Mission Supercritical

Oct. 21, 2004
Benign, Tunable Solvents Show Promise in Drug Manufacturing
Supercritical or near-critical solvents have been used for years to facilitate reactions that either could not occur without them, or that would produce undesirable and costly waste. Researchers are now making strides in key benign solvents—supercritical carbon dioxide and near-critical water, to name two—opening the door for pharmaceutical applications.Supercritical CO2 is carbon dioxide that has been compressed to a degree where it exhibits some liquid, solvent-like properties. It is readily available and easy to remove and recycle following a reaction. While scCO2 is the most commonly used gas for supercritical applications, other gases such as propane and butane have also been used. CO2 is also being tested in reactions using gas-expanded liquids as solvents.Near-critical water is still essentially a liquid, used at temperatures of 250 to 300 degrees C and pressures of 1,000 psi. As water is heated, the hydrogen bonds weaken, allowing dissociation into acidic and basic ions which then facilitate reactions. When reactions return to room temperature, the products separate out. Traditional acid-based processes, on the other hand, require a neutralization step and produce significant waste salts.Supercritical CO2 and near-critical water are benign and may act as both solvent and catalyst, and are easily separable and recyclable, producing little or no harmful or excess waste. What’s more, they are “tunable,” functioning differently with adjustments in temperature and pressure, and thus easily manipulated for industrial applications.Chemists, not surprisingly, have been working to unlock the potential of these solvents and to pass along their findings to industry. Professors Andrew Holmes, director of the Melville Laboratory at Cambridge University (Cambridge, U.K.), and Rick Danheiser and Jefferson Tester of Massachusetts Institute of Technology (Cambridge, Mass.) are discovering ways of using scCO2 in the entire manufacturing process, from drug synthesis on, and some pharmaceutical companies are working to apply their results.Supercritical CO2 is carbon dioxide that has been compressed to a degree where it exhibits some liquid, solvent-like properties. It is readily available and easy to remove and recycle following a reaction. While scCO2 is the most commonly used gas for supercritical applications, other gases such as propane and butane have also been used. CO2 is also being tested in reactions using gas-expanded liquids as solvents.Near-critical water is still essentially a liquid, used at temperatures of 250 to 300 degrees C and pressures of 1,000 psi. As water is heated, the hydrogen bonds weaken, allowing dissociation into acidic and basic ions which then facilitate reactions. When reactions return to room temperature, the products separate out. Traditional acid-based processes, on the other hand, require a neutralization step and produce significant waste salts.Supercritical CO2 and near-critical water are benign and may act as both solvent and catalyst, and are easily separable and recyclable, producing little or no harmful or excess waste. What’s more, they are "tunable," functioning differently with adjustments in temperature and pressure, and thus easily manipulated for industrial applications.Chemists, not surprisingly, have been working to unlock the potential of these solvents and to pass along their findings to industry. Professors Andrew Holmes, director of the Melville Laboratory at Cambridge University (Cambridge, U.K.), and Rick Danheiser and Jefferson Tester of Massachusetts Institute of Technology (Cambridge, Mass.) are discovering ways of using scCO2 in the entire manufacturing process, from drug synthesis on, and some pharmaceutical companies are working to apply their results.One key area of their work is in amines. Professor Holmes and his research partners are among the first to figure out how to use the scCO2 in reactions with amines. Amines typically react with carbon dioxide to form carbamic acids, Holmes says. "We used silyl amines as surrogates for the free amines and believe that judicious choice inhibited carbamic acid formation either through electronic or steric effects or a combination of both."What matters most for pharmaceutical applications is that scCO2 can now be used to produce aromatic amines, key to many neurological drugs. While pharmaceutical companies have used scCO2 for processing drugs into powders, the new findings may mean that scCO2 can be used more broadly for drug synthesis as well, resulting in a more streamlined manufacturing process on the whole. "Continuous flow manufacturing would be the ultimate goal," says Holmes, who notes that the exact potential of supercritical CO2 will depend upon further R&D for individual applications. The researchers are currently working with pharmaceutical firms to this end.Meanwhile, at Georgia Institute of Technology (Atlanta), professors Charles Eckert and Charles Liotta (photo) were recently awarded the 2004 Presidential Green Chemistry Challenge Awards by the U.S. EPA and American Chemical Society for their work with supercritical CO2 and near-critical water.Eckert, a supercritical fluids specialist, and Liotta, an expert in phase transfer catalysis, are turning their attention more and more towards gas-expanded liquids, mainly utilizing CO2. Using CO2-expanded liquid provides even greater reaction purity, Eckert notes, and a solvent which can be used over and over again. Both factors have cost-saving implications."We are developing methods that not only are more benign, but also have economic advantages in producing better products less expensively," says Eckert. Manufacturers, he adds, save the time and cost of dealing with excess unwanted wastes. They also have a wider variety of reaction products to choose from and may opt for those that are cheaper, faster, and most beneficial for their needs.Whether these cost savings will be enough to convince most companies to abandon conventional processes remains to be seen. Because firms have so much invested in their existing facilities, Eckert sees the solvents being used mainly in low-volume applications in the short-term.