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Feature Articles : Nov 1, 2011 (Vol. 31, No. 19)

Green Chemistry Initiatives Take Shape

Embracing More Environmentally Friendly Practices Also Has Economic Benefits
  • Gail Dutton

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.

Medicinal Chemistry

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.

Quantification

“The ACS GCIPR has defined and implemented a process mass intensity metric for measuring material resource efficiency of manufacturing routes to active pharmaceutical ingredients,” because “the total volume of solvent used is also an important measure,” noted Caireen Hargreaves, senior environmental specialist, AstraZeneca.

As Quirinus B. Broxterman, Ph.D., corporate scientist for route scouting and selection at DSM recalled, “When Roundtable members reported their PMIs in 2008, more than half was solvent use, and nearly one-third was water. Most of that occurs in the preclinical phase, as chemists do everything possible to make the compound.” PMI decreases significantly once the compound is in clinical development.

PMI and E-factor are the two leading mass-based quantitative options, but PMI is a better indicator of sustainability than the E-factor equation, Dr. Broxterman said. “PMI relates to kilograms of product you make and, therefore, easily captures the interest of the nonscientific aspects of a company.” The use of PMI also allows the easy transition to carbon footprint measurement.

The Roundtable is rolling out a simple PMI calculator with calculations embedded in a spreadsheet, so users only need enter the quantities of reagents, solvents, and water. “To facilitate more sustainable manufacturing, we need to quantify relevant sustainability parameters. PMI is a first-generation parameter and is a good (starting point) to drive toward a carbon footprint, an ecofootprint, or something to be defined,” Dr. Broxterman concluded.

Solvent Selection Guide

ACS GCIPR introduced its solvent selection guide recently, based upon safety, health, and environmental parameters. “Because effectiveness of a solvent for a particular reaction or work-up step depends upon the chemistry and conditions used, the effectiveness of the solvent was not included in the scope of this work,” Hargreaves said.

The PDF version of the guide is available at www.acs.org/gcipharmaroundtable, and as an iPhone app. The guide may be used to “compare solvents scored in the Roundtable guide to those of their own corporate guides, and to raise awareness and provide a resource.”

“By switching to green solvents, a company can expect equivalent functional and performance with minimized environmental impact.”

Green chemistry also may lower waste disposal costs for harmful solvents, reduce the need for expensive emissions abatement equipment, and lower the costs of virgin solvent when solvents can be recycled. Other speakers added greater efficiency and reduced energy use to green chemistry’s attributes.

But, there are tradeoffs, Hargreaves acknowledged. “Some newer alternatives may still be limited in production scale and the number of available suppliers, and some common laboratory reagents may not be readily available in the new alternative solvents.”

Additionally, there are data gaps for some green solutions, making it difficult to fully assess them against the Roundtable solvent selection guide. “Regulatory guidance is not yet in place for some of the newer alternatives,” she added.