Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

The native chemical ligation reaction (NCL) involves reacting a C-terminal peptide thioester with an N-terminal cysteinyl peptide to produce a native peptide bond between the two fragments. This reaction has considerably extended the size of polypeptides and proteins that can be produced by total synthesis and has also numerous applications in bioconjugation, polymer synthesis, material science, and micro-and nanotechnology research. The aim of the present review is to provide a thorough mechanistic overview of NCL and extended methods. The most relevant properties of peptide thioesters, Cys peptides, and common solvents, reagents, additives, and catalysts used for these ligations are presented. Mechanisms, selectivity and reactivity are, whenever possible, discussed through the insights of computational and physical chemistry studies. The inherent limitations of NCL are discussed with insights from the mechanistic standpoint. This review also presents a palette of O,S-, N,S-, or N,Se-acyl shift systems as thioester or selenoester surrogates and discusses the special molecular features that govern reactivity in each case. Finally, the various thiol-based auxiliaries and thiol or selenol amino acid surrogates that have been developed so far are discussed with a special focus on the mechanism of long-range N,S-acyl migrations and selective dechalcogenation reactions.

The ever increasing industrial production of commodity and specialty chemicals inexorably depletes the finite primary fossil resources available on Earth. The forecast of population growth over the next 3 decades is a very strong incentive for the identification of alternative primary resources other than petro-based ones. In contrast with fossil resources, renewable biomass is a virtually inexhaustible reservoir of chemical building blocks. Shifting the current industrial paradigm from almost exclusively petro-based resources to alternative bio-based raw materials requires more than vibrant political messages; it requires a profound revision of the concepts and technologies on which industrial chemical processes rely. Only a small fraction of molecules extracted from biomass bears significant chemical and commercial potentials to be considered as ubiquitous chemical platforms upon which a new, bio-based industry can thrive. Owing to its inherent assets in terms of unique process experience, scalability, and reduced environmental footprint, flow chemistry arguably has a major role to play in this context. This review covers a selection of C2 to C6 bio-based chemical platforms with existing commercial markets including polyols (ethylene glycol, 1,2-propanediol, 1,3-propanediol, glycerol, 1,4-butanediol, xylitol, and sorbitol), furanoids (furfural and 5-hydroxymethyl­furfural) and carboxylic acids (lactic acid, succinic acid, fumaric acid, malic acid, itaconic acid, and levulinic acid). The aim of this review is to illustrate the various aspects of upgrading bio-based platform molecules toward commodity or specialty chemicals using new process concepts that fall under the umbrella of continuous flow technology and that could change the future perspectives of biorefineries.

Micrometric lipid compartmentation at the plasma membrane is disputed. Using live confocal imaging, we found that three unrelated fluorescent sphingomyelin (SM) analogs spontaneously clustered at the outer leaflet into micrometric domains, contrasting with homogeneous labelling by DiIC18 and TMA-DPH. In erythrocytes, these domains were round, randomly distributed, and reversibly coalesced under hypotonicity. BODIPY-SM and -glucosylceramide showed distinct temperature-dependence, in the same ranking as Tm for corresponding natural lipids, indicating phase behaviour. Scanning electron microscopy excluded micrometric surface structural features. In CHO cells, similar surface micrometric patches were produced by either direct BODIPY-SM insertion or intracellular processing from BODIPY-ceramide, ruling out aggregation artefacts. BODIPY-SM surface micrometric patches were refractory to endocytosis block or actin depolymerization and clustered upon cholesterol deprivation, indicating self-clustering at the plasma membrane. BODIPY-SM excimers further suggested clustering in ordered domains. Segregation of BODIPY-SM and -lactosylceramide micrometric domains showed coexistence of distinct phases. Consistent with micrometric domain boundaries, fluorescence recovery after photobleaching (FRAP) revealed restriction of BODIPY-SM lateral diffusion over long-range, but not short-range, contrasting with comparable high mobile fraction of BODIPY-lactosylceramide in both ranges. Controlled perturbations of endogenous SM pool similarly affected BODIPY-SM domain size by confocal imaging and its mobile fraction by FRAP. The latter evidence supports the hypothesis that, as shown for BODIPY-SM, endogenous SM spontaneously clusters at the plasmalemma outer leaflet of living cells into ordered micrometric domains, defined in shape by liquid-phase coexistence and in size by membrane tension and cholesterol. This proposal remains speculative and calls for further investigations.

This review intends to provide the reader with a clear and concise overview of how preparative continuous flow organic chemistry could potentially impact on current important societal challenges. These societal challenges include health/well‐being and sustainable development. Continuous flow chemistry has enabled significant advances for the manufacturing of pharmaceuticals, as well as for biomass valorization toward a biosourced chemical industry. Examples related to pharmaceutical production are herein focused on (a) the implementation of flow chemistry to reduce the occurrence of drug shortages, (b) continuous flow manufacturing of orphan drugs, (c) continuous flow preparation of active pharmaceuticals listed on the WHO list of essential medicines and (d) perspectives for the manufacturing of peptide‐based pharmaceuticals. Examples related to sustainable development are focused on the valorization of biosourced platform molecules. Besides positive impacts on societal challenges, this review also illustrates some of the potentially most threatening perspectives of continuous flow technology within the actual context of terrorism and drug abuse.