Droplet based microfluidics
A nanocrystal (NC) is a tiny object, composed mostly of crystalline elements, that has at least one dimension smaller than 1,000 nanometers1. Nanocrystals (Fig. 1) can be classified as a subset of nanoparticles, specifically referring to solid particles with crystalline structures at the nanoscale. These materials exhibit distinct properties that stem from their small size and ordered atomic arrangements, making them essential components in a wide range of scientific and technological fields.
Nanocrystals provide significant advantages over bulk materials in terms of enhanced processability, chemical activity, bioavailability, and magneto and optoelectronic functionality. However, to exploit such properties requires exacting control over size, shape and chemical composition. Effective strategies for achieving such control have been developed for gram-scale batch syntheses.3
In 2002, as an alternative to batch synthesis, Edel et al. proposed the use of microscale flow reactors for nanocrystal synthesis, reasoning that the smaller reaction volumes would provide greater homogeneity in the chemical environment, thereby improving product quality.3
A microfluidic flow reactor is an attractive for NC synthesis because it is possible to rapidly and continuously screen through important reaction parameters, while using minimal amounts of reagents, until NCs of the desired size and monodispersity are produced.4
The synthesis of nanocrystals in microfluidic systems is influenced by intricate flow regimes that significantly impact the outcome of the synthesis process. Several studies have emphasized the importance of flow regimes in controlling the size, shape, and properties of nanocrystals synthesized in microfluidic reactors. The geometry of microfluidic devices, along with the hydrodynamic flow conditions (Fig. 2), plays a crucial role in determining the flow regime and, consequently, the characteristics of the synthesized nanocrystals.
A diverse range of microreactor types and configurations available offer researchers versatile tools to explore novel synthesis routes and advance the field of nanocrystal synthesis. To date, different microfluidics systems, including continuous and segmented-flow microfluidic systems have been used to synthesize NCs of various sizes, shapes, and with narrow size distributions.6
A microfluidic tube-based reactor adopts the single-phase continuous flow type microfluidic regime. The synthesis of nanocrystals using microcapillary tube-based reactors has emerged as a promising approach in nanoscience and materials synthesis. These reactors offer precise control over reaction conditions and enable the production of nanocrystals with tailored properties. By confining the reaction within microcapillary tubes, researchers can achieve high reproducibility and scalability in the synthesis process. Tube-based reactors are selected for the synthesis of nanocrystals over chip-based configurations due to their fabrication and operational simplicity, while offering opportunities for facile scale-out production.7
Yang et al. developed a method for the controlled synthesis of CdSe quantum dots (NB: quantum dots are a specific type of nanocrystal). In their experimental setup, two syringes were filled with cadmium and selenium precursor solutions, which were then loaded into syringe pumps. Upon activation of the syringe pumps, the precursor solutions were injected into separate PTFE capillaries with a 300 µm inner diameter and subsequently combined using a Y-shaped junction (Fig. 3). The combined solution underwent mixing in a mixer to ensure homogeneity before passing through a heated tubing section immersed in an oil bath to initiate the reaction. The resulting nanocrystalline product was collected at the outlet of the reactor. 7
Whilst continuous phase reactors are attractive for their relative ease of implementation, they suffer from two principal drawbacks that can hinder their application to nanocrystal synthesis. Firstly, they have a propensity to foul after extended operation; and, secondly, viscous drag at the channel walls causes the fluid to flow at different velocities across the channel, with the central fluid moving fastest and periphery fluid moving progressively slower as the walls are approached.7
Segmented flow (Fig. 4) is induced by introducing an additional immiscible fluid (which can be a gas or a liquid) into the channel, causing the reaction phase to spontaneously divide into a succession of discrete “slugs”7.
Yen et al. reported on the synthesis of CdSe quantum dots in a segmented flow reactor using a gas/liquid system. The researchers utilized a chip-based device made from silicon and glass to carry out the nanoparticle synthesis process. In their study, a squalane reaction phase was employed, which was segmented into slugs by a flow of argon within the reactor setup. The synthesis process involved heating the reaction mixture to 260 °C as it passed through the segmented flow reactor device. This elevated temperature facilitated the nucleation and growth of nanocrystalline CdSe particles. Importantly, the size of the synthesized CdSe quantum dots could be controlled by adjusting the flow rates of the precursor materials within the reactor system. This innovative approach to nanoparticle synthesis offers several advantages. The use of a segmented flow reactor allows for precise control over reaction conditions and enables efficient heat transfer, promoting uniform nucleation and growth of the CdSe quantum dots. The chip-based design of the reactor, fabricated from silicon and glass, provides a stable and controlled environment for the synthesis process.10
Droplet flow (Fig. 5) is an alternative form of segmented flow in which the reagent phase is carried along within the segmenting phase in a succession of discrete droplets.
Nightingale et. al described a versatile capillary-based droplet reactor for the controlled synthesis of metal, metal-oxide and compound semiconductor nanocrystals. The reactor exhibits stable droplet flow over a wide range of flow rates and temperatures and resists fouling even in the presence of solid intermediates or side-products. The non-dispersive flow-dynamics and the exceptional control and stability of the reactor combine to offer a near-ideal environment for performing nanocrystal synthesis. Finally we note that, whilst we have focused here on nanocrystal synthesis, the reactor is also amenable to many other solution phase synthesis procedures where tight control over reaction conditions is required.12 The reactor was successfully applied to the synthesis of metal (Ag), metal oxide (TiO2) and compound semiconductor (CdSe) nanoparticles, and in each case exhibited stable droplet flow over many hours of operation without fouling, even for reactions involving solid intermediates.12
Microfluidics has significantly impacted the synthesis of nanocrystals, providing precise control over reaction conditions, and enabling its application in the production of a wide range of compounds.
