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Solvent selection guidance
Solvent selection guidance
Solvent use is a crucial aspect of Green Chemistry, as recognised by Green Chemistry Principle #5: 'The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and, innocuous when used'. The majority of waste associated with the manufacturing of pharmaceuticals is solvent, and these solvents possess a variety of hazards, some quite severe. Many solvents are flammable and some cause cancer and other health issues. Organic solvents are typically classified as volatile organic compounds (VOCs), creating smog, and some are exo-toxic, polluting waterways. The most common solvents in the pharmaceutical industry are listed below. In addition, specialty solvents such as N,N-dimethyl formamide (DMF), N.N-dimethyl acetamide, N-methyl pyrrolidone, and sulpholane are also required in niche but crucial uses, but are also reprotoxic (meaning harmful to the unborn child).
Air pollution
Air pollution
Across Europe, VOC emissions have generally decreased, mostly due to interventions in the transport sector. An interactive dataset is available. More specific VOC emissions data is available for the UK (see below). Although the overall (non-methane) VOC emissions in the UK have fallen considerably in recent years, the contribution to VOC emissions by solvents has remained fairly stable in the past 2 decades. The majority of UK solvent VOC emissions are caused by domestic products (aerosols, cleaning products). Production of chemicals (including pharmaceuticals) creates relatively low volumes of VOC emissions, but more attention must be dedicated to this issue to avoid complacency as we target further reductions to emissions.
Other considerations
Other considerations
Solvents are responsible for 80% of the waste, 60% of energy use and 50% of post-treatment GHG emissions in a typical pharmaceutical manufacturing process (Jiménez-González et al., 2004).
Reaction solvents are not intentionally incorporated into the final manufactured products, and so they are in some regards optional, or ‘auxiliary’, in chemical processes. However, quite often solids will not react without being dissolved in a solvent, and concentrated liquid reactants tend to react too rapidly, even explosively. The easiest compromise is to minimise the quantity, and the hazards of, the solvents we use. This may lead to the development of aqueous reactions or solvent-free reactions, as explored later.
The choice of solvent is traditionally determined by performance, be it solubility or other desirable traits. Presently, more emphasis is gradually being placed on the health risk, safety, and environmental impact of solvents, and this thinking is being embedded into solvent selection. This must be initiated at the earliest possible stages of drug discovery to avoid getting locked into synthetic strategies that rely on the most hazardous solvents. If safer, greener solvents were routinely used in the pharmaceutical industry, the large investments required for safe solvent storage, ventilation, and protective equipment could be reduced. Waste disposal would also be simplified with less burden on the environment. Using less solvent would also achieve some of these aims.
Additional reading
Additional reading
References
References
Air pollutant emissions data viewer: European Environment Agency, 2024.
Expanding GSK’s solvent selection guide—application of life cycle assessment to enhance solvent selections: Jiménez-González, C., Curzons, A.D., Constable, D.J.C. and Cunningham, V.L., Clean Techn. Environ. Policy 2004, 7, 42-50.
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