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Solvents use in the pharmaceutical industry
Solvents use in the pharmaceutical industry
Solvents are chemical fluids used to dissolve and mix other substances. The main uses of solvents are cleaning, formulation, reaction chemistry and separations. In each case, dissolving other substances through the use of a solvent creates a solution.
Cleaning
Home cleaning products are often a surfactant solution in water, but industrially, oils and greases are regularly removed from surfaces with hydrocarbon solvents or chlorinated solvents. Some domestic cleaning solvents are also based on hydrocarbon solvents when water-based cleaning products are insufficient (e.g. oven cleaners, or white spirit for DIY and maintenance purposes). The cleaning of chemistry glassware or reactors can be conducted with either water or organic solvents depending on the circumstances. The residues in a chemical reactor may be far more diverse in character than the typical stains you would encounter at home, and this will determine the cleaning method.
Formulation
Formulation solvents are required to dissolve the active ingredients in a product, usually to make a homogeneous solution or dispersion. Additionally, the solvent may impart other useful properties such as viscosity or surface tension. The majority of solvents are used to make paints and other types of coatings. These formulations require that the coating polymer is uniformly mixed with additives such as pigments, and the solvent must be volatile enough to evaporate and create a dry, uniform coating. If the solubility of the active ingredients is low, they will settle out of solution as a precipitate. A low-viscosity or slow-drying solvent may lead to poor coating characteristics, especially on vertical surfaces. These factors need to be considered when formulating a product.
Reaction
A reaction solvent is usually required to dissolve the other reaction components, but additionally, the solvent influences which reactions occur and how fast. A significant body of work has arisen to aid with green solvent selection, particularly for the synthesis of active pharmaceutical ingredients (APIs) (Clark et al., 2016).
Separation
Extraction of natural ingredients and the isolation of the reaction products is also solvent dependent, be it through liquid extraction, crystallisation or chromatography. In a multi-step synthesis of a chemical product, the solvent will usually be different in each reaction (and in each separation process), and cumulatively a lot of solvent is required compared to the amount of products that is made.
The second largest user of solvents in Europe (after coatings) is the pharmaceutical industry (ESIG, 2023). The main use of solvents in this sector is for reaction chemistry. Reactors will be cleaned with extra solvent if necessary, and some manufactured medicines require formulation, although in terms of organic solvent formulations, this is more common for agrochemicals than it is for pharmaceuticals.
Solvent use in the pharmaceutical industry
Solvent use in the pharmaceutical industry
Issues surrounding solvent use at different stages in the production of APIs.
Discovery chemistry: Few barriers to solvent selection
Discovery chemistry: Few barriers to solvent selection
In the development of new active pharmaceutical ingredients (APIs), the first use of solvents is to facilitate small-scale reactions to produce large catalogues of novel bioactive molecules for testing (maybe just milligrams of each compound). The structure of these molecules is refined with computational and biological analyses to generate lead drug candidates. This requires a huge number of reactions, and the chemistry is optimised for speed and efficiency. This means the choice of solvents is not dictated by environmental impact. Drug manufacturing is performed to a high level of safety and chemical control so that toxic solvents are routinely used, and residual solvent removed from the final products, without serious consequence. The cumulative quantity of solvent used is extremely high and not recycled. Instead, the waste solvent is sent for incineration.
Process development: More technical requirements introduced
Process development: More technical requirements introduced
Any promising drug targets will then be produced at a larger scale (grams, rather than milligrams) for more extensive testing, and solvent use begins to be determined by safety, health hazards, and other regulatory restrictions, not just reaction compatibility. At larger scales, reactions may be optimised to use less solvent per mass of product, this improves heat transfer and reaction speed, but there will be a limit to how soluble the reactants are which must be taken into account.
Pilot plant: Safety is a priority
Pilot plant: Safety is a priority
To generate significant quantities (kilograms) of new potential medicines for advanced testing, pilot plant operations are needed. At this stage, the final choice of solvents for reaction and purification (and sometimes formulation) is beginning to be finalised with regulatory controls in mind. As the quantity of solvent increases, the safety hazards (e.g. flammability) have greater consequences.
Manufacturing: Difficult to change but risks are managed
Manufacturing: Difficult to change but risks are managed
Once the final manufacturing route is decided, the protocol is submitted to the regulator and is difficult to change. Safer, more sustainable solvents should be introduced earlier in the drug development pipeline while the fundamental optimisation is still ongoing. The reason this is not often a priority is because the procedures used in drug manufacturing are precisely controlled and exposure to workers is extremely low. Ventilation, protective equipment, and other protective measures are operated with the highest adherence to safety. New regulations to reduce the risks associated with toxic solvents have introduced stricter exposure limits in recent years, but the pharmaceutical industry has been operating below those thresholds anyway and so they can continue to use these solvents.
Each step of an API's development requires high quantities of solvent, be it cumulatively from hundreds or thousands of small reactions, or from the manufacturing plant of a blockbuster drug. This is worsened by purification solvents (e.g. for recrystallisation) and reactor cleaning, which are often much greater in volume than the solvent needed for the reaction. In one example of a 1 tonne synthesis of a drug molecule, 84 tonnes of solvent waste was produced (Abou-Shehada et al., 2016).
Relative proportions of waste (organic solvents, water, and reagents) in the synthesis of 1 tonne of a lymphocyte antigen inhibitor. Reprinted from Chemical Engineering and Processing: Process Intensification, 99, Abou-Shehada et al., Tunable solvents: Shades of green, 88-96, Copyright (2016), with permission from Elsevier.
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.
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 this guide 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. The number of solvents has been reduced to 20 in the version below to be more concise.
The hierarchy represented in the Pfizer solvent selection guide was strongly determined by the human health hazards posed by the solvents. Generally, solvents containing oxygen atoms are preferred, with hydrocarbons (only carbon and hydrogen) presenting greater health and safety issues. Extremely flammable and potentially explosive ethers, carcinogens (benzene and chlorine-containing solvents) and solvents with reprotoxic hazards are found in the least desirable ‘red’ column.
Additional reading
Additional reading
References
References
Solvent use in Europe by industry: ESIG, 2023.
Renewable solvent selection in medicinal chemistry: Clark, J.H., Hunt, A.J., Moity, L. and Sherwood, J. in Green and Sustainable Medicinal Chemistry : Methods, Tools and Strategies for the 21st Century Pharmaceutical Industry, 2016, RSC, pp. 28-40.
Tunable solvents: Shades of green: Abou-Shehada, S., Clark, J.H., Paggiola, G. and Sherwood, J. Chemical Engineering and Processing: Process Intensification 2016, 99, 88-96.
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.
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