Green Chemistry Approaches for the Synthesis of Pharmaceutical Intermediates and Active Drug Molecules: A Comprehensive Review

Abstract

Abstract The pharmaceutical manufacturing sector has historically generated significant chemical waste, characterized by high Environmental factors (E factor 25–100 kg waste/kg API) and elevated Process Mass Intensity (PMI). Driven by stringent environmental regulations, economic imperatives, and sustainability mandates, integrating green chemistry principles into the synthesis of pharmaceutical intermediates and active pharmaceutical ingredients (APIs) has become essential. This comprehensive review delivers a critical analysis of transformative green synthetic methodologies, evaluating their operational mechanisms, efficiency metrics, and industrial applicability. We systematically examine: (i) biocatalytic cascades for stereoselective transformations, (ii) earth-abundant transition-metal and heterogeneous nanocatalysis replacing toxic noble metals, (iii) neoteric bio-derived reaction media (Cyrene, 2-MeTHF, and supercritical CO2), (iv) non-conventional energy modalities (microwave irradiation and mechanochemistry), (v) continuous-flow microreactor processing for intensified transport phenomena, and (vi) step-economical one-pot multicomponent cascades. Through quantitative benchmarking against commercial manufacturing routes (sitagliptin, pregabalin, sertraline, and sildenafil), we demonstrate that modern green protocols achieve 75–85% PMI reductions, complete elimination of hazardous chlorinated solvents, and marked energy savings. Finally, this review outlines critical translational bottlenecks, including catalyst recyclability, regulatory compliance under ICH guidelines, and technoeconomic considerations, providing an authoritative roadmap for next generation sustainable drug manufacturing. 

Keywords— Green Chemistry; Pharmaceutical Intermediates; Active Pharmaceutical Ingredients (APIs); Process Mass Intensity (PMI); Biocatalysis; Continuous-Flow Synthesis; Neoteric Green Solvents; Atom Economy.