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In situ extraction offers an effective way to recover products during microbial production of fatty alcohols, which can be operated in multi-cycle mode. Workup steps may be required to increase the driving force for the extraction or to minimize by-product accumulation. Different workup steps, including intermittent glucose addition, dodecane change, and buffer change, were investigated in this study. We demonstrated that reconfiguration of these workup steps (e.g. rare intermittent workup steps) between bioconversion cycles led to significantly improved productivity and sustainability. The optimized reconfiguration enhanced the yield (0.071 g fatty alcohol per g glucose) while reducing the E-factor to 34.98, which was 120-fold lower than that of the control condition without in situ extraction. The results from this work shed light on the sustainable process development of the fatty alcohol production.

Since the industrial revolution, the rapid growth and development of global industries have depended largely upon the utilization of coal-derived chemicals, and more recently, the utilization of petroleum-based chemicals. These developments have followed a linear economy model (produce, consume, and dispose). As the world is facing a serious threat from the climate change crisis, a more sustainable solution for manufacturing, i.e., circular economy in which waste from the same or different industries can be used as feedstocks or resources for production offers an attractive industrial/business model. In nature, biological systems, i.e., microorganisms routinely use their enzymes and metabolic pathways to convert organic and inorganic wastes to synthesize biochemicals and energy required for their growth. Therefore, an understanding of how selected enzymes convert biobased feedstocks into special (bio)chemicals serves as an important basis from which to build on for applications in biocatalysis, metabolic engineering, and synthetic biology to enable biobased processes that are greener and cleaner for the environment. This review article highlights the current state of knowledge regarding the enzymatic reactions used in converting biobased wastes (lignocellulosic biomass, sugar, phenolic acid, triglyceride, fatty acid, and glycerol) and greenhouse gases (CO2 and CH4) into value-added products and discusses the current progress made in their metabolic engineering. The commercial aspects and life cycle assessment of products from enzymatic and metabolic engineering are also discussed. Continued development in the field of metabolic engineering would offer diversified solutions which are sustainable and renewable for manufacturing valuable chemicals.

Immobilization methods have emerged as feasible solutions for increasing the reusability of biocatalysts and for simplifying their separation from the desired products. Immobilized biocatalysts can directly be applied to a continuous-flow system, such as tubular or packed bed reactors. Such continuous-flow systems with immobilized biocatalysts are promising tools for enhancing the sustainability of bioprocessing. This minireview discusses important considerations for successfully developing biocatalyst-based continuous-flow systems, namely immobilization techniques, mass transfer and reactor design. The key sustainability aspects of these systems are highlighted along with recent examples.

Immunotherapy techniques, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cell therapies and cancer vaccines, have been burgeoning with great success, particularly for specific cancer types. However, side effects with fatal risks, dysfunction in tumor microenvironment and low immune response rates remain the bottlenecks in immunotherapy. Nano metal-organic frameworks (nMOFs), with an accurate structure and a narrow size distribution, are emerging as a solution to these problems. In addition to their function of temporospatial delivery, a large library of their compositions, together with flexibility in chemical interaction and inherent immune efficacy, offers opportunities for various designs of nMOFs for immunotherapy. In this review, we overview state-of-the-art research on nMOFs-based immunotherapies as well as their combination with other therapies. We demonstrate that nMOFs are predominantly customized for vaccine delivery or tumor-microenvironment modulation. Finally, a prospect of nMOFs in cancer immunotherapy will be discussed.

Fatty alcohols are widely used for various applications and are found in products ranging from detergents to cosmetics and cleaning agents Currently, over 3 million tonnes of fatty alcohols are produced per year from bio-based and petroleum-based feedstocks through chemical conversion and synthetic processes However, the environmental impact of current fatty alcohol production processes has become a major concern, and several bioprocesses have emerged as alternative methods for synthesis These biological processes are environmentally friendly due to their metal-free nature, low consumption of energy, and mild reaction conditions This review overviews the current status of fatty alcohol production ? both chemical and biological approaches Our focus is on biological synthesis approaches using biocatalysis and metabolic engineering due to their proven efficacy Potential downstream processing for these bioprocesses is also presented ? 2020 Society of Chemical Industry and John Wiley & Sons, Ltd

Purification of nanoparticles is an important step during preparation of nanoparticles in order to remove impurities and excess ligands. Such excess ligands in the solution may have unfavorable effects on downstream processing such as ligand exchange and shell growth. Most purification methods are batchwise and time-consuming. In this work, we developed an extraction system with a membrane separation to continuously purify nanoparticles. Here, silver nanoparticles (AgNPs) in an aqueous solution were used as a case study. AgNPs were synthesized with sodium dodecyl sulfate (SDS) as capping ligands, and ethyl acetate was used as an extraction solvent to remove the ligands. This novel method showed more 56.73% removal of the ligands while maintaining the morphology of the AgNPs. In addition, the AgNPs from this method was compared with those from conventional methods such as precipitation-redissolution in terms of purity well as catalytic activity. The integration of flow synthesis of AgNPs and continuous-flow purification was also demonstrated.

