combined with more efficient FT catalysts optimised for use in them, offer a practical way forward. Microchannel reactors are compact reactors that have channels with diameters in the millimetre range. They are well suited to the job because they greatly intensify chemical reactions, enabling them to occur at rates 10 to 1000 times faster than in conventional systems. For example, microchannel FT reactors developed by Velocys and using a new highly active FT catalyst developed by Oxford Catalysts accelerate FT reactions by 10–15-fold compared to conventional reactors, and exhibit conversion efficiencies in the range of 70% per pass. This is a significant improvement over the 50% conversion (or less) per pass achieved in conventional FT plants. Their efficient conversion rates, combined with their modular construction, makes microchannel FT reactors, in theory, an excellent tool for small-scale distributed production of biofuels from a wide variety of sources.

Demonstration plant

Developing the technology is one thing. Establishing it as a practical and commercially viable solution is another. A demonstration plant now being commissioned in the town of Güssing, Austria, by a coalition that includes project 
developer and lead engineering integrator SGC Energia (SGCE), the Oxford Catalysts Group, developers of the microchannel FT technology, along with the engineering firm, Repotec, the Technical University of Vienna (TUW), and gasification facility owners Biomass CHP Güssing aims to operate an FT microchannel reactor and effectively integrate it with other key steps in the BTL process, including biomass gasification and syngas cleaning.

In the late 1980s, the town of Güssing, located in southern Austria near the borders of Hungary and Slovenia, was the administrative centre of the poorest region in Austria. Then, in the 1990s, the city developed a model to replace energy dependence on fossil fuels with renewable sources. By 2001, Güssing had achieved energy self-sufficiency through the installation of a biomass plant that takes advantage of steam gasification technology. The developments in Güssing led to the establishment of the Renewable Energy Network Austria (RENET). As a result, Güssing has become a magnet for companies and researchers keen 
to develop renewable energy technologies.

Other factors determined the choice of Güssing as the site for a demonstration of FT microchannel biofuels production technology. These included the enthusiasm expressed by the local technology community as well as the availability of a new test facility and R&D building with the utilities in place for SGCE to install the FT and gas conditioning skids necessary for its trial. Güssing is also home to a gasification plant that has been operating in a stable manner for seven years (Figure 1). The syngas resulting from this gasification process has the necessary characteristics and high H2/CO ratio required for FT

Reduced dimensions

Microchannel process technology is a developing field of chemical processing that enables rapid reaction rates by minimising heat and mass transport limitations, particularly in highly exothermic or endothermic reactions. This is achieved by reducing the dimensions of the reactor systems. In microchannel reactors, the key process steps are carried out in parallel arrays of microchannels, each with typical dimensions in the range 0.1–5mm (see Figure 2). This modular structure enables reduction in the size and cost of the chemical processing hardware.

When microchannel technology is employed, plant size is small. Conventional FT reactors are up to 60m tall. In contrast, microchannel reactor assemblies are roughly 1.5m in diameter, have a low profile and sit horizontally. Their modularity and productivity make them convenient for use in small-scale biofuels production plants, and also opens up the possibility for their use on offshore platforms to produce liquid fuel via gas to liquids (GTL) processes.

Microchannel FT reactor design is also flexible. For example, where increasing the size of conventional reactors normally requires plant designers to increase the size of each reactor unit, which alters flow and reaction dynamics in the reactor, the modular structure of microchannel reactors means that increasing plant size to build demonstration or even commercial-sized plants can be done by “numbering up”. This involves simply adding more reactors with the same dimensions.


Microreactor technology comes to Nizhny Novgorod |

Leave a comment

Nizhny Novgorod State University named after Lobachevsky will become the main center of the project to establish the National Center for High Chemical Technologies. On April 18-19, professor of microfluidic chemistry and technological processes at the Eindhoven University of Technology, Volker Hessel, will pay a visit to the region.

Hessel will deliver a report about “the possibilities of application of microstructure reactors in various industries.” The report will be devoted to the European experience and technology transfer to Russia. To date, microreactor technology is used in Europe, USA and Japan. The technology is used in the pharmaceutical industry, oil refining, and other areas.

