August 30, 2006
“When should one miniaturize something that is actually working?” asked the chemist Stephen Haswell from the University of Hull, UK, in his talk titled “Lab on a Chip.” According to Haswell one should do so whenever a system or process can be improved by miniaturization. New technologies, process intensification as well as the current state and acceptance of modern synthesis techniques in research and industry were the main topics at the third meeting of the “Scientific Symposia 2006” series organized by the Schering Stiftung in Berlin, Germany. Experts from around the world attended the symposium entitled “New Avenues to Efficient Chemical Synthesis – Emerging Technologies.”
“In the past a chemist was able to synthesize around 20 new compounds per year,” said Brian Warrington from the University of Cambridge, UK. “Today a whole library of compounds based on one basic structure can be synthesized in much shorter time spans. Through a combination of microreactors and other systems the chemical properties of such compound libraries can be studied in parallel tests.” Warrington, who has been working in the field of chemical synthesis for over 40 years, thinks that time efficiency is one of the most important aspects of microreactor technology.
Microreactors consist of standardized units, which can be assembled like building blocks, allowing their integration into various different systems. The chemical reactions take place in microchannels of around 10-300 µm diameter thus offering a favorable surface to volume ratio for many reactions. Consequently a lot of reactions take place partly more selectively, more efficiently, safer and in much shorter reaction time. Loaded with catalysts the walls of the microchannels can be directly integrated into reactions. Microreactor systems come in steel, glass, silicon or polymer materials. As in conventional reaction systems microreactors can be controlled for flow, temperature, mass and energy transport. However, reaction conditions can be optimized in a fraction of the time it takes to optimize conventional chemical synthesis systems, simply allowing the researcher to perform more experiments. Microreactors can be used for liquids, gases, and solids as well as for crystallization and nanoparticles. Another advantage of microreactors is their mobility, making them particularly interesting for industrial production of chemicals. Biological and biochemical synthesis reactions like polymerase chain reaction (PCR), cell sorting, and cell cultures in high throughput systems are additional fields microreactors are being used in already.
“Synthesis of natural compounds used to be a long and complicated process, which has become a lot simpler through the use of microreactors,” explained Peter Seeberger from the Swiss Federal Institute of Technology Zurich, Switzerland. In 2001 Seeberger first encountered microreactors at the lab of Klavs Jensen at the Massachusetts Institute of Technology in Boston, MA. Today Seeberger and Jensen are leaders of this technology. “We can synthesize up to 40 compounds per day using flow microreactor technology. Coupled with the appropriate analyzing tools, we can test the compounds at the same time,” Seeberger reported during his speech at the symposium.
In the pharmaceutical and fine chemicals industry microreactors have already made it out of the research labs and into the production line. Since 2005 ultra pure nitroglycerine is being produced in a plant in China that uses microreactor technology developed by the Institute for Microtechnology in Mainz, Germany. The use is solely for medical purposes, namely to treat angina pectoris. Still to come this year is a microstructured pilot plant for radical polymerization in Japan.
The second significant development in organic synthesis is microwaves. Oliver Kappe from the University of Graz, Austria, is one of the pioneers of this technology. In 1998 he discovered microwaves for certain selected organic syntheses. While using ordinary household microwaves for his initial experiments he became so convinced that only a year later he began stocking his lab with dedicated microwaves.
Microwaves travel at the speed of light and deliver energy straight into sealed flasks and containers. Coupled to the increased pressure inside the sealed vessel, reaction times are shortened significantly and the overall yield is greater. “Microwaves have made our labs a lot more productive,” said Kappe. “Thanks to shorter reaction times we can try a lot more ideas and optimize reactions a whole lot faster.” A big advantage of microwave technology is the high level of control the researcher has over high temperature reactions and side reactions caused by heat since the energy input can be stopped immediately if necessary. Furthermore biochemical syntheses like PCR benefit from microwave technology. However the constraints of microwaves are definitely in scale-ups. Large batches cannot be completely penetrated by microwaves. Should there be no other way of synthesizing the desired structure, a flow-through microwave-reactor could be an alternative. Whether microwave technology will eventually be used in large chemical plants mainly depends on the energy balance sheet, say experts at the symposium. To date microwaves still use too much energy to make them a viable alternative in large scale chemical synthesis. “However, it is important that we open up to this new technology,” explained Kappe. “Research in the years to come will have to be oriented towards practical as well as theoretical problems of microwave technology.”
During the closing remarks of the symposium all experts and participants of the symposium agreed that microwaves and microreactors have greatly changed everyday lab practice. “Both technologies have become indispensable parts of lab routines in chemical and biochemical labs,” said Stephen Haswell. “Small volumes, fast reaction times, very clean products and ease of handling have convinced many researchers. Only in scale-up do the rules change to such an extent that the use of conventional batch-reactors can be more advantageous.” Both technologies, like high-throughput techniques and automation are very attractive for the pharmaceutical industry. Large compound libraries can be created and tested within short times and with very few staff. Thus, more time remains for true creative research. “The main questions, however, is, how we are going to use these new technologies,” said Thorsten Blume from Schering AG, Berlin, co-organizer of the workshop. “Each new technology needs its pioneers but more importantly research grants, integrated concepts and intensive interdisciplinatory co-operations between different fields of research. Through symposia like this one, new impulses and ideas can boost the entire field of research.” By reviewing the current situation at this symposium the Schering Stiftung hopes to contribute to this process.
The results of the symposium will be published by the Springer publishing house and will be available through bookstores. The “Scientific Symposia” series of the Schering Stiftung will be continued on October 22-24, 2006, with a workshop on “Immunotherapy in 2020 – Visions and Trends for Targeting Inflammatory Diseases in the Future” in Potsdam, Germany.
Prof. Peter H. Seeberger, Swiss Federal Institute of Technology (ETH), Zürich
Dr. Thorsten Blume, Chemical Development, Schering AG, Berlin
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