Nanoparticle capture and elimination by the immune system are great obstacles for drug delivery. Camouflaging nanoparticles with cell membrane represents a promising strategy to communicate and negotiate with the immune system. As a novel class of nanotherapeutics, such biomimetic nanoparticles inherit specific biological functionalities of the source cells (e.g., erythrocytes, immune cells, cancer cells and platelets) in order to evade immune elimination, prolong circulation time, and even target a disease region by virtue of the homing tendency of the cell membrane protein. In this review, we begin with an overview of different cell membranes that can be utilized to create a biointerface on nanoparticles. Subsequently, we elaborate on the state-of-the-art of cell membrane biomimetic nanoparticles for drug delivery. In particular, a summary of data on circulation capacity and targeting efficiency by camouflaged nanoparticles is presented. In addition to cancer therapy, inflammation treatment, as an emerging application of biomimetic nanoparticles, is specifically included. The challenges and outlook of this technology are discussed.

[Image: see text] In-line purification is an important tool for flow chemistry. It enables effective handling of unstable intermediates and integration of multiple synthetic steps. The integrated flow synthesis is useful for drug synthesis and process development in medicinal chemistry. In this article, we overview current states of in-line purification methods. In particular, we focus on four common methods: scavenger column, distillation, nanofiltration, and extraction. Examples of their applications are provided.

Since the industrial revolution, the rapid growth and development of global industries have depended largely upon the utilization of coal-derived chemicals, and more recently, the utilization of petroleum-based chemicals. These developments have followed a linear economy model (produce, consume, and dispose). As the world is facing a serious threat from the climate change crisis, a more sustainable solution for manufacturing, i.e., circular economy in which waste from the same or different industries can be used as feedstocks or resources for production offers an attractive industrial/business model. In nature, biological systems, i.e., microorganisms routinely use their enzymes and metabolic pathways to convert organic and inorganic wastes to synthesize biochemicals and energy required for their growth. Therefore, an understanding of how selected enzymes convert biobased feedstocks into special (bio)chemicals serves as an important basis from which to build on for applications in biocatalysis, metabolic engineering, and synthetic biology to enable biobased processes that are greener and cleaner for the environment. This review article highlights the current state of knowledge regarding the enzymatic reactions used in converting biobased wastes (lignocellulosic biomass, sugar, phenolic acid, triglyceride, fatty acid, and glycerol) and greenhouse gases (CO

Flow chemistry has attracted considerable attention as it offers several advantages over conventional batch chemistry. Several multiphase reactions, including liquid–liquid reactions, are more efficient in flow due to intensified mass transfer. This observation has led to many developments of enabling tools in recent years. In this minireview, an up-to-date overview of such tools will be highlighted. In addition, interesting examples of the integrated continuous-flow process with liquid–liquid reactions will also be presented.

Chemotherapy-induced neutropenia, a symptom of neutrophil depletion, makes cancer patients highly susceptible to invasive fungal infection with substantial morbidity and mortality. To address the cryptococcal brain infection in this condition, this study attempts to arm neutrophils (NEs) with antibiotics to potentiate the antifungal capability of NEs. To allow effective integration, amphotericin B, a potent antibiotic, is assembled with albumin nanoparticles through hydrophobic and hydrogen-bond interactions to form AmB@BSA nanoparticles (A-NPs). The nutrient composition (albumin) and virus-like size (~40 nm) facilitate efficient uptake of A-NPs by NEs to construct the antibiotics-armed NEs. It is demonstrated that the armed NEs can maintain the intrinsic biological functions of NEs, such as cell viability and capacity of migration to an inflammatory site. In a neutropenic mouse model of brain fungal infection, the treatment with the armed NEs allows for preventing fungal invasion more effectively than that with the native NEs, without the apparent systemic toxicity. Such a synergistic anti-infection system maximizes the antifungal effects by taking advantage of NEs and antibiotics. It provides a potential NEs-mediated therapeutic approach for treating fungal infection caused by chemotherapy-induced neutropenia.

The membrane microseparator is a milliliter-scale flow chemistry module that continuously separates a biphasic flow through a PTFE microporous membrane. It has found a wide range of applications in the continuous manufacturing of active pharmaceutical ingredients and fine chemicals, especially those involving multiple synthetic steps. Yet, the accurate prediction and control of the pressure balance needed for successful phase separations is technically challenging. In this article, we present systematic modeling of the operating ranges of the membrane microseparator. We characterize the retention and breakthrough phenomena of the device and develop two new analytic models for retention and breakthrough by taking into consideration the tortuosity factor and pore size distribution. The new models are shown to be better predictors of the experimental results than the original theoretical models based on the simple Young–Laplace equation and the straight-channel Hagen–Poiseuille equation.

Multistage counter-current liquid–liquid extraction (MCCE) is a common unit operation in the chemical industry, but the technique is often difficult to use at laboratory and small production scales, because most MCCE systems are gravity-driven and require a large volume (∼100 mL). We present a new MCCE design that integrates segmented flow mixing and membrane-based phase separators to achieve equilibrium extraction at each stage. Multichannel peristaltic pumps transfer fluids from stage to stage in a counter-current manner, rather than dedicated pumps at each stage. A self-tuning pressure control element incorporated into each separator allows robust operation, even in the presence of variation between stages and imprecise pumping. Experimental data from two classical ternary case studies (toluene–acetone–water and ethyl acetate–acetic acid–water) compare well to ASPEN Plus simulations, showing that the extraction efficiency is ∼100%, regardless of the number of stages. Finally, we demonstrate the efficie...