The use of modern technologies will make production more secure and more efficient.  The microreactor technology allows to cut production costs by reducing production area  (from 100 to 1000 times). It also reduces the environmental risks of chemical production, production time and, most importantly, the time from the development of chemical plant before it is launched into operation.

In Russia, the project starts at multiple sites, with the basic one located in the Nizhny Novgorod State University. The university is a Russian center of chemical science and technology. The level of fundamental and theoretical studies conducted by Nizhny Novgorod chemists, according to Professor Hessel, meets highest modern standards.

Regional centers will be located in Novosibirsk, St. Petersburg and Tver. The centers will deal with solving applied problems on each of key areas in the field of chemical micro-and nanotechnology.

The new project will involve both domestic and foreign experts. It is assumed that the main university of Nizhny Novgorod and will prepare new specialists.  Students and graduate students will be given an opportunity to undergo internship abroad.

According to experts, the establishment of the National Center for High Chemical Technologies in the Nizhny Novgorod region will lead to the modernization of existing enterprises, by introducing latest chemical technologies, creating new industries and, as a consequence, creating new jobs. This will significantly increase tax revenues, develop scientific and educational base and increase the investment appeal of the region.


Microreactor speeds nanotech particle production by 500 times | Oregon State University

Leave a comment

CORVALLIS, Ore. – Engineers at Oregon State University have discovered a new method to speed the production rate of nanoparticles by 500 times, an advance that could play an important role in making nanotechnology products more commercially practical.

The approach uses an arrayed microchannel reactor and a “laminated architecture” in which many sheets, each with thousands of microchannels in them, are stacked in parallel to provide a high volume of production and excellent control of the processes involved.

Applications could be possible in improved sensors, medical imaging, electronics, and even solar energy or biomedical uses when the same strategy is applied to abundant materials such as copper, zinc or tin.

A patent has been applied for, university officials say. The work, just published in the journal Nanotechnology, was done in the research group of Brian Paul, a professor in the OSU School of Mechanical, Industrial and Manufacturing Engineering.

“A number of new and important types of nanoparticles have been developed with microtechnology approaches, which often use very small microfluidic devices,” said Chih-hung Chang, a professor in the OSU School of Chemical, Biological and Environmental Engineering, and principal investigator on the study.

“It had been thought that commercial production might be as simple as just grouping hundreds of these small devices together,” Chang said. “But with all the supporting equipment you need, things like pumps and temperature controls, it really wasn’t that easy. Scaling things up to commercial volumes can be quite challenging.”

The new approach created by a research team of five engineers at OSU used a microreactor with the new architecture that produced “undecagold nanoclusters” hundreds of times faster than conventional “batch synthesis” processes that might have been used.

“In part because it’s faster and more efficient, this process is also more environmentally sensitive, using fewer solvents and less energy,” Chang said. “This could be very significant in helping to commercialize nanotech products, where you need high volumes, high quality and low costs.”

This research, Chang said, created nanoparticles based on gold, but the same concept should be applicable to other materials as well. By lowering the cost of production, even the gold nanoclusters may find applications, he said, because the cost of the gold needed to make them is actually just a tiny fraction of the overall cost of the finished product.

Nanoparticles are extraordinarily tiny groups of atoms and compounds that, because of their extremely small size and large surface areas, can have unusual characteristics that make them valuable for many industrial, electronic, medical or energy applications.


Self-contained chemical synthesis | Chemistry World

Leave a comment

Scientists in the UK have used reactors made on a 3D printer to complete a three stage organic synthesis. The reagents, catalyst and purification step for the synthesis are completely integrated into the chambers of the sealed reactor. When the reactor is rotated, gravity pulls reactants through the different chambers to complete the synthesis.

Initially, Leroy Cronin, who lead the work at the University of Glasgow, had envisaged a ‘Rubik’s cube for synthesis’, where different manipulations of the reactor would produce different products. ‘The code, like opening a safe, would be in the rotation,’ he explains. ‘I thought it was genius. My group told me I was stupid.’ The team convinced Cronin to start with an easier L-shaped three step reactor, but he still plans to create the Rubik’s cube in the future.

A three-step organic reaction sequence was performed in the L-shaped reactor. The sequence began with a Diels–Alder cyclisation followed by formation of an imine and then hydrogenation of the imine to the corresponding secondary amine.

