In-Silico Conceptualisation of Continuous Millifluidic Separators for Magnetic Nanoparticles

Magnetic nanoparticles are researched intensively not only for biomedical applications, but also for industrial applications including wastewater treatment and catalytic processes. Although these particles have been shown to have interesting surface properties in their bare form, their magnetisation remains a key feature, as it allows for magnetic separation. This makes them a promising carrier for precious materials and enables recovery via magnetic fields that can be turned on and off on demand, rather than using complex (nano)filtration strategies. However, designing a magnetic separator is by no means trivial, as the magnetic field and its gradient, the separator dimensions, the particle properties (such as size and susceptibility), and the throughput must be coordinated. This is showcased here for a simple continuous electromagnetic separator design requiring no expensive materials or equipment and facilitating continuous operation. The continuous electromagnetic separator chosen was based on a current-carrying wire in the centre of a capillary, which generated a radially symmetric magnetic field that could be described using cylindrical coordinates. The electromagnetic separator design was tested in-silico using a Lagrangian particle-tracking model accounting for hydrodynamics, magnetophoresis, as well as particle diffusion. This computational approach enabled the determination of separation efficiencies for varying particle sizes, magnetic field strengths, separator geometries, and flow rates, which provided insights into the complex interplay between these design parameters. In addition, the model identified the separator design allowing for the highest separation efficiency and determined the retention potential in both single and multiple separators in series. The work demonstrated that throughputs of ~1/4 L/h could be achieved for 250–500 nm iron oxide nanoparticle solutions, using less than 10 separator units in series

Recent advances in modelling and control of liquid chromatography

For more than a century, chromatography has been indispensable as a separation method for both analytics and purification. Among the variety of chromatographic techniques, liquid chromatography has a special status owing to its efficiency and versatility, and its status is further enhanced by the continuous improvements of analysers, materials, methods and understanding, all supported by computational approaches. High performance liquid chromatography (HPLC) has always held a special place in pharmaceutical processing, and computational HPLC has been explored since the very early stages of computing, although without having yet reached its full potential. Herein, we provide a comprehensive and critical review of recent developments in designing and operating liquid chromatographic systems, focussing on their modelling approaches and control strategies at large scale

Synthetic guidelines for the precision engineering of gold nanoparticles

Gold nanoparticles (AuNPs) are one of the most studied nanomaterials with applications spanning from catalysis to biomedicine. While numerous chemical protocols exist that allow bespoke tailoring of chemical, physical and biological properties, their translation towards industrial-scale production remains a challenge. Batch synthesis often suffers from poor reproducibility and scalability, while emerging approaches, such as continuous flow synthesis, are not widely implemented in research labs. Herein, we provide a critical review of recent developments in the field of AuNP synthesis and identify synthetic guidelines for precision engineering of nanoparticle properties

Self-seeded coprecipitation flow synthesis of iron oxide nanoparticles via triphasic reactor platform: Optimising heating performance under alternating magnetic fields

Liquid-liquid segmentation is a common method to prevent reactor fouling when synthesising nanoparticles in flow, despite limiting synthetic protocols to single reagent addition steps before segmentation. This work demonstrates how a modular triphasic (gas–liquid–liquid) flow reactor platform overcomes this limitation, facilitating a continuous and fouling-free four-step co-precipitation flow synthesis of iron oxide nanoparticles (IONPs) for magnetically induced hyperthermia cancer treatment (MHCT). For this and other biomedical applications water-based IONP syntheses such as co-precipitation are favoured, but producing IONPs > 10 nm as needed for MHCT remains challenging. To overcome this size barrier for co-precipitation syntheses, a seeded growth co-precipitation strategy was employed here for the first time. After demonstrating the synthesis in batch, a triphasic flow reactor was developed to translate the multistep batch protocol into flow. Nitrogen gas was used to space the liquid–liquid segmented slugs evenly, enabling self-synchronised solution addition into the aqueous slugs dispersed in heptane. Three additions of the iron precursor solution followed by citric acid solution addition formed the seeds, grew them to larger IONPs and stabilised them. The flow platform was used for screening of the synthetic parameters to optimise the IONP heating performance in an alternating magnetic field, hence investigating their potential as MHCT heating agents. The optimal reactor settings identified made it possible to continuously synthesise 0.46 gIONPs/h colloidally stable IONPs in the aqueous phase of size ∼15 nm. The fouling-free flow reactor operated at short overall residence times (<5 min) using just ferric and ferrous salts, sodium carbonate and citric acid. The IONPs exhibited high heating performance, with an intrinsic loss power up to 3.76 nH m2 kgFe-1

A Modular Millifluidic Platform for the Synthesis of Iron Oxide Nanoparticles with Control over Dissolved Gas and Flow Configuration

