Discoveries can be slow coming in science. Oh sure, there are Eureka! moments when, with blinding insight, a solution arrives unexpectedly. But scientists mostly spend months or even years conducting experiments hoping to achieve an outcome although often the answer remains elusive. So it is not surprising that after 12 years, organic chemists Andrew Smallridge and Maurie Trewhella were thrilled to discover a relatively simple, environmentally friendly method of making ephedrine - the key ingredient in cold, cough, asthma and hay fever medicines.

Associate Professor Smallridge and Adjunct Research Fellow Associate Professor Maurie Trewhella work at Victoria University in Melbourne, Australia. Ephedrine was once produced from the ephedra plant and is a pharmaceutical chemical that ranks fourth in terms of global production behind paracetamol, ibuprofen and amoxicillin.

Hundreds of tonnes of ephedrine are produced each year, a third of it in China where the bulk of the production is from the ephedra plant and involves an expensive and wasteful system to extract the pure ephedrine.

Ephedrine is made through a yeast fermentation process, a method discovered in the 1920s that requires large volumes of water at first, followed by substantial quantities of highly toxic and expensive organic solvents to extract the ephedrine. As well, the fermentation reaction has to be kept at a constant temperature and continually stirred, both operations requiring huge amounts of energy.

"Maurie and I have long had an interest in bio-catalysis using enzymes and micro-organisms to conduct chemical reactions," Smallridge says. "We had been working with yeast for a while because it is a cheap source of enzymes that can catalyse a number of reactions.

"We were also interested in commercial outcomes so we looked at various pharmaceutical products and tried to come up with better ways of making these common medications. But we were also keen on 'green chemistry' which was new when we started this investigation in the 1990s and we wanted to reduce the environmental impacts arising from the manufacture of drugs."

Trewhella had worked at a research institute in Holland in 1990 where super-critical carbon dioxide was being used. This curious cross between the gaseous and liquid forms of CO2 has the properties of both: it is free flowing like a gas and will penetrate into small spaces but also acts as a liquid, able to dissolve a large range of other compounds.

"Super-critical carbon dioxide is the fourth phase of CO2," Smallridge says. "If the gas is subject to a high pressure of about 70 atmospheres, at a temperature on only 31oC, you reach a critical point where it becomes a super-critical fluid."

The fluid has been used for many years in the food industry, such as extracting cholesterol from butter and decaffeinating coffee. Like a gas, super-critical CO2 can penetrate the tough outer shell of the coffee bean but, like a liquid, it can also dissolve and remove the caffeine.

"From an environmental point of view, if you release the pressure it converts back to a gas, which you obviously collect, and then you are left with decaffeinated beans and pure caffeine," Smallridge says.

At present, ephedrine is produced using yeast in much the same way bread or alcohol is made: yeast is added to a sugar solution, it starts fermenting. But to make ephedrine, the chemical benzaldehyde is added to the mix; the yeast ferments the benzaldehyde to produce an intermediate product called PAC, which is extracted using organic solvents, and then the PAC is converted into ephedrine in a second catalytic reaction which also requires the use of solvents.

"Our idea was that we could replace all the organic solvents in this process using super-critical CO2," Smallridge says. "We had one benefit, we weren't microbiologists so we paid no attention to claims that yeast would not ferment in CO2; in fact, we were lucky - although the yeast does not ferment in super-critical CO2, it has exactly the same reaction with benzaldehyde as it does in water and sugar."

This meant the two chemists had effectively designed a batch process similar to extracting caffeine from coffee beans: pass super-critical CO2 through a column of yeast undergoing a chemical reaction with benzaldehyde, release the pressure and capture the gas, leaving the clean PAC which is then subject to a second reaction, again using CO2 with a metal catalyst to produce ephedrine.

Having demonstrated the process could produce ephedrine in the laboratory, the scientists began discussions in 2001 - five years after the project had started - with international pharmaceutical companies. But the companies needed convincing that a process only demonstrated in the laboratory could be scaled up to a large chemical plant.

It was not until 2006 the two chemists gained access to a pilot plant in New Zealand where they were able to produce 100 grams of PAC - the precursor to ephedrine. This showed the process had large-scale potential and it was then the prospect of success loomed large. The next stage will be a trial production run.

geoff.maslen@uw-news.com

Comment:

This is a ground-breaking work with enormous potential for pharmaceutical companies manufacturing ephedrine.

Dr T.K.Raja

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