Panariello, Luca; (2020) Reaction engineering approach to the flow synthesis of nanomaterials for sensing and biomedical applications. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Nanomaterials promise to revolutionize technologies belonging to many different fields thanks to their peculiar properties arising from their small size, at the interface between that of molecules and that of particles, high surface area and distinctive optical and electronic properties. Some nanomaterials-based products started appearing on the market over the last two decades. However, a striking difference still exists between the number of nanomaterials-focused scientific contributions being published and the number of nanomaterials-based products currently sold, with full exploitation of the benefits coming from the use of nanomaterials in everyday life still far from happening. This distance between science and the market appears even more evident in the field of biomedicine. Different reasons hide behind the very low ratio between available nanomaterials-based medical products and scientific effort in the field. One of these reasons is the difficulty in manufacturing these materials in a reproducible manner and on a sufficiently large scale. Scale-up of these productions often leads to irreproducible results and a lack of the desired materials properties, especially when facing the strict regulations for medical application. Conventional manufacturing strategies based on the use of batch systems suffer from batch-to-batch variability, caused by slow and irreproducible mixing and inhomogeneous temperature profile. Flow reactors represent a solution to these issues, thanks to their high surface area, product volumes higher than reactor volume, and reduced human intervention during operation. Over the last decade, the number of works regarding flow synthesis of nanomaterials exponentially increased. Nonetheless, a formal design protocol for such reactors is still not available, with researchers relying on a pure black-box approach. This approach is experimentally intensive and case dependent, complicating the scale-up of the reactors. Difficulties arise also in implementing model-based control systems, essential in industrial settings. The aim of this thesis is to develop a design approach for flow reactors synthesizing nanomaterials based on the combination of kinetics studies and classic reactor design principles. A theoretical background was first established using the well-studied synthesis of silica nanoparticles. A model was developed demonstrating the possibility of describing the reactor behaviour through the combination of residence time distribution theory and kinetic data obtained in batch. Supported by this theoretical background, the thesis shows the successful attempt at designing two flow reactors for the synthesis and growth of gold nanoparticles, eventually enabling control over the particle size between 10 and 150 nm, as well as granting high synthesis reproducibility (with deviation in the average size between runs in the order of ). The reactor design used to develop these reactors started from kinetic data acquired in batch via in situ time- 4 resolved UV-Vis spectroscopy, which are used to determine the process operating conditions of the flow reactor. The first reactor designed for the synthesis of gold nanoparticles produced 11 nm gold seeds through a modified Turkevich method developed in this thesis, named passivated Turkevich method, where the precursor coordination sphere is engineered to maximize the synthesis reproducibility. The second reactor developed in this thesis uses the seeds produced by the first reactor and grows them to a controllable final size (up to 150 nm) in a single growth step. The growth was performed through a different synthetic protocol, and again, the design of the reactor followed the same principles, starting with the study of the synthesis kinetics in batch via in situ time-resolved UV-Vis spectroscopy, showing the flexibility of the proposed reactor design approach. To obtain a detailed description of the particle evolution during their synthesis, this thesis also focused on the development of a model for the interpretation of the time-resolved UV-Vis data obtained during the synthesis of Au nanoparticles. The developed model renders the evolution of the particle size and number density during the synthesis. This model also explains the distinctive evolution of the Au nanoparticles optical properties observed during the Turkevich synthesis, with the peak absorbance moving from low to high energies. This phenomenon is explained through the adsorption of Au precursor species on the surface of the growing nanoparticles, which induces a change in the particle free electron density. The model reconciles in this way the latest mechanistic studies of the Turkevich synthesis (where no particle aggregates are observed) with the Mie theory. The design approach proposed in the thesis is useful for the translation of nanomaterials synthesis from batch to flow. However, flow reactors can access operating conditions hardly achievable in batch, possibly enabling new nanomaterials syntheses or further optimization of existing ones. This was demonstrated in this thesis for the synthesis of iron oxide nanoparticles, where flow reactors allowed the straightforward introduction in the aqueous system of gaseous reactants at high pressures and temperatures. Four reactor systems were designed by a combination of two modules, namely a membrane gas-liquid contactor and a reaction coil. These reactor systems allowed control over the flow profile, use of gaseous reactants as well as access to temperatures above the solvent boiling point through straightforward system pressurization. Control over these variables led to a significant decrease in the reaction time (from several hours down to 3 min) and control over particle crystal structure, size, and morphology. Finally, one of these reactor systems was scaled up by a factor of 5 without loss in product quality. The advantages of flow reactors to perform synthesis aided by low penetration depth radiations was then explored. Microwave heating is currently attracting attention as an alternative heating 5 technology which could allow faster heating rates and more homogeneous temperature profiles in large scale flow systems as a result of the bulk microwave heating mechanism, against surface-mediated conventional heating. This thesis investigated the use of microwave heating to perform the synthesis of iron oxide nanoparticles via the aqueous coprecipitation of iron chlorides in basic media, followed by stabilization through the addition of citric acid and dextran. The microwave synthesis led to the generation of multicore assemblies of iron oxide nanoparticles with a similar single-core size of conventionally produced ones, but with significantly larger hydrodynamic diameters. This suggests changes possibly induced by either the different heating profiles or the microwave radiation itself in the nucleation and aggregation rates, which determine the final assembly size. The scale-up of the microwave reactor was then investigated, with a successful increase in the production rate by a factor of 8. Eventually, the development of a new synthetic protocol for the synthesis of thermoresponsive magnetic nanogels and its translation from batch to flow are presented. This nanomaterial is developed through a bottom-up approach studying the synthesis of each unit composing the final product. The core of this material comprises iron oxide nanoparticles, produced via flow chemistry: different particles were screened with varying size and surface chemistry. Colloidal stability and hydrophobicity of the coating determined the successful encapsulation of the particles in the nanogel. In parallel, the nanogel formulation was optimized to achieve the desired size and transition temperature for the eventual temperature-triggered drug release application. The coating kinetics were studied, demonstrating that the synthesis finishes after ~5-10 min, a much shorter reaction time than those normally employed in the literature. The kinetics information is then used to guide the design of a single-phase flow reactor producing said nanomaterial, leading to a g/day production scale in a lab setting.

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