Life cycle assessment of active pharmaceutical ingredient production: A Case study of (–)–chloramphenicol

Abstract: Reducing the environmental impacts associated with active pharmaceutical ingredient (API) synthesis is essential for improving sustainability within the pharmaceutical sector. This study uses chloramphenicol—whose annual production reaches several thousand metric tons—as a representative case to compare two fundamentally different manufacturing approaches. An 11 step traditional route from benzaldehyde (Path A) and a modern 5–step route from 4–nitrobenzaldehyde featuring asymmetric organocatalysis (Path B) were evaluated using green chemistry metrics and Life Cycle Assessment (LCA). Laboratory scale data were combined with scale–up frameworks enhanced by machine learning predictions of key thermodynamic properties to accurately estimate process energy demands. Path A showed its primary hotspot in the catalytic hydrogenation of the aromatic nitro group, while impacts in Path B were dominated by organocatalyst production. Transitioning from laboratory to industrial scale reduced impacts by 18–80% for the classical route and 52–92% for the modern route. At industrial scale, Path B demonstrated superior environmental performance in most categories, surpassing Path A by 20–95%. Monte Carlo uncertainty analysis supported the reliability of these results. These findings underscore the critical influence of synthetic strategy and scale–up on the environmental footprint of API manufacture, and highlight the potential of contemporary catalytic methods to enable cleaner pharmaceutical processes.