Gas–liquid reactions are poorly explored in the context of nanomaterials synthesis, despite evidence of significant effects of dissolved gas on nanoparticle properties. This applies to the aqueous synthesis of iron oxide nanoparticles, where gaseous reactants can influence reaction rate, particle size and crystal structure. Conventional batch reactors offer poor control of gas–liquid mass transfer due to lack of control on the gas–liquid interface and are often unsafe when used at high pressure. This work describes the design of a modular flow platform for the water-based synthesis of iron oxide nanoparticles through the oxidative hydrolysis of Fe2+ salts, targeting magnetic hyperthermia applications. Four different reactor systems were designed through the assembly of two modular units, allowing control over the type of gas dissolved in the solution, as well as the flow pattern within the reactor (single-phase and liquid–liquid two-phase flow). The two modular units consisted of a coiled millireactor and a tube-in-tube gas–liquid contactor. The straightforward pressurization of the system allows control over the concentration of gas dissolved in the reactive solution and the ability to operate the reactor at a temperature above the solvent boiling point. The variables controlled in the flow system (temperature, flow pattern and dissolved gaseous reactants) allowed full conversion of the iron precursor to magnetite/maghemite nanocrystals in just 3 min, as compared to several hours normally employed in batch. The single-phase configuration of the flow platform allowed the synthesis of particles with sizes between 26.5 nm (in the presence of carbon monoxide) and 34 nm. On the other hand, the liquid–liquid two-phase flow reactor showed possible evidence of interfacial absorption, leading to particles with different morphology compared to their batch counterpart. When exposed to an alternating magnetic field, the particles produced by the four flow systems showed ILP (intrinsic loss parameter) values between 1.2 and 2.7 nHm2/kg. Scale up by a factor of 5 of one of the configurations was also demonstrated. The scaled-up system led to the synthesis of nanoparticles of equivalent quality to those produced with the small-scale reactor system. The equivalence between the two systems is supported by a simple analysis of the transport phenomena in the small and large-scale setup

Boosting the Photoactivity of Grafted Titania: Ultrasound-Driven Synthesis of a Multi-Phase Heterogeneous Nano-Architected Photocatalyst

The herein presented low-power high-frequency (500 kHz) ultrasound-assisted precipitation synthesis (LPHF-US) leads to a unique multiphase nano-structured titanium dioxide, grafted with oxygen-containing organic functionalities. The material exhibits a high porosity (surface area 326 m2 g−1 and total pores volume 0.484 cm3 g−1) and heterogeneous surface chemistry. In the used LPHF-US synthetic protocol, the energy-demanding calcination step leading to crystallization is eliminated and an organic residue is simultaneously grafted to the surface. That organic residue affects the anatase nanocrystals, size (4–7 nm), which are embedded in an amorphous titanium hydroxide network. This nanomaterial shows superior performance as a heterogenous photocatalyst either in a gaseous phase by decomposing toxic vapors of chemical warfare agents (a mustard-gas surrogate), or in a liquid phase by selectively oxidizing benzyl alcohol, a model lignin-biomass-derived compound. The grafted organic phase enhances the catalyst's photoreactivity under visible light, by acting as a photosensitizer (antenna effect) and/or as a source of chromophores

In-Silico Conceptualisation of Continuous Millifluidic Separators for Magnetic Nanoparticles

Magnetic nanoparticles are researched intensively not only for biomedical applications, but also for industrial applications including wastewater treatment and catalytic processes. Although these particles have been shown to have interesting surface properties in their bare form, their magnetisation remains a key feature, as it allows for magnetic separation. This makes them a promising carrier for precious materials and enables recovery via magnetic fields that can be turned on and off on demand, rather than using complex (nano)filtration strategies. However, designing a magnetic separator is by no means trivial, as the magnetic field and its gradient, the separator dimensions, the particle properties (such as size and susceptibility), and the throughput must be coordinated. This is showcased here for a simple continuous electromagnetic separator design requiring no expensive materials or equipment and facilitating continuous operation. The continuous electromagnetic separator chosen was based on a current-carrying wire in the centre of a capillary, which generated a radially symmetric magnetic field that could be described using cylindrical coordinates. The electromagnetic separator design was tested in-silico using a Lagrangian particle-tracking model accounting for hydrodynamics, magnetophoresis, as well as particle diffusion. This computational approach enabled the determination of separation efficiencies for varying particle sizes, magnetic field strengths, separator geometries, and flow rates, which provided insights into the complex interplay between these design parameters. In addition, the model identified the separator design allowing for the highest separation efficiency and determined the retention potential in both single and multiple separators in series. The work demonstrated that throughputs of ~1/4 L/h could be achieved for 250–500 nm iron oxide nanoparticle solutions, using less than 10 separator units in serie

Stable Iron Oxide Nanoflowers with Exceptional Magnetic Heating Efficiency: Simple and Fast Polyol Synthesis

