Continuous-Flow Chemistry at Hundreds of Grams to Hundreds of Kilogram Scale: Recent Advances in Pharmaceutical Intermediates, APIs, and Selected Fine Chemicals

Abstract Continuous-flow chemistry has emerged as a transformative technology for the development and manufacture of active pharmaceutical ingredients (APIs) and advanced pharmaceutical intermediates, offering enhanced process safety, improved heat and mass transfer, reduced reactor inventory, and efficient scale-up. Numerous reviews have highlighted advances in flow chemistry methodology and laboratory-scale applications that demonstrate the potential for future scale-up; however, a critical review of recent examples demonstrating successful implementation at preparative, pilot, and manufacturing scales is of considerable interest to flow enthusiasts, and scientific and industrial communities. This review aims to summarize and critically evaluate advances reported between 2023 and 2025 in the continuous-flow synthesis of pharmaceutical intermediates, API precursors, APIs, and selected fine chemicals, with a particular focus on processes demonstrated at scales ranging from hundreds of grams to hundreds of kilograms. By focusing specifically on manufacturing-relevant published examples, this review highlights key strategies enabling successful industrial implementation and underscores the expanding role of continuous-flow technologies in pharmaceutical and fine chemical production. Representative examples are categorized into: (1) organometallic and cryogenic-sensitive chemistry, (2) hazardous and energetic transformations, (3) integrated continuous manufacturing, (4) catalytic/multiphase/reactor engineering-driven transformations, and (5) flow photochemistry.