Green methods and techniques

Alternative solvents

Despite the fifth principle of Green Chemistry stating 'the use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and, innocuous when used', arguably no field of research has benefited more from Green Chemistry than solvents. Instead of removing solvents from products and processes, scientists were spurred on to create benign solvents that avoided the environmental health and safety issues generally associated with solvents. We now have a plethora of new solvents with intriguing properties that can be used to make chemistry safer and more sustainable. Read on for further information on bio-based solvents, ionic liquids, water, carbon dioxide, and solvent-free reactions and how they might be used to make active pharmaceutical ingredients (APIs).

Bio-based solvents

Bio-based solvents (those derived from biomass) are varied in their sources, but can broadly be classified as either made by sugar fermentation, heating or chemical transformation of sugars, essential oil-based (terpenes), or vegetable oil-based (Clark et al., 2016).    

A biomass feedstock may be directly transformed into a solvent, such as bio-ethanol by the fermentation of sugars, or limonene by the steam distillation of citrus fruit peels. Some bio-based solvents are obtained after further chemical transformations. There are bio-based solvents that have familiar structures and known petrochemical equivalents (ethanol and acetone for example). These bio-based solvents can be introduced into products and processes as direct replacements if their biogenic origin is advantageous (e.g. for labelling or regulatory purposes, or for sustainability reasons). There are many other bio-based solvents with unusual chemical structures that are not easily produced from crude oil. These so-called ‘neoteric’ solvents impart unique combinations of properties that can be advantageous if understood and deployed correctly.  

Ionic liquids

Ionic liquids are a fascinating category of solvents (Hallett and Welton, 2011). Most, maybe all the ionic compounds you will be familiar with are solids with very high melting points. Sodium chloride (table salt) has a melting point of 801 °C, and the psychiatric medicine lithium carbonate melts at 723 °C. However, it is possible to make salts with low melting points if they are discouraged from crystallising. This can be achieved by choosing ions that are oddly shaped or that have weak charges.

Currently, ionic liquids are not solvents for pharmaceutical synthesis, at least not on a manufacturing scale, but there is interest in developing ionic liquid-based drug-delivery systems. In one example, anti-cancer chemotherapy drug Paclitaxel can be formulated for transdermal delivery (absorption through the skin) with an ionic liquid. This replaces intravenous injection which requires stabilising chemicals that can cause numerous side effects. 

Water

Water is sometimes referred to as the universal solvent given its preponderance over any other liquid in nature. However, this is a misnomer, with many a chemist quick to bemoan the poor solubility of reactants in water, and dismiss it as a viable option for a reaction solvent. At some point early in the development of modern organic chemistry we diverged from the processes of nature and prioritised lipophilic substances that only dissolve in oils. Later, chemists devised a variety of synthetic organic solvents that remain commonplace today.

The use of water as a reaction solvent to make APIs has been re-energised by the introduction of designer surfactants that facilitate chemical reactions and the reuse of the water. The research of Bruce Lipshutz has shown that many pharmaceutically-relevant reactions are highly efficient within the micelles of the TPGS-750-M surfactant (and other recently developed surfactants) (Lipshutz et al., 2011). This work has escalated to process chemistry scale in pharmaceutical company Novartis, where Fabrice Gallou has pioneered the use of aqueous surfactant systems in the synthesis of actual APIs. 

Supercritical fluids

We are taught in school that there are three states of matter: solid, liquid and gas. This is sufficient to satisfy most people, even most scientists. But substances cannot always be classified so conveniently as this, for under extreme conditions matter can behave in unfamiliar ways. For instance, neon lighting works by creating plasma, which is neither solid, liquid or gas. Less well known is the supercritical fluid state of matter. Substances have a critical point, which (much like a melting point or boiling point) is defined by a specific temperature and pressure. At the critical point (or any temperature and pressure above it) the distinction between liquid and gas is lost as the substance becomes a supercritical fluid. The properties of a supercritical fluid are between that of its liquid and gas forms.  improve

For most substances, the critical point is not realistically achievable in a laboratory setting, only being observed at very high temperature and pressure. However, carbon dioxide becomes a supercritical fluid at about 31 °C and 73 atmospheres of pressure. These conditions can easily be maintained by specialist apparatus, and allow supercritical carbon dioxide (scCO2) to be used as a solvent. Perhaps the most beneficial application of scCO2 is extraction. The isolation of bioactive compounds from harvested plants is possible with scCO2. The conditions can be tuned by varying the temperature or pressure, and sometimes a co-solvent (often methanol) is added to improve solubility. Once the extraction is complete, releasing the pressure removes all solvent residue (for carbon dioxide returns to being a gas). This means food-grade and pharmaceutical-grade extracts can be prepared. The carbon dioxide can be recycled within the apparatus, and sourced from the brewing industry or other sources of CO2 waste.  

Solvent-free

The primary reason for using a solvent in organic synthesis is to dissolve the reaction components so that they can combine and react. In some instances, no additional solvent is required to conduct a reaction. This may be because one or more of the reactants is a liquid. Alternatively, friction may cause low melting solids to melt and provide localised fluid for reaction sites. Otherwise, moisture (from humid air) may lubricate the solid surfaces and facilitate a reaction. And of course there are a few rare (and usually inorganic) reactions that appear to occur between solids without liquid (initially) present.  

The art of solvent-free chemistry between solid reactants is generally called mechanochemistry. The name invokes the grinding or other application of force that is exerted upon the reactants instead of stirring a solution. There are a few ways to combine solid reactants. A mortar and pestle is a simple way to prepare small samples, but for larger experiments a ball mill can be used. For industrially relevant syntheses, an extruder is capable of the mixing necessary for solvent-free flow chemistry at large scales.  

The benefits of solvent-free reactions include the reduction of waste and the removal of hazardous solvents. The environmental impact of the synthesis of nitrofurantoin (an antibiotic) is highly dependent on whether the process is solution-phase or mechanochemical. Using a twin-screw extruder in this process had massive benefits on the quantity of waste produced and the amount of greenhouse gas emissions released.  

So why do we have a lingering dependence on solvents in synthetic chemistry? The use of a solvent can have important safety benefits, even if it is flammable. Dilution in a solvent avoids hot-spots in exothermic reactions that would otherwise lead to runaway reactions and the possibility of an explosion. At large scales, solutions can be pumped into reactors but solids must be transported to where they need to be  dispensed, which can add some time and manual effort to the process. However, it is probably the initial investment in new infrastructure, and the redundancy of much of the existing manufacturing infrastructure, that poses the greatest barrier to the implementation of solvent-free reactions. Ultimately, much more solvent is used in purification and cleaning than in the actual reactions, and so mechanochemistry does not eliminate the need for solvents. But what it does do is (potentially) remove the requirement for some of the most toxic solvents, those being the ones that are typically used as reaction solvents. For this reason, mechanochemistry is growing in popularity.