Sometime, less is more. In keeping with this motto, chemists and engineers have been fine-tuning production processes for decades, in the pursuit of maximizing the overall quality, production volumes and level of efficiency. Experts’ attention has now turned to the topic of sustainability in an effort to conserve the environment and reduce production costs. Two examples at Bayer demonstrate how this can be successfully achieved.
The chemicals industry is increasingly facing the challenge of becoming more sustainable.
Bayer experts from all parts of the company are working on implementing the twelve sustainability principles for large-scale technical active ingredient production in the best-possible way.
Applying the principles of green chemistry lowers energy consumption and chemical input volumes, and it’s also more environmentally friendly and in many cases reduces the overall costs.
The first time our scientists held molecules of the active substance rivaroxaban in their hands, they could not imagine how successful it would turn out to be.
You can’t tell how talented the tiny crystals are in the test tube, but once they are in the human body these unassuming molecules reveal the full extent of their impressive capabilities – they inhibit blood clotting. “The first time our scientists held molecules of the active substance rivaroxaban in their hands, they could not imagine how successful it would turn out to be,” says Dr. Konrad Siegel from Research & Development at Bayer Pharmaceuticals. The situation was similar for the insecticidal active substance flupyradifurone, which is especially environmentally friendly. The full potential harbored by a substance, whether it’s a drug or crop protection product, can neither be conclusively determined at the research stage, nor is it possible to precisely predict how high the prospective market demand will be.
The commercial production of an active substance is still in the distant future for the chemists in the laboratory, but increasingly becomes a focus as the product development stage progresses.
Once the laboratory phase is over, the process developers assume responsibility, and seek a way to transform the manufacturing concept into a viable means of technical production. “The commercial production of an active substance ultimately requires a safe, reliable and efficient process as well as consistent high quality at the lowest possible cost. “Reconciling these business aspects with sustainable production poses an incredibly challenging task for our process developers,” explains Siegel.
“That’s because sustainability is playing an increasingly important role in chemical production, especially in terms of how to link economic, ecological and social aspects,” says Dr. Markus Hadley, head of Corporate Business Stewardship at Bayer AG. To this end, industrial companies are focusing to a greater extent on the concept of “green chemistry,” which is more commonly referred to as sustainable chemistry. A wealth of knowledge and experience is required to ensure that the synthesis and processing steps as well as the deployed substances and solvents meet both business and environmental requirements.
Sustainability is playing an increasingly important role in chemical production.
Chemical syntheses are like exquisite recipes
Similar to an haute-cuisine dish, an ingenious recipe is required to produce an active substance. This process involves ensuring that the original molecules are dissolved in the right liquids, which are called solvents. Additional liquid, solid or gaseous components are then successively added, while other substances are detached. Special temperature and pressure profiles are usually needed to ensure that the deployed molecules achieve the intended reaction, create further building blocks and ultimately produce the final active substance after several reaction and processing steps have been conducted. “If it starts to become evident that a development candidate possesses the desired efficiency and thus market potential, we need a technically feasible and safe production method that is also cost-effective and environmentally friendly,” explains Dr. Christian Funke, Product Supply at Crop Science. “That was the case with the insecticidal active ingredient flupyradifurone.”
The Bayer researchers initially used a process based on chemicals that were only available in limited quantities, coupled with the use of components that were too expensive for technical production. In addition, certain reaction steps didn’t take place efficiently. A Bayer team comprised of experts from the Process Research and Chemical Process Development departments at Crop Science therefore searched for a more effective method. “To achieve this, we went back and closely analyzed the structural formula of the flupyradifurone molecule and considered where we could make modifications and yet still arrive at the same end molecule,” says crop protection expert Funke, explaining the procedure. There were dozens of possibilities, plus a correspondingly broad spectrum of chemicals and reagents. The Bayer team’s underlying goal was to find the most cost-effective and sustainable method.
Sustainable chemistry often also translates into lower costs
“A positive side effect is that these two aspects usually go hand in hand,” says Dr. Wahed Moradi from Chemical Process Development at Crop Science. As a process developer, he and his team are responsible for ensuring optimal adherence to the twelve sustainability principles in the commercial production of active substances. “For example, processes that take place at room temperature and under ambient pressure are not only more technically feasible, but also energy-efficient. And if the fewest possible synthesis steps lead to the desired result with a high yield and low waste volume, then it’s definitely beneficial to the environment and positive for overall production costs,” explains Moradi. Furthermore, the use of catalysts frequently proves to be helpful. These are substances that allow a reaction to take place very selectively and under simpler process technology conditions, ideally so that the desired product is created. What’s more, catalysts lower the energy input because they basically prepare the molecules for the chemical transformation, loosen bonds and bring atomic groups into a favorable spatial position. Another primary goal of sustainable chemistry is to avoid waste during production. “The type and amount of deployed solvents play an especially important role here,” stresses Siegel. “Water is probably the best known solvent, but we also need organic solvents such as alcohols, ether or other hydrocarbons to produce pharmaceutical active ingredients.” The goal is to use as few of these substances as possible, and preferably only those that are ecologically safe. To this end, Bayer has developed a manual containing 90 different solvents that are sorted according to their chemical and physical properties – such as the boiling point, water solubility or polarity – and categorized using a traffic light system. “With this list, researchers can choose a ‘greener,’ safer component with a comparable profile of characteristics – and thus play a role in pursuing a more sustainable course of production at an early stage,” the pharmaceutical expert explains.
as much of the desired active substance flupyradifurone as at the beginning with the same inputs.
One indicator representing the ratio between the total amount of deployed raw materials and the active substance produced is what is referred to as the PMI (process mass intensity) value. “For rivaroxaban, we were already able to reduce this indicator by three quarters at the early stage of development,” says Siegel. This means that the same input amounts can be used to produce approximately four times as much of the active substance. “Making further improvements during the advanced stage of development and shortly before the market launch is difficult. That’s because there are stringent quality requirements and each change in the production process must be intensively coordinated with the regulatory authorities. We nonetheless reduced the PMI value by a further 17 percent,” notes the development expert. In addition, the Bayer team managed to reduce the number of solvents.
Use of green chemistry in all production processes
The crop protection specialists took the same approach. Over a period of several years, they tested various different methods before finally developing an economical and environmentally friendly production process. “For example, we now produce an output component in a highly efficient and sustainable manner thanks to a catalytic process,” says process developer Moradi. “We designed one reaction step in such a way that it produces an excellent yield under very mild reaction conditions.” Furthermore, the team also succeeded in replacing en vironmentally questionable components, increasing yields and selectivities, and recovering a critical solvent throughout the subsequent transformation stages. After sufficient purification and processing, the latter is reentered into the reaction cycle. The crop protection experts’ success is also reflected in the PMI. “We can now produce five times as much of the desired active substance flupyradifurone as at the beginning with the same inputs,” explains Funke.
“Developing a sustainable chemical process is an incredibly complex task. You have to fine-tune various aspects,” says Hadley, who has joined his colleagues in advocating sustainability issues in the production process throughout the Bayer Group. This applies to new active ingredients as well as existing processes. For this purpose, well-versed teams have been closely examining existing chemical production at Bayer for just under ten years. Adds Hadley, “Establishing sustainable processes represents an investment in the future for companies. Ultimately, this can only prove to be beneficial – in financial terms because it increases the level of efficiency by reducing the amount of energy and resources that are required for production purposes, and also with regard to making the processes even safer and more environmentally friendly.”