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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 kinetics, and so high solubility may become more important.
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.
In the following sections, the implications of using so much solvent, approaches to solvent selection for optimised safety and sustainability, and new types of solvents that could revolutionise the chemistry of the pharmaceutical industry are discussed.
References
References
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.
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