The team’s next challenge is to use 3D printing to trap reactive intermediates within the device. Research into this is already underway. The scientists suggest that sensors could also be included to monitor the reactions. ‘Closed loop synthesis–sensor–synthesis would be a revolution,’ says Cronin.

Filipe Vilela from Max Planck Institute of Colloids and Interfaces, Potsdam, Germany, an organic synthsis expert, says that apart from having an incorporated catalyst and purification step, which leads to a stand-alone reactor for a multi-step synthesis and purification, this technology stands out for its inexpensive nature and will soon rival other multi-step reactors like micro and millifluidic devices.

‘The 3D platform allows for the reproduction of a reactive system in any laboratory that has a 3D printer,’ says Vilela. ‘Given the open-source nature of this technology, a scientist can download the 3D printing files made available by the authors and load the 3D printer with the materials originally used to reproduce the system.’ He envisages that in the future, with this technology, experimental protocols will have the simple sentence “3D printing verified” to validate a particular reaction and/or system.


Industrial nitroglycerin made fast and safe | Chemistry World

Leave a comment

A microreactor (Credit: Micronit)Since the invention of nitroglycerin in the mid nineteenth century, people have been trying to find safer ways to manufacture the highly unstable liquid explosive. Now, researchers at the Fraunhofer Institute for Chemical Technology (ICT) in Pfintzal, Germany, have come up with what might be the safest approach yet – using microreactors to produce nitroglycerin continuously rather than in batches. This is not only safer but also quicker, facilitating a tenfold increase in production rate.

Nitrogylcerin is made by adding glycerol, a simple hydrocarbon with three hydroxyl groups, to a mixture of sulfuric acid and nitric acid. The reaction is extremely exothermic, but if the temperature gets too high – somewhere above 30°C for example – ‘runaway’ can occur, increasing dramatically the risk of explosion.

Therefore manufacturers continually cool the reaction mixture and – in the traditional batch process – add the glycerol drop-by-drop to the acid to give time for the heat to dissipate and maintain an excess of acid, essential to ensure complete nitration of the all the hydroxyl groups.

‘This is quite old fashioned chemistry,’ says Stefan Löbbecke, deputy director for explosive materials at the Fraunhofer ICT. Switching to a continuous process in a microreactor means working with much smaller quantities – safer for several reasons. It makes it is easier to control the overall temperature and the degree of mixing, which is important to avoid localised temperature variations and dangerous ‘hotspots’. It also makes it easier to control the decomposition products. And in the event of something going very wrong, the resulting explosion would be much smaller.

The microreactor is a hand-sized clear polymer tile with an internal channel that meanders across the plane. The internal channel has two entrances but only one exit – the reactants are brought together at the start and then mixed as they move through the microreactor by turbulence caused by a complex pattern of grooves and ridges on the sides of the channel.
To scale up production, you simply add more microreactors in parallel. A single microreactor might be used to make 10-50kg  of nitroglycerine per day, says Löbbecke. But his group has experimented with production at 2-3 tonnes per week by ‘numbering up’ the microreactors.

That said, this is not an approach for bulk production of nitroglycerin. Low grade product, primarily for the mining and construction industries, can be made cheaply in bulk already. Where this approach is a real advantage, says Löbbecke, is in the manufacture of smaller quantities of nitroglycerin, and other nitric esters, at very high grades for use in the pharmaceutical industry. Nitroglycerin is not only a powerful explosive but also a potent drug (sometimes called glyceryl trinitrate), widely used for treating angina and other heart problems.

The improved safety of the approach reduces costs for the manufacturer, as does the higher rate of production. The microreactor approach is already in use industrially, although Löbbecke declined to say where owing to commercial sensitivities.


Microreactors tame osmium tetroxide | Chemistry World

Leave a comment

Researchers in South Korea and India have made microfluidic reactors that safely harness the synthetically powerful but noxious catalyst osmium tetroxide.

