Safer solvent use in the pharmaceutical industry

Criteria for solvent selection

If we are motivated to replace the most hazardous solvents with benign alternatives, how do we go about optimising solvent selection? In the early days of organic chemistry, the availability of suitable liquids was limited. The success of the petrochemical industry has since created innumerable solvents of vastly different properties (and hazards). One way to optimise the solvent for a reaction is to trial a selection of different solvents and choose the one that led to the highest yield. This is still common practice today, and the scientific literature discussing new synthetic methodologies routinely features data tables of unsystematically chosen solvents and the corresponding yield. This approach has limited benefits. It is better to understand the fundamental requirements of the reaction and choose an appropriate solvent that has complementary properties. If several solvents are found that adequately perform their intended task, the final selection should consider the least hazardous and least impactful option.

To begin with, we should explore the suitability of solvents based on their physical properties. A solvent with no or few hazards is of little use if it cannot dissolve the reactants.

Use the solvent selector below to refine a list of 20 solvents to only those meeting the criteria that you specify

What the criteria actually are depends on how the solvent will be used. You can change the acceptable property ranges simply to explore the data, or if you have an application in mind you can optimise the solvent list to only show suitable candidates.  

Physical property requirements

• Liquid at operational temperatures (except for distillation)

  1. 1. • The melting point shall be below the reaction temperature. 

        • The boiling point shall be above the reaction temperature. Reactions are often conducted slightly below reflux temperature to save energy. A maximum boiling point may also be relevant for solvent recovery: solvents with high boiling points require more energy to distil and recover (Prat et al., 2016). 

• Density 

• The density of the solvent has an impact on the design of separations, especially extractions involving water. Solvents denser than water can be tapped off directly, which is very advantageous when operating at large scales. 

• Viscosity 

• Most common solvents have similar viscosity values and this property is often overlooked as a variable in solvent selection for organic synthesis. Higher viscosity, present in multi-functional polar solvents such as diols, can affect mass transfer in reactions, slow the pumping of large volumes of solvent through chemical plants, or the pumping of small volumes of solvent through analytical apparatus (or flow microreactors), and increase reactor stirring energy (although this last issue is usually a minor contributor to the total energy usage of a process compared to heating). 

• Surface tension 

• Surface tension is important for biphasic systems and interactions with surfaces. This may affect the activity of heterogeneous catalysts but polarity is usually a more significant variable in this regard. 

• Dissolve reactants and auxiliaries as required. Facilitates necessary separations (e.g. extraction, crystallisation) 

• Polarity scales can be used to match solvents to solutes. 

• Above, the Hansen Solubility Parameters were used, which correlate to solubility. The parameters of solvent must be similar to those of the reactants to form a solution. 

• Miscibility with water may affect isolation of the product (e.g. during an aqueous-organic biphasic separation). 

Safety hazards

• Flash point and explosive vapour range 

  • • Organic liquids will often ignite in the present of a spark. This temperature-dependent property is known as the flash point. Solvents are routinely used at temperatures above the flash point but these environments must be free of any sources of ignition. It is preferable for safety reasons that the flash point is above room temperature, but to completely avoid classification as a flammable liquid, the flash point of a solvent must be above 60 °C. 

• Auto flammability 

• Some way above the flash point, many solvents can spontaneously ignite without a source of ignition. This autoignition temperature is specific to each solvent, and must be above the anticipated operating temperature of all components potentially exposed to the solvent during its use.  

• Electrical conductivity (not in selector) 

• Low-polarity solvents are poor conductors of electricity. This can cause static electric charge to build up, only to be discharged and create a spark, subsequently igniting the solvent. Hydrocarbons and some ethers have dangerously low electrical conductivity and precautions are required, especially when pumping large quantities of solvents in a manufacturing plant. 

Health hazards

Health hazards are included in the solvent selection guides that are covered later.

• Acute toxicity 

• Solvents possess a myriad of hazards that can cause immediate minor health complaints or longer term health issues. However, solvents are not usually poisonous or acutely toxic in the conventional sense like cyanide is for example. Nevertheless, short term exposure to solvents is known to cause immediate death in rare circumstances, as a result of solvent-abuse, or accidents involving paint strippers in enclosed, poorly-ventilated spaces. 

• Chronic toxicity and CMR 

• Some of the most serious health issues caused by solvents are categorised as chronic toxicity. This means repeated, long-term exposure to these solvents results in medical conditions resulting in permanent health deterioration or death. Most notably these are cancer, reprotoxic effects (harm to the unborn child), and mutagenicity (damage to DNA). Several chlorinated solvents may cause cancer, and amide solvents may cause reprotoxic effects. 

• Irritation and corrosivity 

• The most commonly encountered health issues caused by solvents are skin, respiratory, and eye irritation, and even eye damage in some cases. Some solvents may cause allergic reactions or drowsiness. Appropriate personal protective equipment and sufficient ventilation is required to avoid these effects. 

Environmental hazards

Environmental hazards are included in the solvent selection guides that are covered later. Typical categories include the following:

• Aquatic toxicity 

• Hydrocarbon solvents can be toxic to the aquatic environment. Lipophilic substances, including hydrocarbon solvents, can also bioaccumulate. 

• VOC/atmospheric chemistry 

• Most solvents are categorised as volatile organic compounds (VOCs). Once solvent vapour is released, it has the propensity to form aerosols which lead to poor air quality at low levels. Solvents that cause stratospheric ozone depletion were once common but now are banned. 

• Environmental impact 

• Making, using, and disposing of chemicals, including solvents, has an environmental impact. We frequently use climate change impact, as measured through emissions of carbon dioxide equivalents, as a catch-all indicator of environmental impact. Climate change is certainly amongst the most important environmental impacts to measure and minimise, but water use and other forms of pollution are also significant. Solvents tend to be similar in structure to the precursor feedstock (crude oil, sugar, etc.) and are not synthetically complex. Therefore the environmental impact of solvent production (per mass) is much less than that of an active pharmaceutical ingredient (API). Still, it is important to recognise that the large volumes of solvents that are typically used in chemical processes, and their subsequent heating and eventual disposal, create a considerable cumulative environmental impact.