Magnetically induced hyperthermia has reached a milestone in medical nanoscience and in phase III clinical trials for cancer treatment. As it relies on the heat generated by magnetic nanoparticles (NPs) when exposed to an external alternating magnetic field, the heating ability of these NPs is of paramount importance, so is their synthesis. We present a simple and fast method to produce iron oxide nanostructures with excellent heating ability that are colloidally stable in water. A polyol process yielded biocompatible single core nanoparticles and nanoflowers. The effect of parameters such as the precursor concentration, polyol molecular weight as well as reaction time was studied, aiming to produce NPs with the highest possible heating rates. Polyacrylic acid facilitated the formation of excellent nanoheating agents iron oxide nanoflowers (IONFs) within 30 min. The progressive increase of the size of the NFs through applying a seeded growth approach resulted in outstanding enhancement of their heating efficiency with intrinsic loss parameter up to 8.49 nH m2 kgFe-1. The colloidal stability of the NFs was maintained when transferring to an aqueous solution via a simple ligand exchange protocol, replacing polyol ligands with biocompatible sodium tripolyphosphate to secure the IONPs long-term colloidal stabilization

Synthesis of Fine-Tuning Highly Magnetic Fe@FexOy Nanoparticles through Continuous Injection and a Study of Magnetic Hyperthermia

Core@shell Fe@FexOy nanoparticles (NPs) have the potential to be promising tools for many applications, thanks to their combination of an iron core, with a high magnetic moment and an iron oxide shell which could protect the core from oxidation. However, the deterioration of NPs structure can lead to the shrinking of the core and the hollowing of the structure, diminishing the magnetic properties. The ability to retain the iron core under biomedically compatible conditions is desirable for many applications. In this paper, we have developed a synthetic method to produce core@shell α-Fe@FexOy NPs with tunable sizes and evaluated the retention of the stable magnetic α-Fe core upon exposure to air and after ligand exchange and its resulting effect on the magnetic hyperthermia. In particular, using a continuous injection of the precursor, we were able to finely tune the final size of the core@shell NPs producing four samples with average sizes of 12, 15, 18, and 20 nm. The structural properties of the particles were studied, and while the size increases, the chemical stability of the iron core is enhanced, and the magnetic properties improved accordingly. Particles larger than 20 nm were shown to be prone to aggregation, resulting in an abrupt increase of the particle size distribution. Two samples with high magnetization saturation value and low polydispersity, 15 and 18 nm, were transferred in water using a dopamine-functionalized poly(isobutylene-alt-maleic anhydride) polymer, resulting in colloidal stability over a wide range of pH and ionic strength comparable to physiological conditions. We found that the 18 nm particles retain their chemical properties over 2 months, with less oxidation of the Fe core; this results in a specific absorption rate (SAR) value of 660 W g−1 and intrinsic loss power (ILP) of 3.6 nHm2 kg−1 , while the 15 nm NPs resulted in the reduction of their properties due to oxidation of the core

Development of an in-line magnetometer for flow chemistry and its demonstration for magnetic nanoparticle synthesis

Despite the wide usage of magnetic nanoparticles, it remains challenging to synthesise particles with properties that exploit each application's full potential. Time consuming experimental procedures and particle analysis hinder process development, which is commonly constrained to a handful of experiments without considering particle formation kinetics, reproducibility and scalability. Flow reactors are known for their potential of large-scale production and high-throughput screening of process parameters. These advantages, however, have not been utilised for magnetic nanoparticle synthesis where particle characterisation is performed, with a few exceptions, post-synthesis. To overcome this bottleneck, we developed a highly sensitive magnetometer for flow reactors to characterise magnetic nanoparticles in solution in-line and in real-time using alternating current susceptometry. This flow magnetometer enriches the flow-chemistry toolbox by facilitating continuous quality control and high-throughput screening of magnetic nanoparticle syntheses. The sensitivity required to monitor magnetic nanoparticle syntheses at the typically low concentrations (<100 mM of Fe) was achieved by comparing the signals induced in the sample and reference cell, each of which contained near-identical pairs of induction and pick-up coils. The reference cell was filled only with air, whereas the sample cell was a flow cell allowing sample solution to pass through. Balancing the flow and reference cell impedance with a newly developed electronic circuit was pivotal for the magnetometer's sensitivity. To showcase its potential, the flow magnetometer was used to monitor two iron oxide nanoparticle syntheses with well-known particle formation kinetics, i.e., co-precipitation syntheses with sodium carbonate and sodium hydroxide as base, which have been previously studied via synchrotron X-ray diffraction. The flow magnetometer facilitated batch (on-line) and flow (in-line) synthesis monitoring, providing new insights into the particle formation kinetics as well as, effect of temperature and pH. The compact lab-scale flow device presented here, opens up new possibilities for magnetic nanoparticle synthesis and manufacturing, including 1) early stage reaction characterisation 2) process monitoring and control and 3) high-throughput screening in combination with flow reactors