New Challenges, Green Solutions
With mounting concerns about the sustainability of chemical manufacturing, it is vital that the pharmaceutical industry adopts robust green chemistry into their processes.1 Green chemistry practices display all the hallmarks of good process development. Their adoption will naturally lead to both economically viable and environmentally sustainable means of turning molecules into medicines. Here, we point to some of the most exciting technologies that could help develop sustainable chemical processes.
Waste not, want not
A major ambition for any green chemistry is the elimination of waste products in chemical manufacture. Biocatalysis is the use of naturally derived systems, such as enzymes, and has great potential for the replacement of toxic metal catalysts. By utilising milder reaction conditions and eliminating expensive metal catalysts and their waste streams, biocatalysis can transform a process and even an entire area of molecular design. In recent years, where the field was recognised with a Nobel Prize,2 this growing area of research has shown the power of novel and innovative biocatalysts in the pharmaceutical industry. The design of ligands for metal-catalysed processes is an equally important parameter to consider in the development of enhanced catalytic reactivity. For example, Buchwald has developed state-of-the-art precatalysts and ligands, which enable the use of lower catalyst loadings and reaction temperatures.3
Furthermore, with increased time pressures, novel combinations of photocatalysts and transition metal catalysis have started to emerge in discovery chemistry. Photocatalysis is the acceleration of a reaction promoted by light in the presence of a catalyst. This process exploits transient highly reactive species that could otherwise not be accessed and have profoundly different or enhanced reactivities to those that are available in the absence of light. This process has begun to impact a wide range of industries, providing new routes to molecules through far less wasteful reactions.
Combinations of these catalysts with flow chemistry, a continuous pipeline for pressurised high-throughput chemistry, have permitted greener reactions with far higher efficiency and little or no waste. In particular, flow photochemistry can benefit from this; a better, more uniform irradiation when compared to batch processes gives each molecule a close to consistent processing experience. This results in far shorter and more selective reactions, permitting efficient scale-up. Flow chemistry has been used extensively outside of the pharmaceutical industry in the production of petrochemicals. However, its use within the pharmaceutical sector is starting from a low base.
Regulation, Regulation, Regulation
Alongside these technological advancements, an essential facet of green chemistry is ensuring alignment with the rules and regulations and keeping up to date with their periodic updates. Regulations continue to change in order to safeguard the environment and guarantee the health and safety of employees and the public. Moreover, the majority of regulations have the knock-on impact of driving industry to become more efficient, forcing a transition to green approaches and more streamlined technologies to address any tighter process controls, which are costly. Accordingly, these regulations drive the discovery and deployment of new and innovative processes to make world-class therapeutics while not damaging the environment.
One difficulty lies with staying current on how compliance and the right to practice varies from country to country – a frustrating situation since environmental damage has no respect for borders. The chemical industry is also forced to adapt frequently to other global variations, whether there are challenges involving patented enzymes or from the sourcing of precious metals from countries with precarious political situations. With these pressures, the need to eliminate unsustainable metals and solvents remains a major goal for many businesses, and a key motivation behind advancing chemical R&D.
Guiding a green future
There is a growing demand for chemical manufacturing to be more sustainable, with regularly tightened regulations challenging the industry to make positive changes to their environmental footprint. There is always a drive to encourage the development of economically sustainable processes, which will often also drive down costs. Moreover, regulatory requirements are mandating cleaner reactions. As just one notable example of necessity being the mother of invention, a recent study that employs highly reactive organolithium compounds in low concentrations had a positive impact on the reaction throughput – further minimising environmental impact.4
At CatSci, we pride ourselves on being a fast growing, adaptable and award-winning Contract Research Organisation (CRO), putting customers at the heart of our work. We are dedicated to developing economically and environmentally sustainable chemical processes that support the delivery of affordable best-in-class small molecule therapeutics to meet the evolving healthcare needs of the world.
1. Valimaki C. Why Sustainability Is the Future of the Chemical Industry – Sustainable Brands. Sustainable Brands. https://sustainablebrands.com/read/chemistry-materials-packaging/why-sustainability-is-the-future-of-the-chemical-industry. Published 2018 [Accessed June 9, 2020]
2. Chen K, Arnold FH. Engineering new catalytic activities in enzymes. Nat Catal. 2020;3(3):203-213. doi:10.1038/s41929-019-0385-5
3. Kirlikovali KO, Cho E, Downard TJ, et al. Buchwald–Hartwig amination using Pd(i) dimer precatalysts supported by biaryl phosphine ligands. Dalt Trans. 2018;47(11):3684-3688. doi:10.1039/C8DT00119G
4. Colella M, Nagaki A, Luisi R. Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents. Chem – A Eur J. 2019;26(1):19-32. doi:10.1002/chem.201903353
Joe Renny, Associate Principal Scientist at CatSci Ltd