Jun et al. presented a novel approach to synthesizing hierarchical Cu2O nanocrystals with a focus on their application as electrocatalysts for the selective reduction of CO2 to C2 products. The study describes the fabrication of a unique hierarchical structure of Cu2O, termed h-Cu2O ONS, achieved through the modulation of nanocrystal growth kinetics using flow chemistry in a microfluidic system.
This innovative synthesis method aims to enhance the catalytic performance of Cu2O nanocrystals in the electrochemical reduction of CO2, particularly towards the selective generation of C2 products. The hierarchical Cu2O nanocrystals synthesized through microfluidics hold promise as efficient electrocatalysts for the conversion of CO2 into valuable C2 products, such as C2H4 and C2H6. By leveraging the advantages of microfluidic-assisted synthesis, the research contributes to the development of advanced materials for CO2 reduction applications, offering potential solutions for sustainable energy conversion and storage.13
The transformation of drug microcrystals into drug nanoparticles can result in the production of either a crystalline or an amorphous product, depending on the method of production. While an amorphous drug nanoparticle technically should not be classified as a nanocrystal, it is commonly referred to as “nanocrystals in the amorphous state.” This process of producing drug nanocrystals offers the advantage of reducing the size of poorly water-soluble drug particles to the nanometer scale, thereby altering the drug’s thermodynamic and kinetic properties and addressing challenges related to its biopharmaceutical delivery.14
Drug nanocrystals exhibit enhanced adhesion to surface/cell membranes compared to microparticles due to their smaller size and increased surface area, facilitating improved interactions. Additionally, drug nanocrystal suspensions demonstrate long-term physical stability when appropriately stabilized, preventing aggregation of the nanocrystals and inhibiting the Ostwald ripening phenomenon.14
Furthermore, the application of microfluidics in nanocrystal synthesis extends to the use for the synthesis of advanced drug delivery systems15,16. Liu et al. introduces a novel approach that combines the advantages of polymeric nanoparticles and drug nanocrystals in a nano-in-nano vector. This innovative vector aims to leverage the strengths of both polymeric nanoparticles and drug nanocrystals to enhance drug delivery systems. By merging these two components, the nano-in-nano vector offers a promising strategy for optimizing drug therapeutic efficacy, improving drug stability, and achieving controlled drug release. The study highlights the potential of this hybrid approach in advancing drug delivery systems and highlights the synergistic benefits of integrating polymeric nanoparticles and drug nanocrystals in a single vector for enhanced pharmaceutical applications.17
Sorafenib (SFN) and itraconazole (ICZ) nanocrystals encapsulated by folic acid (FA) conjugated spermine-functionalized acetylated dextran (ADS), HSFN@ADS-FA and ICZ@ADS-FA, were produced through multistep microfluidics nanoprecipitation configuration same as the one depicted in (Fig. 6). The PTX@HF and SFN@HF nanocrystals showed ultrahigh drug loading degree (42.6 and 45.2%, respectively), pH sensitive drug release, an increased drug dissolution kinetics, and high-throughput production rate at ~700 g/day on a single device.14
Nanocrystalline semiconductors are of considerable scientific and commercial interest owing to their tunable optical and electronic properties, and potential applications in a wide range of electronic devices. Physical characteristics of nanocrystallites are determined primarily by spatial confinement effects with properties such as the optical band gap often differing considerably from the bulk semiconductor.18
The semiconductor nanocrystal has been widely investigated for three decades now and forms one of the centerpieces of the modern nanoscience revolution19. CdSe nanocrystals possess exceptional optical and electronic properties that render them valuable in diverse semiconductor applications, including biological labeling, light-emitting diodes, and solar cells. Hirokuyi et.al. presented a study that focuses on the preparation of CdSe nanocrystals in a micro-flow-reactor. The research explores the synthesis of CdSe nanocrystals using a microfluidic system, aiming to investigate the efficient production of these nanocrystals in a controlled environment. By utilizing microfluidics, the researchers aim to enhance the reproducibility and scalability of the synthesis process, potentially leading to the production of high-quality CdSe nanocrystals with tailored properties for various applications.20
Moreover, the application of microfluidics in nanocrystal synthesis extends to the fabrication of composite materials like α-CsPbI3/m-SiO2 nanocomposites for solid-state lighting applications.
Guo et.al. presented a microfluidic-based continuous large-scale fabrication of CsPbI3– mesoporous SiO2 (CPI/m-SiO2) nanocomposites to solve the problem of large-scale continuous production of stable, repeatable, high-quality perovskite NCs.21 CsPbI3 perovskite nanocrystals are known for their limited chemical stability compared to other CsPbX3 perovskite nanocrystals due to their thermodynamically metastable nature. The research aims to address this limitation by synthesizing α-CsPbI3/m-SiO2 nanocomposites in a continuous manner using a microfluidics reactor. The resulting nanocomposites exhibit enhanced stability and are intended for use in solid-state lighting applications.
The utilization of microfluidics in the synthesis of nanocrystals has revolutionized the field, offering numerous advantages and opportunities for advancements in nanomaterial production. This technology has been instrumental in the production of various nanomaterials, including semiconductor nanocrystals, drug nanoparticles, and perovskite nanocrystals, showcasing its versatility and impact across different disciplines. The use of microfluidics has not only enhanced the reproducibility and efficiency of nanocrystal synthesis but has also facilitated the exploration of novel synthesis techniques and the development of advanced materials with unique characteristics. Overall, the integration of microfluidics in nanocrystal synthesis represents a promising avenue for the future of nanotechnology, offering new possibilities for the design, fabrication, and application of nanomaterials in diverse fields.
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