Gallou, Fabrice (2025) Solvent Sustainability in Drug Discovery: Where Are We Now, and How Can We Improve? Journal of medicinal chemistry.

Abstract

Solvent selection plays a critical role in promoting synthetic chemistry reactions. Metrics from member companies of the ACS Green Chemistry Institute Pharmaceutical Roundtable (ACSGCIPR) have led to an estimate that solvents utilized contribute to 80-90% in terms of the mass of waste streams and 75-80% of the overall life cycle impact of pharmaceutical manufacturing processes. While the bulk of the solvents are typically utilized in development and manufacturing, it has been estimated that up to 3.5 million kilograms of waste are generated from chemistry associated with drug discovery through preclinical studies with the sheer number of chemical reactions performed off-setting the relatively small scale that each reaction is run on. Herein, the medicinal chemistry team of the ACS-GCIPR have performed a systematic study of the most common transformations (over 400k reactions) utilized in the drug discovery phase examining the solvents that these reactions are performed in. Specifically, we have focused on the use of several solvents, which are undesirable based on their hazardous nature and/or known adverse effects on human health. The data has shown that in over 40% of the cases, the reactions profiled are conducted in what is considered to be an undesirable solvent with the use of methylene chloride (DCM) and N,N-dimethylformamide (DMF) being particularly prevalent (notably the most utilized transformation, amide bond formation, is carried out ~ 70% of the time in these solvents). In addition, the methods/solvents used in the workup/purification phases of these reactions was also studied with again a ca. 40% incidence of non-sustainable solvent use being recorded (most notably DCM in both extractions and chromatography). While numerous resources such as solvent guides/selection tools have been developed, and technologies such as High-Throughput Experimentation (HTE) enable solvent screening on sub-mg scales, the continued use of undesirable solvents based on legacy habits in drug discovery campaigns represents a cause for concern from a sustainability perspective. This can also place a significant onus specifically in terms of time pressure on development organizations in having to re-develop chemistry in alternative reaction media when a specific compound progresses towards the clinic.

Item Type:	Article
Date Deposited:	20 Dec 2025 00:45
Last Modified:	20 Dec 2025 00:45
URI:	https://oak.novartis.com/id/eprint/57428