We report continuous solvent-free biphasic alcohol oxidation with hydrogen peroxide and in-line separation of the tungsten polyoxometalate catalyst and phase transfer catalyst from the product. Zinc-substituted polyoxotungstate in combination with the selected phase transfer catalyst drives the oxidation reaction to completion within a short residence time (5–10 min) in a silicon Pyrex microreactor. This continuous and small-scale reactor allows for fast optimization of reaction conditions for each substrate and selection of the phase transfer catalyst. Scaling of the production rate (up to 650 times) is achieved with a Corning low flow reactor (LFR) and an advanced flow reactor (AFR). New scaled-up, in-line membrane-based liquid–liquid extraction units at the reactor outlet first separate the tungsten polyoxometalate catalyst with the aqueous waste stream from the organic product stream. A three-stage countercurrent liquid–liquid extraction then removes more than 90% of the phase transfer catalyst from t...

A compact, fully integrated, and automated system is developed for end-to-end production, purification, and formulation of the active pharmaceutical ingredient (API) lidocaine hydrochloride, a widely used local anesthetic. The purification strategy includes appropriate combination of extraction, reactive crystallization, and antisolvent cooling crystallization that enables the production of lidocaine hydrochloride formulated solution, for topical application meeting US Pharmacopeia (USP) standards. On the basis of the optimal yield observed in each step, the system sustains a daily production of 810 doses (dosage strength = 20 mg mL–1, i.e., 2% formulation in commercial denomination).

The reliable and efficient production of radioisotopes for diagnosis and therapy is becoming an increasingly important capability, due to their demonstrated utility in Nuclear Medicine applications. Starting from the first processes involving the separation of 99mTc from irradiated materials, several methods and concepts have been developed to selectively extract the radioisotopes of interest. Even though the initial methods were based on liquid-liquid extraction (LLE) approaches, the perceived difficulty in automating such processes has slowly moved the focus towards resin separation methods, whose basic chemical principles are often similar to the LLE ones in terms of chelators and phases. However, the emerging field of flow chemistry allows LLE to be easily automated and operated in a continuous manner, resulting in an even improved efficiency and reliability. In this contribution, we will outline the fundamentals of LLE processes and their translation into flow-based apparatuses; in addition, we will provide examples of radioisotope separations that have been achieved using LLE methods. This article is intended to offer insights about the future potential of LLE to purify medically relevant radioisotopes.

A novel and rapid method to identify contamination of Vibrio parahaemolyticus during an enrichment was developed. The principle was based on the bacteria's capability of carbohydrate fermentation and amino acid decarboxylation. Six different broths were developed with four sugar substrates, namely, dextrose (DEX), arabinose (ARA), mannose (MAO), mannitol (MAI), and two amino acids, namely, lysine (LYS) and ornithine (ODB). Bromocresol purple (BP) and phenol red (PR) were added to detect pH changes of the broths. The absorbance of the color change was determined for all sugar broths at 600 nm and both amino acids at 550 nm. Salinity and pH were adjusted to suppress competitive bacteria. The optimal conditions for the sugar substrates and the amino acids were 8% NaCl/pH = 9.0 and 6% NaCl/pH = 6.0, respectively. In real samples, this method was capable of detecting V. parahaemolyticus with a limit of detection of 0.1–1.0 log CFU/mL (measured as an initial cell concentration in the samples). At 24 h, this method also yielded a 100% sensitivity and improved a specificity to 95%–100%, compared to the 88% specificity as obtained in the conventional method. Integrating the detection of V. parahaemolyticus provided a quick and effective screening for the presence of V. parahaemolyticus.

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards.

This paper presents a fully-continuous novel liquid–liquid-extraction (LLE) platform for the purification of nanoparticles. The use of multistage operation enhances the purity of the final stream without the expense of high solvent consumption. Two case studies, purification of CdSe quantum dots in organic solvent and that of gold nanoparticles in water, demonstrate that the LLE platform is versatile, non-destructive, and highly efficient.

We describe the development and application of an improved, membrane-based, liquid–liquid separator. Membrane-based separation relies on the exploitation of surface forces and the use of a membrane wetted by one of the phases; however, successful separation requires accurate control of pressures, making the operation and implementation cumbersome. Here we present an improved separator design that integrates a pressure control element to ensure that adequate operating conditions are always maintained. Additionally, the integrated pressure control decouples the separator from downstream unit operations. A detailed examination of the controlling physical equations shows how to design the device to allow operation across a wide range of conditions. Easy to implement, multistage separations such as solvent swaps and countercurrent extractions are demonstrated. The presented design significantly simplifies applications ranging from multistep synthesis to complex multistage separations., Novartis-MIT Center for Continuous Manufacturing, United States. Defense Advanced Research Projects Agency (Grant N66001-11-C-4147)

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.