Safer solvent use in the pharmaceutical industry

Aqueous reactions

Water is sometimes referred to as the universal solvent given its preponderance over any other liquid or solvent 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, and later, the synthetic organic solvents that remain commonplace today. It is for this reason that water is rarely suitable as a true solvent for synthetic organic chemistry, one in which all the reactants are dissolved.  

Some classic studies showed that water may not hinder a reaction, even if solubility is poor, and in the case of cycloadditions, the poor solubility of reactants in water is actually beneficial. This phenomenon is sometimes called ‘on-water’ chemistry. Other classical methodologies that involve water without it being the primary solvent include biphasic reactions, of which, the Williamson ether synthesis is maybe the most useful. However, for the most part water as a reaction solvent did not catch on, and organic petrochemical solvents prevailed.  

At the advent of Green Chemistry, interest in using water as a solvent returned. Water has no health hazards, is naturally abundant, and non-flammable. Even some organometallic chemistry was determined to benefit from water being used as the solvent. Grignard reagents can be replaced by indium species for allylations in water with the added benefit of reversing the product selectivity. And so more examples of water-based chemistry were developed, but overall, water remained an obscure choice of reaction solvent. There has remained some suspicion over the general applicability of water as a solvent, and the energy-intensive purification of water and risk of environmental pollution has created concerns that water is in fact not really a green solvent afterall.

Despite these earlier issues, the use of water as a reaction solvent 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 active pharmaceutical ingredients (APIs).