An old science
Water chemistry
Green gains
New norm
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    Dissolving a toxic tradition

    Organic solvents are as natural to chemistry as the ubiquitous test tubes. But the fossil origin of some widely used solvents, which are also used in drug development, are a threat to the environment. Special soap-like substances that can work like nanomachines might dissolve part of this toxic problem and help chemistry become more natural.

    Text by Goran Mijuk, photos by Nicolas Heitz, Illustration by Alan Abrams

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    Bruce Lipshutz was among the first scientists to look into designer surfactants as a replacement for toxic solvents. These soap-like particles, which form into spherical shapes, can trigger chemical reactions in water. Fabrice Gallou from Novartis joined him early on in these efforts.

    arrow-rightAn old science
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    Published on 03/09/2020

    Fuming smokestacks and the pungent smell of burning coal were once signs of civilizational progress and industrial advance, powered by breakthrough discoveries in chemistry which were at the forefront of scientific progress during the 19th and early 20th century.

    But these times are long gone. Chemistry has lost its prior luster as many of its once lauded discoveries such as plastic, fertilizer and radiation, which have changed our lives so completely and helped us industrialize societies in the first place, are now considered toxic and an outright threat to human life on earth.

    Since Rachel Carson’s groundbreaking book Silent Spring, which was published in 1962 and in which the author highlights the consequences of industrial pollution, civilization and chemistry, once used almost synonymously, seem at odds with each other. 

    Though efforts to make chemistry greener and to use different methods for producing new environment-friendly materials have been stepped up in the late 20th century, their use so far is limited given that it is hard to replace classic fossil-based chemical processes.

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    The picture shows a details of a large- scale lab on the Campus in Basel, which Fabrice Gallou’s team utilizes to demonstrate novel, water-based chemical processes.

    An old sci­ence

    “Chemistry is an old science,” says Fabrice Gallou, an award-winning chemist who works as a Principal Fellow at the Chemical & Analytical Development unit at Novartis. “Many processes have stayed the same for decades. Changing them, even if this were to have a beneficial effect on the environment, is difficult not only technically but also for cultural reasons.”

    The challenge of switching to other technologies does not only relate to combustion, the ubiquitous use of plastic and other fossil-based products that are damaging the environment. Hundreds of chemical compounds in everyday appliances are created with the help of oil-derived solvents, which are toxic, flammable and difficult to degrade.

    This is also the case in medicine. In order to manufacture a drug, dozens of chemical reactions need to take place to produce an active pharmaceutical ingredient. In most, if not all, instances, petroleum-based solvents are used to create a stable molecule. Without these solvents, modern-day medicine would not exist. 

    Understanding inefficiencies

    Gallou, who started his professional career in the United States in 2001 after finishing his Ph.D. at The Ohio State University, has seen the good, the bad, and the ugly of the chemical industry, having worked as a chemist both in early-phase process research labs and in large-scale production units.

    “I learnt tremendously during my time in the plant,” Gallou explains. “I really saw what the job was all about, what the challenges were and started to see the inefficiencies. For my career it was important to understand those challenges in order to recognize what the longer-term focus of the industry should be.”

    When he joined Novartis in 2006, he received the chance to develop new ideas on how to improve some of the standard chemical processes used in drug development. He took the opportunity and launched the so-called Green Chemistry Group, which today encompasses a loose group of around 10 people who focus on establishing new process and synthesis protocols using new classes of solvents.

    “When we started, there were not many options to make chemistry greener. But the real breakthrough came about 12 years ago, when Bruce Lipshutz from the University of California at Santa Barbara developed a soap-like “solvent” that could work in water,” Gallou explains. “This was the starting point to dive more deeply into this novel field and develop new approaches.”

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    Water and soap are mixed to prepare the chemical process.

    Wa­ter che­mis­try

    In 2008, Lipshutz and his team were among the first to experiment on new solvent technology by tapping into so-called designer surfactants. These soap-like particles, which are traditionally used in cleaning agents due to their special properties, have the ability to separate dirt particles from water.