Dong-Pyo Kim at POSTECH in Pohang, South Korea, and colleagues trapped OsO4 in poly(4-vinylpyridine) (P4VP) ‘nanobrushes’ on the inner walls of silicone microreactors. Their reactors catalysed dihydroxylation and oxidative cleavage – steps important in natural product, pharmaceutical and fine chemical synthesis – of 10mmol of various olefins with yields of more than 90%. Only 50µg of OsO4 was needed, making the microreactor catalyst 50 times more efficient than bulk supported systems.

OsO4 powers reactions like the chemistry Nobel prize winning Sharpless asymmetric dihydroxylation, but is toxic and unusually volatile, and therefore produces deadly fumes. ‘Many researchers have tried to stabilise or immobilise it on a polymer or inorganic substrate,’ Kim tells Chemistry World. ‘But leaching and exposure to the environment is inevitable in a bulk reaction system.’

So Kim’s team sought to trap OsO4 in microreactors by moulding two pieces of silicone holding mirror image nano-sized channels using soft lithography. As silicone normally swells in organic solvents they spin-coated the channels with protective polyvinylsilazane (PVSZ) layers, which they then bonded PV4P nanobrushes to. After putting the two halves of silicone together, the researchers infused the microreactor with aqueous OsO4.

Initially, catalytic activity disappeared after just a day. To boost the reactor’s stability, the team reduced OsO4 to a dark blue oxoosmium(VI) complex by feeding tetrahydrofuran through it after catalyst loading. In testing on biomass-based olefins, dihydroxylation reactions exceeded 98% conversion in 10 minutes, and oxidative cleavage reached similar levels in seven minutes. But the reactor’s volume limits it to around 1mmol of product per hour.

Reactor performance did not change significantly after 10 hours’ continuous use, or three months’ storage. Reaction mixtures contained just 30–50ppb osmium, around 100 times lower than other reported systems, Kim says. ‘We are now working on scale-up of our reactor system for possible industrial application and further developing microchemical systems for hazardous heterogeneous catalysts,’ he adds.

Paul Watts, who researches microfluidic continuous flow chemistry at Nelson Mandela Metropolitan University in Port Elizabeth, South Africa, notes the increasing interest in such reactors’ safety potential. He says Kim’s team’s reactor ‘provides a very elegant way to use OsO4 within research’. ‘I envisage the methodology being of significant use to other organic chemists,’ he adds.


MicroReactors Eyed For Industrial Use | Chemical and Engineering News

Leave a comment

Chemistry in microreactors has been touted as faster, safer, and cheaper, so it’s not surprising that interest in such systems continues to intensify. Microreactors typically consist of plates containing microstructures that define a very small reaction volume, as well as pumping accessories for continuous operation. Now that microreactors are available off the shelf at modest cost, more and more companies engaged in fine chemicals production are testing the technology.

Recently, Sigma-Aldrich took the plunge. Last February, it installed a standard Cytos Lab System microreactor at its R&D facilities in Buchs, Switzerland. Developed by CPC (Cellular Process Chemistry Systems GmbH, Frankfurt), the system has a list price of about $187,000. Sigma-Aldrich is in good company: Sixteen other pharmaceutical and fine chemicals producers are interested in CPC’s technology, according to Sigma-Aldrich’s Fabian Wahl, manager of R&D for Europe. Wahl’s group is spearheading the firm’s technology evaluation.

The key feature of microchemical systems is the high ratio of surface area to volume. That ratio is 200 for a microreactor with a reaction volume of 1.5 mL, such as that of CPC’s, and only 0.6 for a 1- m3 reactor. Mass transfer, heat transfer, and mixing are vastly more efficient in a microreactor, allowing far more precise reaction control and far better product quality control than can be achieved with conventional reactors, Wahl says.

In addition, an optimized process can be run at any scale without further R&D by simply running in parallel as many reactors as are required. Such a mode of operation is easily executed because microreactor systems typically are modular.

The technology would reduce the cost of scale-up and resources deployed to develop safe and stable processes, Wahl concludes. It is useful and practical for Sigma-Aldrich’s businesses, particularly for developing and making catalog products.

Many of Sigma-Aldrich’s catalog products are produced under usual lab conditions in flasks of up to 20 L. Of the more than 2,000 compounds in this portfolio, about 800 could be produced in microreactors with little or no process modification, Wahl says. For such cases, microreactors would reduce reaction time and cost.

