Safer solvent use in the pharmaceutical industry

Solvent-free reactions

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 (the same could be said of flow chemistry and other specialised techniques). Unfamiliarity with mechanochemistry processes across the drug development pipeline may also hinder its introduction. 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 (i.e. dipolar aprotic solvents). For this reason, mechanochemistry is growing in popularity.