Synthesising active pharmaceutical ingredients (APIs) requires a series of multiple chemical reactions and large quantities of solvents. Ask any API manufacturer how they’d like to improve this process and the response is likely to be “make the reactions faster”, “make the reactions cheaper” or “make the reactions more efficient”. Increasingly, you might also hear “make the reactions more environmentally-sustainable”.

Large pharmaceutical companies can each produce anywhere from 3,000 to 6,000 metric tons of hazardous waste per year, most of it (by volume) solvents. Several companies have developed methods for solvent recycling and recovery. Some also repurpose spent solvents for resale in the paint or industrial sectors for a second lease of life, thus reducing their overall carbon footprint. However, such approaches centre on waste management rather than on making the entire process green from the start. Are environmental factors a key concern for the industry or is it just an afterthought – can we work smarter?

Planting the seed

Industry observers agree that production processes would be a greener venture if drug makers developed their API manufacturing techniques with the environment in mind from the start, rather than focusing on solvent recovery later in the game. To address this issue, university-based researchers are developing methods to reduce solvent use, make one-pot reactions and cut waste from beginning to end of the process. Solvent selection is often a key consideration. Emerging neoteric solvents that are environmentally-benign compared to commonly used dipolar aprotic solvents such as DMF, DMAc and NMP have become of increasing interest to researchers. With the aforementioned now labelled as SVHCs (Substance of Very High Concern) and with a more stringent regulatory landscape, solvent choice is all the more important.

Many of the originators and an increasing number of generic companies have a green, sustainable agenda. Very often, they approach it through a focus on green solvents: use of water or greener solvents, or green chemistry in general; less steps of synthesis, change of catalysers, non-toxic raw materials and flow chemistry. There are some breakthroughs in the market, even if most companies are still in the early stages. Pfizer has designed a green route for the synthesis of pregabalin and they have reported that almost 38 million litres of alcoholic organic solvents and nearly 2,000 metric tons of raw materials were eliminated on an annual basis. GSK has announced a green reaction for paroxetine, sold as Seroxat, and Paxil, which is used for anxiety disorder. They have indicated that the yield of the overall transformation was almost double that of the process in conventional route, resulting in a greener, shorter and more cost-efficient method. Sertraline hydrochloride, also known as Zoloft, is a selective inhibitor of serotonin reuptake that is utilised for the treatment of depression. When it was synthesised by the conventional synthetic route, chemical reagents and metal salts were consumed. On the other hand, the removal of metal salts and the use of a Pd/C catalyst gave a more selective and greener protocol. Colberg and co-workers in Pfizer Global Research and Development have designed a green protocol for sertraline in which toxic solvents such as toluene and hexane were removed from the strategy.  A comparison of solvent utilisation between the first commercial route and the new green route showed that 76.000 litres of solvents, 440 tons/year of TiO₂-MeNH₂.HCl waste, and about 40 tons of the unwanted trans-isomer waste were eliminated.

Therefore, the first steps in green API manufacturing could be as simple as reducing the number of reactions and isolations required to produce a given molecule. Fewer steps mean less solvent to recover and dispose of. The second step could be to replace volatile harmful solvents and dangerous reagents with those that are better for the environment. It is recognised that making a process greener is seldom enough to entice a manufacturer into altering an established production process. The time, expense and regulatory filings needed to change an established manufacturing process are enough to make any drug manufacturer shake in its boots. However, bringing greener solutions into the API manufacturing process from the outset can influence the proliferation of more sustainable APIs of the future.

IMCD greener solutions

Sustainable APIs start with sustainable reactions. Through IMCD’s Greener Solvents Seminar, we offer alternatives to some of the potentially toxic or environmentally-harmful solvents commonly used in chemical synthesis today. For example, as replacements to DMAc, DMF or NMP, one might consider the emerging neoteric dipolar aprotic solvents GVL and NBP, or the more established DMSO, which is now gaining new interest as a sustainable alternative, particularly for solid phase peptide synthesis.

Similarly, in place of THF, there is growing interest in CPME, MeTHF, and MTHP, which have the potential to beneficially impact lithiation chemistry, for example. Here, reactions can be conducted at -20°C versus the traditional -70°C in THF with little loss in yield, thus resulting in less energy input and less solvent wastage.

We can also help with alternatives to elements more abundant, less harmful and more cost-effective than many on the so called ‘dangerous’ list. As an example, Palladium is a well-known precious metal catalyst used widely in classical C-C bond forming chemistry e.g. Buchwald couplings in addition to hydrogenation reactions. However, the mining of Palladium is far from sustainable and has one of the worst eCO₂ footprints of all the precious metals. Switching to alternative catalysts based on Nickel or Copper that are more abundant, more economical and less harmful has been shown to work well in a number of reactions.

Is the future looking green?

One of the commitments of the European Green Deal is to reduce emissions by 50% by 2030 and become climate neutral by 2050. The year 2030 is still seven years away, but the API manufacturers with aspirations to work with the pharma industry will benefit if green solvents or chemistry is part of their production lines. With the help of the authority bodies, we expect green chemistry to become not only compulsory, but a necessity in creating a greener future for us all.

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