For example, the condensation of 2-trimethylsilylethanol and p-nitrophenyl chloroformate to produce 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate requires 14 hours to complete in a conventional setup but only 18.4 minutes in a microreactor. Because contact between reagents and products is so brief, the possibility that the desired product will degrade or that by-products will be formed is vastly reduced, Wahl says.

Even more attractive is the opportunity microreactors offer to run problematic chemistries, such as those that are highly exothermic, produce unstable products, or form difficult-to-separate side products. Wahl’s team has explored use of microreactors for two such reactions.

The first is ester hydrolysis to produce an alcohol that readily degrades. Wahl declines to identify the ester or the alcohol. He says only that Sigma-Aldrich could not keep up with the demand for the alcohol because yield deteriorates as the reaction is scaled up: 70% at 5 L, 35% at 20 L, and 10% at 100 L.

Because Sigma-Aldrich’s original process requires an insoluble component, it could not be carried out in a microreactor. “We had to change the chemistry, but we did not know in which way,” Wahl says. With microreactors, they found out quickly.

It took less than a day to run a model reaction under 12 different conditions. A substrate that yields a stable alcohol was used so as not to complicate process development with degradation of the alcohol product of the actual substrate. After the best conditions were identified for the model system, it took only two hours to optimize the reaction of the actual substrate.

The second problematic chemistry tested by Wahl’s team is preparation of methylenecyclopentane from a substrate that Wahl does not wish to disclose. The reaction is highly exothermic, and process control is not good under conventional conditions. Furthermore, up to 30% of the yield consists of the more thermodynamically stable product, 1-methylcyclopentene, which is difficult to separate. For these reasons, production of methylenecyclopentane had been discontinued.

Using the CPC microreactor, Wahl’s team devised a reaction that gives 70% conversion, no by-product, and a throughput of 300 g per hour, Wahl says. A 70% conversion with no by-product is better than a higher conversion with some by-product because separating the product from the precursor is easier than separating it from the by-product, he explains.

Wahl expects microreactor technology also to have a positive impact on Sigma-Aldrich’s custom synthesis business, in which rapid process development is a competitive advantage. His expectation that microreactors would reduce development time by 40% has been met so far. Thus, Sigma-Aldrich is inclined to adopt microreactor technology more widely, he says.

The major drawback is the inability to work with gases and insoluble reagents. A minor one is the fact that the CPC microreactors are fabricated from steel, which is chemically sensitive. CPC is now testing microreactors made with Hastelloy, the chemically resistant material widely used in conventional reactors.

The CPC microreactors are easy to work with, Wahl says. The most common problem is blockage, which often is solved with one call to CPC’s hotline. Changeover from one process to another requires only a five-minute rinse with solvent.

Last month, Wahl visited Massachusetts Institute of Technology for a close look at the microchemical system being developed by Klavs Jensen, a professor of chemical engineering. The MIT system is different from CPC’s in three major ways. First, the reaction volume is in the microliter range, making it possible to carry out a lot of experiments with minuscule amounts of materials. Second, the reactor is made of silicon, which can be oxidized to form glass surfaces familiar to chemists. Because silicon and silicon oxide (glass) surfaces are easy to modify, it is possible to fabricate reactors that are preloaded with catalysts, Wahl says. And third, the structured surfaces of the MIT system are covered with glass, making it possible to observe reactions as they take place.

The MIT system is not yet available commercially. But when it becomes available, Sigma-Aldrich will be considering it for possible adoption into its business operations, Wahl says. Meanwhile, Sigma-Aldrich will be closely following the further development of MIT’s technology, hoping for a chance to test a prototype.


All Glass Micro-Reactor Created as Lab-On-A-Chip | Kurzweil AI

Leave a comment


Yo Tanaka from the RIKEN Quantitative Biology Center has developed a reliable and durable system for incorporating glass microfluidics into lab-on-a-chip devices.

Lab-on-a-chip devices are microfluidic cells that incorporate pipes, reaction vessels, valves and a host of other implements typically found in laboratories. These components are typically carved into an inexpensive flat plastic plate, made of polydimethylsiloxane (PDMS), to enable efficient processing of microliter-volume samples.

