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Manufacture Small Molecules

Solvents: Making the Green Choice

This article is part of our special focus on "traditional" pharma: The Small Molecule Manufacturer (read more here). You can find more articles from The Small Manufacturer here.

Alan Steven, Senior Principal Scientist at CatSci.

In a time when the world is more focused on green manufacturing than ever before, companies must find methods of sustainably developing essential medicines. The volumes of solvents used for processing can significantly influence the size of a company’s environmental footprint, so it pays to carefully consider which solvents are used. At the same time, identifying the solvents that produce the best overall outcome for the product and process across reaction, work-up, and product isolation operations is a challenging task.

Given the high value of the pharmaceutical materials, there is clear economic pressure to maximize process yields. From a solvent perspective, a more inclusive assessment includes the plant time and energy usage associated with removing and swapping solvents. Further requirements, such as the disposal or recycling of solvent, must also be factored into overall cost. But this consideration is complicated by the limited visibility of the long-term manufacturing scenario for a given product and the non-uniform way in which manufacturing sites dispose of solvent waste. The best overall option may require the limited use of a solvent which, when considered in an isolated context, has poor sustainability credentials.

Reaction solvents are heat sinks for energetic reactions and provide a means of controlling the reaction temperature – a property that justifies their use versus solvent-free conditions. Savvy chemists may use them – sacrificing the reaction yield – if they can control the amount of reaction waste generated in workup and isolation reactions. For example, forming an oil that can be easily drained away from an immiscible phase bearing the reaction impurities, or crystallizing the product directly from the reaction mixture are common tricks of the trade.

Companies have a variety of tools at their disposal that can help make it easier to weigh up options when it comes to solvent choice. For decades, labs have had access to well-thumbed or laminated guides that inform chemists of the liabilities and environmental credentials of common processing solvents, but these are now being replaced with electronic versions that enable faster dissemination of information. The American Chemical Society’s Green Chemistry Institute has developed one such guide whose filters allow the process chemist to interact with the data (1). The consortium has also developed a tool that can make predictions around likely solvent usage associated with particular synthetic transformations, allowing chemists to find the relative sustainability of route options at the outset of the design process.

Modeling is also an effective tool in choosing the best solvent for the job. Experimentally acquired solubility data from a few solvents and predictive methods can be used to establish the relative solubility of a compound in hundreds of different solvents, reducing the amount of wet chemistry experimentation required. As well as single solvents, relative solubility in solvent mixtures can be modeled, unearthing privileged solvent pairs like methanol and toluene, or methanol and anisole, whose combination in certain ratios produces parabolic solubility greater than either individual component.

External factors at work

Decisions made during the design of pharmaceutical manufacturing processes can have long-lasting environmental ramifications. When registering an API manufacturing process with a regulatory health authority, you will need to commit to using a specific solvent. Though this commitment can, in theory, be amended, doing so is a daunting challenge, given that health regulators move at different speeds and have different processes and hoops to jump through.  

Regulations relating to the safety of solvents are reshaping solvent selection practices. Annex XIV of REACH, for example, identifies particular substances of very high concern (2), whose use after a phase out “sunset” date requires authorization in the EU. Permission for authorization requires demonstration of the overall socio-economic benefit of the process in which it is used, along with evidence of how the solvent behaves versus alternatives. This legislation has, for example, accelerated a move away from the use of diglyme for the manufacture of the chronic obstructive pulmonary disease treatment indacaterol.

Supply stability is another potential source of concern. In 2008, the global economic slowdown prompted a reduction in acrylonitrile production, triggering a shortage of a byproduct called acetonitrile – a commonly used solvent. Any future, sustained shortage of acetonitrile would hit oligonucleotide manufacture particularly hard, as it uses large amounts of acetonitrile for washing the solid support to which the growing drug is attached. If the experimental drug inclisiran, a promising treatment for patients with atherosclerotic cardiovascular disease, is approved and manufacturing is scaled up, there is unlikely to be enough acetonitrile in the world to meet the needs of its current manufacturing process...

Decisions made during the design of pharmaceutical manufacturing processes can have long-lasting environmental ramifications.

Ionic liquids, deep eutectic salts, supercritical carbon dioxide, and surfactant “solutions” are all reaction media, which each have their own useful properties. As they are not yet a necessity for other manufacturing sectors, demand remains weak, pushing up costs and discouraging their investigative use. One example is dihydrolevoglucosenone, a material touted as a replacement for dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP) – both solvents are toxic to reproduction and are or will be restricted according to REACH regulation (3, 4). However, the current production of dihydrolevoglucosenone is limited to 20 tonnes per annum (5), whereas 18,000 tonnes of NMP are manufactured in Europe each year (6). Though the number of economically sustainable solvents should only increase, the numbers show that we are still far from widespread adoption.

Increasingly, pharma must consider transitioning from solvents that work for the bottom line of a balance sheet to those that also work for the world. As conversations continue to consider how the overall benefit of a pharmaceutical product to mankind might be outweighed by the negative environmental impact of its manufacture, attention will increasingly fall on the role of solvents.

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  1. ACS, “Solvent Selection Tool” (2018). Available at bit.ly/2Jj3ZYU.
  2. Health and Safety Executive, “Reach Authorisation” (2016). Available at bit.ly/2TzXuCL
  3. European Chemicals Agency, “Substance Infocard 1-methyl-2-pyrrolidone” (2020). Available at bit.ly/34DrWlI
  4. European Chemicals Agency, “Substance Infocard N,N-dimethylformamide” (2020). Available at bit.ly/34DrYdk
  5. Chemical and Engineering News, “New solvent, Cyrene, takes on NMP” (2019). Available at https://bit.ly/36pZk0I
  6. OECD, “Economic valuation in 1-Methyl-2-pyrrolidone (NMP) regulation” (2018). Available at bit.ly/2HKz3Al

About the Author

Alan Steven

Senior Principal Scientist at CatSci

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