Non-fouling flow reactors for nanomaterial synthesis

This review provides a holistic description of flow reactor fouling for wet-chemical nanomaterial syntheses. Fouling origins and consequences are discussed together with the variety of flow reactors for its prevention

Predicting sample injection profiles in liquid chromatography: A modelling approach based on residence time distributions

The pharmaceutical and bio-pharmaceutical industries rely on simulations of liquid chromatographic processes for method development and to reduce experimental cost. The use of incorrect injection profiles as inlet boundary condition for these simulations may, however, lead to inaccurate results. This study presents a novel modelling approach for accurate prediction of injection profiles for liquid chromatographic columns. The model uses the residence time distribution theory and accounts for the residence time of the sample through the injection loop, connecting tubes and heat exchangers that exist upstream of the actual chromatographic column, between the injection point and the column inlet. To validate the model, we compare simulation results with experimental injection profiles taken from the literature for 20 operating conditions. The average errors in the predictions of the mean and variance of the injection profiles result to be 8.98% and 8.52%, respectively. The model, which is based on fundamental equations and actual hardware details, accurately predicts the injection profile for a range of sample volumes and sample loop-filling levels without the need of calibration. The proposed modelling approach can help to improve the quality of in-silico simulation and optimization for analytical chromatography

Crystal shape modification via cycles of growth and dissolution in a tubular crystallizer

Besides size and polymorphic form, crystal shape takes a central role in engineering advanced solid materials for pharmaceutical and chemical industry. This work demonstrates how multiple cycles of growth and dissolution can manipulate the habit of an acetylsalicylic acid crystal population. Considerable changes of the crystal habit could be achieved within minutes due to rapid cycling, i.e., up to 25 cycles within <10 min. The required fast heating and cooling rates were facilitated using a tubular reactor design allowing for superior temperature control. The face specific interactions between solvent and the crystals’ surface result in face specific growth and dissolution rates and hence alterations of the final shape of the crystals in solution. Accurate quantification of the crystal shapes was essential for this work, but is everything but easy. A commercial size and shape analyser had to be adapted to achieve required accuracy. Online size, and most important shape, analysis was achieved using an automated microscope equipped with a flow-through cell, in combination with a dedicated image analysis routine for particle tracking and shape analysis. Due to the implementation of this analyser, capable of obtaining statistics on the crystals’ shape while still in solution (no sampling and manipulation required), the dynamic behaviour of the size shape distribution could be studied. This enabled a detailed analysis of the solvent’s effect on the change in crystal habit

High temperature flow synthesis of iron oxide nanoparticles : size tuning via reactor engineering

Batch thermal decomposition syntheses of iron oxide nanoparticles (IONPs) provide precise control of particle properties, but their scalability and reproducibility is challenging. This is addressed in this work via a versatile high temperature flow reactor with adjustable temperature profiles through three individual stages operated between 180 °C and 280 °C. The tuneable temperature profiles in combination with self-seeded growth methods made it possible to synthesise IONPs between 2 and 17 nm (a size increase that corresponds to a >600 fold particle volume increase) at production rates of several gIONP per day. The precursor solutions contained only iron(III) acetylacetonate in a polyol solvent and no nucleation or growth inhibitors, oxidation or reducing agents, ligands or any other additives . This broad size range covers most biomedical applications and is of special interest for T1 MRI contrast agents (2–5 nm), as well as for magnetic hyperthermia cancer therapy (>10 nm). The potential of the IONPs produced was demonstrated by their high longitudinal relaxivity >16 mM−1 s−1 at a transversal/longitudinal relaxivity ratio <2.5 (small IONPs) and specific absorption rates increasing with the IONP size up to180 W/gFe. In addition, the polyol method employed allowed for simple ligand exchange with biocompatible sodium tripolyphosphate to make the IONPs stable in water, thus rendering them suitable for biomedical applications. The continuous high temperature process presented shows how to control the particle size not via the chemistry (e.g., chemical additives affecting the particle size through the surface chemistry), but engineering parameters, i.e., reactor temperature profiles, reagent addition sequences and seeded growth strategies