Plastics, however, have several disadvantages, including degradation when exposed to reactive chemicals and a tendency to adsorb sample molecules before they can be analyzed. They can also interfere with analysis techniques that rely on shining a light through the device due to their imperfect transparency, and are difficult to fabricate due to their fragility.

Glass is an attractive alternative because it is chemically resistant, transparent to light and also capable of withstanding higher fluid pressures than PDMS. Producing flexible and durable glass valves, however, has proved difficult.

To allow glass to be used in these devices, Tanaka developed a Teflon frame to hold an ultrathin sheet of glass so that it could be handled without breaking and incorporated the frame into an all-glass lab-on-a-chip.

Next, Tanaka used hydrogen fluoride to etch channels and chambers into a pair of glass slides, and covered these chambers with ultrathin glass sheets in a way that allowed fluid to be prevented from passing through the chamber by simply pressing down on the glass cover. He then fused the glass sheets together by heating them at 750 °C.

After trying various thicknesses of ultrathin glass sheets, Tanaka found that a 10 micrometer-thick glass film was ideal: strong enough to withstand more than 100 depressions yet able to deform by up to 126 microns — enough to completely close the valve. Tests using water containing small fluorescent polystyrene beads demonstrated that closing the valve using this method blocked fluid flow within 0.12 seconds.

Tanaka now plans to develop his all-glass device for applications such as highly sensitive biochemical analyses and cell studies.


Continuous flow microreactors in nanoparticle synthesis | Syrris

Leave a comment

Although the pharmaceuticals industry has been the main driving force behind the rise of flow chemistry since early 2000, other chemicals-related industries have now taken an interest in this new laboratory technique. For years, organic synthesis has been the main focus of all research work conducted on flow chemistry equipment and the advantages offered by flow chemistry are now well established and documented.1-3 Other fields– such as biofuels, petrochemistry and nanoparticles – can also benefit from these same advantages.

Syrris has seen growing demand for Asia, its latest flow system (pictured below), from companies and universities specialising in nanoparticle synthesis. In addition, there has been an increasing number of publications on the subject of continuous formation of nanoparticles, quantum dots and colloidal metals.

Automated Asia Flow Chemistry System

Nowadays, nanoparticles are used in a wide range of fields because of their physical and chemical properties, resulting in a growing demand that challenges chemists to provide a reliable supply of large amounts of good quality nanoparticles.

Various chemical methods have been applied to produce nanoparticles in batch, but these all present problems: non-homogeneity in mixing, the importance of ageing, the difficulty of accurate temperature control and questionable reproducibility from batch to batch. Often a batch process relies as much on the skill of the chemist as on the chemistry itself.

All of these issues become even more difficult to address when scaling up the manufacturing. Flow chemistry offers a number of advantages that help to overcome these challenges, notably fast and reproducible mixing, excellent temperature control, the ability to carry out pressurised reactions, modularity and easy scale-up.

Accurate reaction control

One of the key characteristics of a flow chemistry system is the very small diameter of its internal wetted channels, which are typically in the range of 0.3-1 mm. This has a huge impact on both the quality of mixing and temperature control in microreactors.

The flow conditions in a system are defined by the Reynolds number (Re), i.e. the mean viscosity of fluid multiplied by characteristic dimension and divided by kinematic viscosity. For a low Reynolds number (below 4,000), flow conditions are laminar; for a high Reynolds number, they are turbulent. In a flow system, the channel dimension results in the Reynolds number always being small (usually <100), therefore flow conditions are always laminar.

Microreactor size (µl) Total flow rate (µl/min) Estimated mixing volume (µl) Estimated mixing time (secs) Residence time (mins)
1 62.5 60 3.3 3.30 1.04
2 62.5 240 6.6 1.65 0.26
3 250 240 12.6 3.15 1.04
4 250 1000 5.6 0.34 0.25
5 250 5000 5.6 0.07 0.05
6 1000 240 19.8 4.95 4.17
7 1000 1000 19.8 1.19 1.00
8 1000 5000 19.8 0.24 0.20

Table. 1 – Phenolphthalein & sodium hydroxide mixing tests

Under laminar flow conditions, mixing is diffusion-limited and extremely fast. Typically, in a Syrris microreactor the mixing is in the order of 1-5 seconds (Table 1). It is also very reproducible, as the shape of the microreactor does not change and no physical stirrer is involved.

