Green Chemistry in the Real World: Schering-Plough’s Successes

The Green Processing conference brought more on pure chemistry, with Kevin Shaughnessy of the University of Alabama talking about recyclable catalyst systems using aqueous phase cross-coupling reactions catalyzed by palladium. However, the next few presentations were very "hands on" and discussed actual implementations of green chemistry.  Ingrid Mergelsberg, director of chemical development at Schering-Plough, discussed the industrial aspects of green chemistry and some successes that she and her team have achieved so far.  The main driver is not "responsible care" or corporate stewardship, but cost reduction (the other is a side benefit).  It can also add new intellectual property to a company's portfolio. In Schering's case it brought continuous processing into the mix. The company has developed a Process Sustainability Index (PSI) benchmark for solvents, process materials, total material use, total reactants, total water. Schering also tracks the materials used per kilogram of API produced.  Generally, dramatic decreases are seen as a drug moves from preclinical to phase 2, 3 and then commercial phase. The earlier in the cycle, the more waste is generated. Mergelsberg says, understandable since only a few candidates will make the cut.  "The challenge is to find the right balance," she said, and to know how much to invest in a process before you know whether or not it will result in a successful drug. "We try to make people aware very early on, in discovery, to build green chemistry right from the start of process development and get it right the first time….build in quality from the beginning of process development….that way we don’t have to change the processes later on. This requires some changes in behavior and attitude, she noted.  "We need to increase awareness very early on and involve discovery teams." Typically, she noted, chemical development chemists are involved 6-12 months before a molecule is recommended for chemical development R&D has  developed tools to help chemists find alternatives….screening solvents and reagents with respect to different criteria including carcinogenicity, mutagenicity, reproductive toxicity, solubility, partition coefficient and biodegradability. From this, they have developed a  “Chemical Selection Guide,” which currently contains data for some 400 chemicals. When a new chemical comes into development, Dr. Mergelsberg said, the chemist must issue new notification sheet, list all solvents required and their impact, must explain clearly why the risk of using a solvent that psoes risks is worth it. In addition the company doesn't just list possible solvents, but gives alternatives for extraction, chromatography, precipitations, in a chart that goes from red to yellow to green. This information is included early on with discovery chemists. "It's rare that we get processes from discovery with chlorinated solvents," she said. "If we get them there’s a reason." The company has developed a web based process sustainability index data base….capture process changes from early phase of development to commercial synthesis, tracking kg of raw materials/kg of API. PSI trend charts are then developed, so that one can get to root cause of problems (e.g. when there’s an upward spike during commercialization----in one case, solvents used for cleaning reactor added to total level.) She then discussed some successful applications of green chemistry, which were achieved before the compounds went into commercial production: Solvent substitution and recycling, TCH solvent substitution, which eliminated 2000 L of MTBE during workup…reduced 2250 L of organic wastes Replacement of lithium hydroxide with sodium hydroxide in one process, which reduced costs overall by 6.3% compared with original process chemistry, including energy and waste disposal and treatment costs. "The product gets a lot purer, cleaner," she explained. "Originally we had to recrystallize," she said. Another example is the in situ elimination of cyanide waste….in a one pot conversion involving in-process oxidation of cyanide wastes. The process eliminated KCN and cyanide bearing aqueous and organic wastes, offering consistent 78% yield and 98% purity.  "This is as green as cyanide can get," she noted, and the new process reduced waste by about 30%.also looked at unit operations and decided to optimize distillation to increase process efficiency (reduce cycle time as batch size increases, reduce cost per kilo of API produced," she said. Her team characterized equipment capacity, built distillation models based on heat and mass balances using simulation software from Dynochem. They validated distillation models by comparing predictions with existing runs in the plant, defineed and run them. More examples:  Solvent swaps, use of continuous distillation, and use of supercritical fluid chromatography in place of HPLC, which reduced run times by 95%, from 1950 to 90 hours; recovery from 90% to 95%; reduced costs from $6,892 to $165 per kg of intermediate API. The company is also recovering and reusing API that would otherwise have been wasted from capsule and tablet development.  More on this and other companies' strategies in our next issue. Stay tuned. AMS