Many innovative companies are embracing green chemistry, citing environmental sustainability, increased efficiency, and lowered costs, as they develop the tools and measurements that inform the choices of solvents and reagents throughout a compound’s development and manufacturing, according to speakers at the American Chemical Society’s (ACS) recent “Green Chemistry and Engineering” conference.
“Green chemistry is gaining prominence, paralleling regulatory and economic movements. There is a global expectation for sustainable resource use, chemical safety, and transparency as stakeholders are becoming more precautionary and risk adverse,” Richard Williams, Ph.D., president and founder of Environmental Science & Green Chemistry Consulting, said.
“Since 2003, 18 U.S. states have collectively passed 71 chemical control laws calling for the use of green chemistry, phase-out of specific substances, data collection, or the reduced industrial use of toxic chemicals.
“Green chemistry is just good chemistry,” Dr. Williams said. “As new science develops, it delivers economic and environmental benefits. For example, Pfizer improved the manufacturing process for sertraline, the active ingredient in Zoloft®.”
The original three-step sequence was streamlined to one step, producing chirally pure sertraline in much higher yield and with greater selectively. Raw material usage for three materials declined by 60%, 45%, and 20%, respectively.
Employing ethanol as a solvent eliminated the use, distillation, and recovery of four more hazardous solvents. The green approach has eliminated nearly 2 million pounds of chemical waste per year, improved safety and material handling, reduced energy and water use, and doubled overall product yield, Dr. Williams reported.
One aspect of Amgen’s sustainability initiative focuses on medicinal chemistry. “Although the scale of reaction is small, the cumulative footprint is significant,” noted Emily Peterson, Ph.D., scientist and green chemistry team lead for Amgen Massachusetts (AMA) medicinal chemistry.
The goal at Amgen, then, is to “equip medicinal chemists with working knowledge of green chemistry, provide access to tools to guide green solvent and reagent selection, and apply restraint rather than constraint,” to chemists’ choices. Immediate challenges include reducing chlorinated solvent usage, phasing out toxic and noneconomical reagents, modifying wasteful ordering and disposal habits, and encouraging use of green conditions.
These changes are seeing results. For example, since November 2010, the use of dichloromethane at the AMA site has declined 40%. “Ten percent was achieved just by picking up a different squirt bottle when chemists rinsed their tubes,” Dr. Peterson explained.
Much of the rest was achieved by education and replacing dichloromethane chromatography with greener solvent systems (like heptanes, ethyl acetate, and ethanol) and by replacing normal-phase chromatography with reverse-phase medium-pressure liquid chromatography, which allows purification of highly polar compounds using aqueous media.
“You can load large amounts onto the column, including crude reaction mixtures, and you can reuse the columns, which gives nice flexibility,” Dr. Peterson added.
At Amgen, “we also crafted our own green chemistry solvent selection guide. We made it into magnets and put them on all the hoods, so chemists are reminded daily of greener options.”
At Dr. Peterson’s site, the T3P amide coupling reagent has become a popular reagent in medicinal chemistry, she said. “You can work it up with water, and the product is often pure enough to go to the next step without contamination with other reagents.”
To reduce waste, Amgen partners with ASDI to store its chemicals. Therefore, research sites can order just the quantities they need from among Amgen’s own supplies. The company also changed its chemical disposal policy, retaining chemicals with long-term stability rather than discarding all chemicals after three years. In shipping 500 compounds to ASDI, “we saved $3,000 on disposal alone.”
Chemists contemplating green chemistry cite concerns about re-optimization timeframes, costs, access to established chemicals, or methods and regulatory issues. “The key to adoption is to use green technologies that are superior to current methods.” Amgen also operates a green chemistry awards program for labs that make the greatest green chemistry gains. “Cash talks,” she said.
Ingrid Mergelsberg, Ph.D., director of process chemistry at Merck and immediate past co-chair of the ACS Green Chemistry Institute Pharmaceutical Roundtable (GCIPR), agreed. “Since 2007, the Roundtable has awarded $950,000 in research grants based on green principles and formed academic liaisons with industry.”
Roundtable members lead by example. “Merck has pioneered advances in areas such as asymmetric and enzymatic catalysis, high-throughput screening in catalysis, and supercritical fluid chromatography for chiral and achiral separations, which avoid the creation of significant amounts of solvent waste,” Dr. Mergelsberg said.
To create a green chemistry environment, “it’s essential to have routine demonstrations of commitment to green chemistry and engineering from senior management. We’ve implemented a cross-functional green chemistry team with measurable goals and objectives supported by senior management. Merck has also created a green chemistry e-learning course that will be available in the next few months, and a green chemistry toolbox.
“Tools are very powerful to facilitate chemists getting greener,” Dr. Mergelsberg continued. Merck’s own green chemistry toolbox includes a process mass intensity (PMI) and analytical method volume intensity total solvent consumption calculator, solvent selection guide, pathway to greener solvents, and a reagent selection guide tool kit for enzymatic and catalytic reactions.
By 2020, the Roundtable plans to have a database of highly efficient transformations, a predictive tool for greener route design, and standard quantitative key performance indicators and measures of greenness.”
Merck has developed its own green chemistry electronic notebook templates based on the reagent selection guide. The Roundtable has initiated discussions with e-notebook suppliers.
She also aims to influence the research agenda. “Most chemistry journals haven’t embraced green chemistry policies and principles yet. In many broadly referenced articles, chloroform, benzene, and other absolutely nongreen solvents and reagents are still used. Thus, medicinal chemists naturally start with nongreen reagents because they are following established protocols.”
Dr. Mergelsberg sees progress, however. “Organic Process Research and Development has accepted some of the Roundtable’s wishes, by not accepting papers with solvents of benzene or of chloroform.”
The Roundtable is also preparing a reagent selection guide. Its goal is to identify the most environmentally benign conditions for chemical transformations and analyze reactions for five green criteria: the environmental degradation of reagent and degradation products, solvent compatibility to green solvents, availability from natural feedstocks, atom efficiency of transformation, and toxicity and process safety hazards.