Syrris Micromixer

Syrris Micromixer

The mixing time can be reduced even further to below one second, by using specially designed microreactors called micromixer chips (pictured right). This makes the micromixer chip a reactor of choice for nanoparticle synthesis protocols, where mixing is a critical parameter.

The small diameter of the microreactor channels also means that its surface-to-volume ratio is extremely high. This results in excellent heat transfer and fast, efficient temperature control and response. Not only is there no temperature gradient – as seen in a batch reactor – but any exotherm or endotherm is very quickly absorbed, maintaining a homogeneous temperature throughout the microreactor.

Prof. Seeberger and co-workers at the Max Planck Institute of Colloids & Interfaces noted the key role played by precise control over experimental conditions in a paper describing a process for continuous quantum dot synthesis in a glass microreactor.4 The quantum dots synthesised in flow by Seeberger’s group have a much narrower particle distribution than those obtained using a similar batch protocol. This trend has also been shown by Fitzner and co-workers for the preparation of colloidal gold in a flow microreactor.5

More recently, a continuous synthesis protocol for the synthesis of iron nanoparticles has been developed in Syrris’s laboratory. Here, the size of the particle is critical, as it determines its paramagnetic characteristics. Performing the synthesis in microreactors allowed ultra-fast mixing and, subsequently, the formation of fine magnetic iron nanoparticles with better quality and reproducibility than in batch synthesis.6

Process flexibility

Other advantages of using a flow system for making nanoparticles include easy scalability, the modularity of the system and the ability to carry out high pressure reactions and multi-step processes.

A flow chemistry system consisting of a pump, a microreactor and a pressure controller is a good starting point for nanoparticle synthesis. This system will allow the user to run a series of experiments to determine the best reaction conditions. Once the optimised reaction conditions have been established, the same set-up is used to synthesise multi-gram quantities of nanoparticles continuously in suspension.

By adding an autosampler and automating the system via software, the system’s capabilities are expanded and it becomes ideal for process optimisation and the study of reaction parameters. A series of experiments can quickly be set up, run automatically and all the samples collected separately for analysis. Fitzner and co-workers used this kind of set-up to study the effect of reaction temperature on the particle size distribution of colloidal gold.5

Flow chemistry systems are also very easily and safely pressurised using a back pressure regulator. This allows solvents to be heated above their boiling point, which is commonly called ‘superheating’, thus increasing the reaction kinetics and creating ultra-fast reaction conditions. On top of this, pressurising the system minimises any degassing effect that might occur when a reaction produces gas as a by-product.

Finally, microreactors and flow chemistry are ideal for multi-step processes, commonly called ‘telescoping synthesis’. By simply connecting the output of the first reactor to the input of a second, a two-step reaction can be set up. Seeberger’s group used this flow chemistry benefit in their quantum dot process. First, cadmium-selenium nanoparticles were formed in a microreactor, then the nanoparticles were covered with zinc sulphide in a second microreactor connected in series. This two-step reaction was run as one continuous process, therefore saving time and manual effort.4


Flow chemistry is as an effective technology for the optimisation of nanoparticle reactions and their large-scale synthesis. Among the key advantages of flow chemistry which can assist the nanoparticle industry are excellent reaction control, flexibility and easy scale-up. These benefits are of such importance that, in the near future, continuous-flow is likely to become the method of choice for nanoparticle synthesis.


  1. M. Drobot, Speciality Chemicals Magazine 2011, 31(6)
  2. C. Wiles & P. Watts, Green Chemistry 2012, 14, 38-54
  3. L. Malet-Sanz & F. Susanne, J. Med. Chem., forthcoming
  4. P. Laurino, R. Kikkeri & P.H. Seeberger, Nature 2011, 6, 1209-1220
  5. M. Wojnicki, K. Paclawski, M. Lutyblocho, K. Fitzner, P. Oakley & A. Stretton, Rudy I Metale Niezelane 2009, 12
  6. – a video of the experiment


Older Entries


Get every new post delivered to your Inbox.

Join 293 other followers