Scientists find way to clean up the drugs market

Researchers from the University of Cambridge and the Massachusetts Institute of Technology have made a breakthrough by using supercritical carbon dioxide (scCO2) as a reaction medium for the preparation of molecules of interest to the pharmaceutical industry.

Many industries throughout the world have begun using the non-toxic, environmentally friendly scCO2 as a solvent, replacing harsher volatile organic solvents, such as chlorinated hydrocarbons and chlorofluorocarbons.

Until now it was not considered possible to make certain classes of molecules in CO2 because it was thought that they would react with the CO2. Cambridge University's Professor Andrew Holmes, Director of the Melville Laboratory, together with MIT's Professors Rick Danheiser and Jefferson Tester, have changed all that by figuring out how to use scCO2 for reactions without it reacting with the reagents.

Supercritical CO2 in action Thomas Swan and Co Ltd (UK) has been exploring the application of supercritical fluids in the broader arena of synthetic organic chemistry. This work, which was initiated by Prof Martyn Poliakoff's team at the University of Nottingham, lead to the construction of the world's first multi-purpose, continuous flow, supercritical fluid plant with a capacity of up to 1000 tonnes per year. Supercritical fluid systems combine the mass transport properties of gases with the mass density of liquids. This results in increased reaction kinetics and, hence, high throughputs from a relatively small reactor system. Furthermore, such a continuous flow reactor also allows reactions to be controlled kinetically, as opposed to thermodynamically, affording products which would be difficult to obtain under conventional conditions. Supercritical fluid technology offers chemists a powerful tool for the simplification of chemical processes as well as facilitating improvements in yield and selectivity over batch processing. These advantages, coupled with the ability to carry out novel chemistries under continuous flow conditions, generate potential economic benefits as a result of the harnessing of this exciting technology. The process The fluid, used as solvent, is stored in the work tank from where it is sub-cooled before being fed to the pump unit. The pump increases the pressure of the fluid, which is then heated to the desired supercritical conditions. The operating conditions vary between different reactions and are therefore adjustable in the process. The reactants are fed into the solvent, then into a mixer and onto the reactor. In the reactor the reactants pass over a heterogeneous catalyst where the reaction takes place. On leaving the reactor the product mixture passes through a pressure control valve, which reduces the pressure of the product mixture to subcritical conditions, creating a two-phase system. The mixture enters the separator where heat can be added to evaporate the solvent. The liquid product will stay in the separator and is periodically collected. The gas phase from the separator enters the condenser where the solvent is condensed and returned to the work tank. So far the process has been proven to achieve excellent conversion and selectivity for hydrogenations, Friedel-Crafts reactions and hydroformylations, while quantitative conversion has been achieved for etherification reactions. The use of continuous processing, fixed-bed reactors and supercritical solvent enables the products to be easily recovered, with minimal downstream processing while incorporating built-in recovery of the solvent.

Since the 1990s, scCO2 has emerged as an environmentally benign substitute for more conventional solvents used for organic synthesis, such as those that enter the atmosphere from sprays and similar products. Dry cleaners, plastics manufacturers, food producers and various industries involved in the extraction of flavours and fragrances are already using the 'benign' solvent, resulting in more environmentally friendly industrial practices. Using scCO2 as the extractive agent to remove caffeine selectively and leave the flavour of fresh coffee, for example, produces decaffeinated coffee beans. However, only in the last few years have chemists really begun exploiting the properties of supercritical fluids for synthesis.

Although a greenhouse gas, scCO2 can be obtained in large quantities as a by-product of fermentation and combustion. The ready availability, coupled with its ease of removal and recycling, makes scCO2 an exciting prospect for synthetic and industrial applications.

Supercritical fluids exist in a hybrid state between liquid and gas above a critical temperature and pressure and as such have some bizarre and very useful solvent properties as they retain both liquid-like solvent properties and gas-like densities.

SCFs are gases heated above their critical temperature (TC) and compressed above their critical pressure. Carbon dioxide, for instance, goes critical at close to ambient temperature, 31.3°C and at 72.9 times atmospheric pressure. It is non-flammable, non-toxic, and inexpensive and in the supercritical phase has extremely low viscosity.

Pharmaceutical companies have begun using scCO2 for processing drugs into powder consistently, but the researchers' findings may soon mean that the entire manufacturing process can be integrated, using scCO2 for both synthesis and processing them into powders.

Organic solvents can always react in undesired ways, so an advantage to using this non-toxic supercritical fluid is that it reduces the chances for alternative and less-desired outcomes.

Another major advantage to using supercritical fluids for organic synthesis is the ability of these physical properties to be tuned simply by a change in pressure and/or temperature.

Professor Holmes dreams of helping the pharmaceutical industry streamline the drugs manufacturing process with the techniques he and his team have developed. "We're making molecules of interest to pharmaceutical companies - aromatic amines - which are a key fragment in many neurological drugs. Before it was considered impossible, but we've got preparations of aromatic amine reactions to work in supercritical carbon dioxide."

A patent has been filed on behalf of the work done at Cambridge and MIT, which was funded by the Cambridge-MIT Institute (CMI). The researchers have published their findings in Chemical Communications, (The Royal Society of Chemistry) 2004.

In addition to the collaboration with MIT, the CMI project has enabled scientists at Cambridge to work closely with Professor Gerry Lawless and his team at the University of Sussex.

Pharmaceutical giant AstraZeneca is one of a number of companies that has long been interested in and supportive of Professor Holmes' work in scCO2.