APPLICATION OF GREEN CHEMISTRY AND BIOCONVERSION METHODS FOR SUSTAINABLE PHARMACEUTICAL API AND INTERMEDIATE SYNTHESIS

Abstract

The pharmaceutical industry has historically carried one of the highest environmental (E)factors of any manufacturing sector, generating tens to hundreds of kilograms of waste per kilogram of active pharmaceutical ingredient (API) produced, largely from stoichiometric reagents, protecting-group chemistry, and organic solvent use. Over the past two decades, the twelve principles of green chemistry, together with quantitative greenness metrics such as atom economy, the environmental factor (E-factor) and process mass intensity (PMI), have provided a systematic framework for redesigning API and intermediate synthesis toward greater sustainability. Biocatalysis and microbial bioconversion have emerged as particularly powerful enablers of this redesign, since enzymes and whole-cell biocatalysts operate under mild aqueous conditions, are inherently biodegradable, and offer a level of regio-, chemo- and stereoselectivity that is difficult to match with conventional organic synthesis — an advantage of direct relevance given that most modern APIs are chiral. This review consolidates recent literature on the application of green chemistry principles and bioconversion methods to pharmaceutical API and intermediate manufacture, examining the underlying enzyme classes (transaminases, ketoreductases, halohydrin dehalogenases, cytochrome P450 monooxygenases and nitrilases), whole-cell microbial hydroxylation and bioreduction, and engineeredmicroorganism platforms. Five case studies are analysed in depth: the transaminase catalysed asymmetric synthesis of sitagliptin, the ketoreductase/halohydrin dehalogenase cascade used for the atorvastatin side-chain intermediate, the actinomycete-mediated microbial hydroxylation of compactin (mevastatin) to pravastatin, the engineered-yeast route to semisynthetic artemisinin, and the whole-cell fungal bioreduction of a chiral rivastigmine intermediate by a locally isolated strain of Fusarium graminearum, including the reported effects of pH, temperature, incubation period and agitation speed on conversion and enantiomeric excess. Complementary green technologies — solvent selection guides, continuous-flow biocatalysis, and directed enzyme evolution — are also discussed, alongside the persisting technical, economic and regulatory challenges that continue to limit the wider adoption of bioconversion routes at commercial scale. The review concludes by identifying machine-learning-guided enzyme engineering, synthetic biology and standardised green metrics as the most promising directions for the continued sustainable transformation of pharmaceutical manufacturing.