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Solvent selection guides
Solvent selection guides
Solvent selection has long been performed on the basis of intuition, matching solvents with desirable properties to the requirements of the process at hand. Concerns over the safety of solvents have always been prominent in large-scale operations but historically overlooked for small reactions. Over time, some obvious substitutions became standard practice, such as using toluene in place of the carcinogenic benzene, or dichloromethane instead of trichloromethane (chloroform). In both instances, structurally similar solvents were selected to impart similar properties, but these substitutes also bear similar (albeit slightly less severe) hazards as the solvents they replaced. We will consider alternative solvents that circumvent the link between chemical structure and health and safety hazards later in the module (see the section on bio-based solvents).
In 2007, the idea of solvent selection on the basis of ‘greenness’, a combination of health, safety, and environmental hazards, was formally established with the Pfizer solvent selection guide. The ‘traffic signal’ format of this guide has become the standard presentation and has been replicated in tools produced by a number of other pharmaceutical companies. The purpose of these guides is to influence decision-making in early-stage chemistries, so that if it becomes desirable to scale-up a reaction there has already been some consideration over the appropriateness of the solvent. Here, some of the terminology has been unified and the number of solvents reduced to 20 in each example of a solvent selection guide to help comparison.
The hierarchy represented in the Pfizer solvent selection guide was strongly determined by the human health hazards posed by the solvents. Generally, oxygenated solvents are preferred, with hydrocarbons presenting greater health and safety issues. Extremely flammable and potentially explosive ethers, carcinogens (benzene and halohydrocarbons) and solvents with reprotoxic hazards are found in the least desirable ‘red’ column.
GSK, AstraZeneca (not published), and Sanofi all followed suit with their own solvent selection guides. GSK initially created solvent selection guides for larger-scale processes, and the medicinal chemistry guide for small-scale chemistry retains its technological and life cycle approach. The Sanofi guide is derived from exposure limits rather than the numerical scoring scales used by GSK.
The Sanofi guide includes an extra category for solvents that are forbidden within the company, and offers more information as to why each solvent is categorised the way it is by separating safety, health, and environmental impact issues. For example, acetone is recommended even though it has some safety issues relating to its flammability. Ethylene glycol is considered to be problematic because of its toxicity, but N,N-dimethyl formamide (DMF) has more severe chronic toxicity and so is in a worse category.
The GSK solvent selection guide has a large number of categories. The level of information that is provided allows for a thorough analysis, at the expense of the simplicity of other guides. The environmental impact of producing the solvents (derived from life cycle analysis, LCA) and waste treatment was included.
The pharmaceutical and academic collaboration CHEM21 created this solvent selection solvent selection guide.
In 2015, an attempt was made to create a unified solvent selection guide with input from different pharmaceutical industries within the ‘CHEM21’ research project consortium. The methodology is mostly limited to the interpretation of hazard statements, making it a logical extension to risk assessments and replicable so that any user can add new solvents.
The CHEM21 solvent selection guide uses the three safety, health, and environment categories of the equivalent Sanofi guide, but with a numerical score as developed by GSK (although the scoring values are reversed). The statements giving the overall assessment of each solvent are determined by the scores in the safety, health, and environment categories. Note that some of these statements were changed after consultation, which is telling of the subjective and heavily context-dependent nature of Green Chemistry.
Comparing the assessments of each solvent across the four solvent selection guides, we can conclude that oxygenated solvents (apart from ethers) are greener than ethers and hydrocarbons. Chlorinated solvents and amide solvents (e.g. DMF and NMP) should be avoided where possible.
It is important to acknowledge that this style of solvent selection guide serves as an introduction to the relative hazards posed by common solvents. These guides do not replace an understanding of solvent properties, compatibility, and ultimately suitability for a process. For successful solvent substitution, we also need to know how the solvent influences the reaction or process. Optimising a reaction with the correct choice of solvent reduces waste and energy consumption, both of which are fundamental tenets of Green Chemistry.
A summary of the solvent selection guide headline conclusions. The colours relate to the statement category, either ‘recommended’ in green, ‘problematic’ in yellow, ‘substitute’ in red, or ‘banned’ in black (Sanofi only).
Additional reading
Additional reading
References
References
Green chemistry tools to influence a medicinal chemistry and research chemistry based organisation: Alfonsi, K., Colberg, J., Dunn, P.J., Fevig, T., Jennings, S., Johnson, T.A., Kleine, P.H., Knight, C., Nagy, M.A., Perry D.A., and Stefaniak, M., Green Chem. 2008, 10, 31-36.
Updating and further expanding GSK's solvent sustainability guide: Alder, C.M., Hayler, J.D., Henderson, R.K., Redman, A.M., Shukla, L., Shuster, L.E. and Sneddon, H.F., Green Chem. 2016, 18, 3879-3890.
Sanofi’s solvent selection guide: a step toward more sustainable processes: Prat, D., Pardigon, O., Flemming, H.-W., Letestu, S., Ducandas, V., Isnard, P., Guntrum, E., Senac, T, Ruisseau, S., Cruciani, P. and Hosek, P., Org. Process Res. Dev. 2013, 17, 1517-1525.
CHEM21 selection guide of classical- and less classical-solvents: Prat, D., Wells, A., Hayler, J., Sneddon, H., McElroy, C.R., Abou-Shehada, S., and Dunn, P.J., Green Chem. 2016, 18, 288-296.
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