Whither Magnetic Hyperthermia? A Tentative Roadmap

The scientific community has made great efforts in advancing magnetic hyperthermia for the last two decades after going through a sizeable research lapse from its establishment. All the progress made in various topics ranging from nanoparticle synthesis to biocompatibilization and in vivo testing have been seeking to push the forefront towards some new clinical trials. As many, they did not go at the expected pace. Today, fruitful international cooperation and the wisdom gain after a careful analysis of the lessons learned from seminal clinical trials allow us to have a future with better guarantees for a more definitive takeoff of this genuine nanotherapy against cancer. Deliberately giving prominence to a number of critical aspects, this opinion review offers a blend of state-of-the-art hints and glimpses into the future of the therapy, considering the expected evolution of science and technology behind magnetic hyperthermia.This work was supported by the NoCanTher project, which has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 685795. The authors acknowledge support from the COST Association through the COST actions "RADIOMAG" (TD1402) and "MyWAVE" (CA17115). D.O., A.S.-O. and I.R.-R. acknowledge financial support from the Community of Madrid under Contracts No. PEJD-2017-PRE/IND-3663 and PEJ-2018-AI/IND-11069, from the Spanish Ministry of Science through the Ramon y Cajal grant RYC2018-025253-I and Research Networks RED2018-102626-T, as well as the Ministry of Economy and Competitiveness through the grants MAT2017-85617-R, MAT2017-88148R and the "Severo Ochoa" Program for Centers of Excellence in R&D (SEV-2016-0686). M.B. and N.T.K.T. would like to thank EPSRC for funding (grant EP/K038656/1 and EP/M015157/1) and AOARD (FA2386-171-4042) award. This work was additionally supported by the EMPIR program co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation program, grant no. 16NRM04 "MagNaStand". The work was further supported by the DFG grant CRC "Matrix in Vision" (SFB 1340/1 2018, no 372486779, project A02)

Crystal Engineering in Continuous Plug-Flow Crystallizers

Size, shape, and polymorphic form are the critical attributes of crystalline particles and represent the major focus of today’s crystallization process design. This work demonstrates how crystal properties can be tuned efficiently in solution via a tubular crystallizer that facilitates rapid temperature cycling. Controlled crystal growth, dissolution, and secondary nucleation allow a precise control of the crystal size and shape distribution, as well as polymorphic composition. Tubular crystallizers utilizing segmented flow such as the one presented in our work can provide plug flow characteristics, fast heating and cooling, allowing for rapid changes of the supersaturation. This makes them superior for crystal engineering over common crystallizers. Characterization of particle transport, however, revealed that careful selection of process parameters, such as tubing diameter, flow rates, solvents, etc., is crucial to achieve the full benefits of such reactors

Crystal Engineering in Continuous Plug-Flow Crystallizers

Size, shape, and polymorphic form are the critical attributes of crystalline particles and represent the major focus of today’s crystallization process design. This work demonstrates how crystal properties can be tuned efficiently in solution via a tubular crystallizer that facilitates rapid temperature cycling. Controlled crystal growth, dissolution, and secondary nucleation allow a precise control of the crystal size and shape distribution, as well as polymorphic composition. Tubular crystallizers utilizing segmented flow such as the one presented in our work can provide plug flow characteristics, fast heating and cooling, allowing for rapid changes of the supersaturation. This makes them superior for crystal engineering over common crystallizers. Characterization of particle transport, however, revealed that careful selection of process parameters, such as tubing diameter, flow rates, solvents, etc., is crucial to achieve the full benefits of such reactors

Crystal Size Control in a Continuous Tubular Crystallizer

This paper describes a simple model-free (i.e., empirical) control strategy for crystal size tuning in a continuously operated tubular crystallizer. The crystallizer is designed for a seeded cooling crystallization process and acetylsalicylic acid crystallization from an ethanol solution was used as model system. Using a crystal size distribution (CSD) analyzer and minor initial studies, we developed a feedback controller that accurately tuned the mean crystal size within the range of 90–140 μm. In addition, we created a cleaning concept for long-term runs based on a consistency study, which demonstrated that the CSD of the products remained robust when process settings were kept constant. Sufficiently small and uniform seed crystals were generated via ultrasound irradiation

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 m kg . 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