    “The idea to look into surfactants was a result of a meeting with our Health, Safety and Environment officer on our Campus in Santa Barbara, who told me sometime in 2005 that my lab was the biggest polluter in the county,” Lipshutz says, recalling the time he decided to break from traditional petroleum-based chemistry. “This really opened my eyes and our team started to look into ways to use new benign ‘solvents’ and do chemistry in water, like nature does.”

    At the time, Lipshutz and his team were doing research on vitamin E-derived surfactants, which had special, solvent-like properties that looked promising. “It was a sort of a hunch I had since we were already doing research with these nanoparticles and we gave it a try to use them as solvents in some chemical reactions.”

    That it worked right from the start surprises Lipshutz even in retrospect. “We did not understand the entire process from the beginning. It was only when we started to investigate what was actually happening that our understanding deepened and we were able to design increasingly efficient surfactants which would help us create reactions that before were only possible with classical solvents.”

    As Lipshutz intensified his scientific investigation, it became clear that the vitamin E-derived surfactants formed sphere-like nanoreactors in which the chemical process takes place. This allows them to perform reactions in water not only in a non-toxic way, but also at lower temperatures and with fewer steps. 

    The team was also able to create new surfactants able to perform chemical reactions that are important for the pharmaceutical industry, such as amide couplings and Suzuki-Miyaura cross-couplings, attracting the interest of Fabrice Gallou and his team, among others.

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    The same procedure is a repeated in larger recator.

    Green gains

    Gallou, who early on followed the work of Lipshutz and worked closely with him on some projects, initially developed blueprints for potential future projects within Novartis. “Our approach was to first design processes and spend more time conceptualizing rather than focusing on optimizing existing methods.”

    Gallou says that this cautious approach “was probably a good thing” as the willingness to embrace new chemical processes was initially low within the company. The team, he says, was thus able to establish clear principles, which would later prove instrumental in gaining the trust of colleagues and receiving the opportunity to start on several early-stage drug development projects. “This helped us become more visible within Novartis and gain traction over time,” Gallou says. 

    One key focus area over the past few years was to get rid of dimethylformamide, often abbreviated as DMF. This solvent is used in many industrial applications with annual global demand of about 360 000 tons. Around 10 percent stems from the pharmaceuticals and life sciences industries. 

    Gallou is convinced that the new solvent they created – a vitamin E-derived surfactant – could lead to DMF being completely phased out. This would be just in time as the European Union is seeking to reduce the use of toxic solvents such as DMF as part of the regulatory framework REACH, which aims to protect human health and the environment from toxic chemicals. 

    “We were not only able to show that we can phase out DMF. There are many other advantages such as the fact that we save water,” Gallou says. “The beauty, when we do this, is that we tend to have very mild conditions, so we can work at lower reaction temperatures too, saving energy. Also, this leads to less decomposition and waste. And, on top of that, this new process does not require any extra capital investment and routinely costs 20 to 30 percent less than standard procedures.”

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    When all aspects of the process have been thoroughly addressed, the process is moved to a large-scale production environment, where it is again carefully run and monitored (by Nikola Kovacic) to make critical observations and to gain experience in a large-scale production environment.

    New norm

    Since the Green Chemistry team started its efforts, the group has worked on several dozens of early-phase compounds, some of which are now in late-stage development, but not yet in commercial production.

    “Before our new processes can become part of established industrial practices, it will take several more years,” Gallou concedes. “But we have been able to prove that this concept could one day help us create greener chemistry. Of course, we won’t get rid of all fossil solvents in the near future. But our understanding and our toolbox are growing. It will be a long road, but one that is very worthwhile to travel.”

    Meanwhile, Lipshutz, who is accelerating his research to broaden water-based chemistry, believes that his approach will become standard because the method, a concept tested by nature for millions of years, is elegant and efficient. “On the one hand, we have been doing petroleum-based chemistry for 200 years,” Lipshutz says. “On the other hand, nature has been doing chemistry in water and has been doing it for hundreds of millions of years. Who are you going to bet on?”

    Once asked by a reviewer to point out some downside risks to water-based chemistry in a research paper, he wrote: “What’s the downside to making the switch to water? Downside? This is akin to asking what’s wrong with the way nature does chemistry. Perhaps not surprisingly, no general drawbacks have yet appeared. It is only a matter of time before chemistry in water becomes the norm.”

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