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Solvents
Solvents
The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and, innocuous when used.
Although we think of chemical reactions as being (usually) 2 reactants combining to make a product, it is common to add other substances to facilitate the reaction. Solvents are the main example of a so-called 'auxiliary' substance, meaning they do not directly participate in the reaction. Solvents are chemical fluids used to dissolve and mix other substances. They are unreactive and are not incorporated into the chemical structure of reaction products. Because they are not integral to the reaction, Green Chemistry suggests we should minimise the use of solvents as they contribute a lot to wastestreams. When they must be used, they should be non-hazardous.
The obvious example of a solvent is water, which dissolves salt or sugar. The main uses of solvents are cleaning, formulation, reaction chemistry and separations. In each case, dissolving other substances (the 'solutes') 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 oil-like solvents (hydrocarbons). 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 solution or a dispersion. The majority of solvents are used to make paints and other types of coatings. These formulations require that the ingredients are uniformly mixed 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 reactants and 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), which is discussed below.
Separation
Solvents are used to extract substances. Once example is caffeine extraction from coffee beans to make decaffeinated coffee. Certain oils from plants are also extracted by solvents. It is common in chemical reactions to extract and purify the product using solvents.
The largest user of solvents in Europe is the paints and coatings sector. Then it is the pharmaceutical industry. The use of solvents in pharmaceutical manufacturing is described subsequently. Other important uses of solvents include adhesives (glues) and inks. The manufacture of ingredients for cosmetics and home care products also uses solvents even though they do not appear in the final product. Industrial cleaning is the majority of the remaining solvent use.
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 chemicals for testing (maybe just milligrams of each compound). 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.
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 procedure is submitted to the regulator and is difficult to change thereafter. 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.
Solvent selection guides
Solvent selection guides
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 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 (containing only carbon and hydrogen) presenting greater health and safety issues. Extremely flammable and potentially explosive solvents, as well as carcinogens (e.g. benzene) and solvents that harm child development are found in the least desirable ‘red’ column. Please note that the majority of chemical reactions are not suited to the 'green' solvents (water, ethanol, acetone, etc.). Maybe the reactants do not dissolve, or they could react with the solvent molecules instead of how they were intended to react. This means that chemists must be knowledgeable about solvent properties to use a solvent selection guide effectively, prioritising safer solvents and using them wherever possible.
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