A practical process for the preparation of naldemedine tosylate hydrate was developed from naltrexone hydrochloride. The key β-keto ester intermediate was prepared through an O-to-C carbonate transfer using diethyl pyrocarbonate. The subsequent aminolysis with the oxadiazole-containing amine was accomplished by simple heating of a neat mixture under reduced pressure. Final debenzylation, tosylate salt formation, and hydrate formation furnished naldemedine tosylate hydrate on a 300 g scale in four steps and 52% overall yield with >99.5% purity.
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.
Abstract Organic solvents contribute more than 80% of total process mass intensity (PMI) in pharmaceutical manufacturing. Although organic solvent nanofiltration (OSN) diafiltration processes can improve sustainability, achieving high product yield typically requires large solvent volume to operate. Here, we present a digital-assisted workflow, built on the OSN Designer framework, that enables rapid screening of OSN process configurations to identify architectures that minimize solvent consumption while maintaining API recovery. The framework integrates a solution-diffusion transport model, film theory for concentration polarization, and non-steady-state mass balances, calibrated from crossflow experiments with compound A on the Borsig oNF-3 membrane in 2-methyltetrahydrofuran. Validated with average concordance correlation coefficient (ccc) of 0.72 across steady-state and dynamic operating regimes, the model was applied without recalibration to evaluate four process configurations. A two-stage membrane cascade with closed-loop permeate recycling achieved a process mass intensity (PMI) of 7.76─a 92.4% reduction relative to the single-stage constant-volume diafiltration baseline (PMI 101.5). The formalized four-phase workflow reduces experimental effort to approximately 3 weeks from more than 6–8 months and is directly transferable to other pharmaceutical OSN systems.
Abstract Cold plasma generates multiple physical and chemical phenomena that can promote crystal nucleation. However, its use for crystallization under process-relevant conditions remains unexplored. In this work, cold plasma was evaluated as a novel strategy to initiate the crystallization of paracetamol, a model pharmaceutical active ingredient (API), in acetonitrile within a stirred tank reactor. An in-house probe was designed to generate nanosecond repetitively pulsed (NRP) discharges inside nitrogen bubbles injected into the solution. Above a supersaturation threshold within the metastable zone, cold plasma treatment significantly decreased the induction time and improved its reproducibility. Enhancing the number of plasma-treated bubbles further reduced the induction time and increased the desupersaturation rate. Surprisingly, no significant effect on the final particle size distribution was observed, probably due to agglomeration. This work demonstrates, for the first time, that cold plasma is an effective tool to trigger the crystallization of API on-demand, automatically, and without seed preparation. It offers a promising nonintrusive alternative to conventional seeding.
Abstract High-throughput experimentation laboratories in industrial settings routinely generate large amounts of data in search of promising hits for further optimization. Due to their importance in C–C and C–heteroatom bond formation, palladium-catalyzed Suzuki–Miyaura and Buchwald–Hartwig reactions are routinely screened. Although significant advances have been made in this space, these screening efforts generally remain a trial-and-error endeavor. In this study, we show that leveraging historical palladium-catalyzed data sets from the high-throughput experimentation group within process chemistry at Pfizer allows the development of machine learning models capable of increasing efficiency by narrowing ligand selection through virtual screening.
