Synthesis of crystals and particles by crystallization and polymerization in droplet-based microfluidic devices

The recent advances in crystallization and polymerization assisted by droplet-based microfluidics to synthesize micro-particles and micro-crystals are reviewed in this paper. Droplet-based microfluidic devices are powerful tools to execute some precise controls and operations on the flow inside microchannels by adjusting fluid dynamics parameters to produce monodisperse emulsions or multiple-emulsions of various materials. Major features of this technique are producing particles of monodispersity to control the shape of particles in a new level, and to generate droplets of diverse materials including aqueous solutions, gels and polymers. Numerous microfluidic devices have been employed to generate monodisperse droplets of range from nm to μm, such as T junctions, flow-focusing devices and co-flow or cross-flow capillaries. These discrete, independently controllable droplets are ideal microreactors to be manipulated in the channels to synthesize the nanocrystals, protein crystals, polymer particles and microcapsules. The generated monodisperse particles or crystals are to meet different technical demands in many fields, such as crystal engineering, encapsulation and drug delivery systems. Microfluidic devices are promising tools in the synthesis of micron polymer particles that have diverse applications such as the photonic materials, ion-exchange and chromatography columns, and field-responsive rheological fluids. Processes assisted by microfluidic devices are able to produce the polymer particles (including Janus particles) with precise control over their sizes, size distribution, morphology and compositions. The technology of micro-fluidics has also been employed to generate core-shell microcapsules and solid microgels with precise controlled sizes and inner structures. The chosen “smart” materials are sensitive to an external stimulus such as the change of the pH, electric field and temperature. These complex particles are also able to be functionalized by encapsulating nanoparticles of special functions and by attaching some special groups like targeting ligands. The nucleation kinetics of some crystals like KNO₃ was investigated in different microfluidic devices. Because of the elimination of the interactions among crystallites in bulk systems, using independent droplets may help to measure the nucleation rate more accurately. In structural biology, the droplets produced in microfluidic devices provide ideal platforms for protein crystallization on the nanoliter scale. Therefore, they become one of the promising tools to screen the optimal conditions of protein crystallization.     

Microfluidics for producing polylactide nanoparticles and microparticles and their drug delivery application

This review presents use of the microfluidics technique for the preparation of polylactide (PLA) based particles for developing novel drug delivery systems. Droplet‐based microfluidics allow uniform single, double and higher order emulsions to be generated that yield highly uniform microspheres, microcapsules and polymersomes. Typically, the building blocks of these complex microparticle systems are PLA macromolecules, their copolymers with different comonomers and recently stereocomplexes composed of an equimolar mixture of poly(l ‐lactide) and poly(d ‐lactide). In addition, the technique offers several advantages over conventional emulsion methods and the highly uniform droplets obtained allow for encapsulation of small drug molecules in polymer network meshes or within their hollow interior. The novel approach in this area is to use the microfluidics technique to produce nanoparticles in the microfluidics channel by micromixing/nanoprecipitation in glass capillary devices. Therefore, this review is divided into three main sections in which we discuss the formation of microspheres from single emulsion droplets, microcapsules and polymersomes from higher order emulsion droplets, and nanoparticles from nanosuspensions in a microfluidic channel. Finally, we compare the drug release from these different particles, focusing mainly on those formed from sensitive or supramolecular networks. © 2018 Society of Chemical Industry     

Recent developments in scale-up of microfluidic emulsion generation via parallelization

Microfluidics affords precise control over the flow of multiphasic fluids in micron-scale channels. By manipulating the viscous and surface tension forces present in multiphasic flows in microfluidic channels, it is possible to produce highly uniform emulsion droplets one at a time. Monodisperse droplets generated based on microfluidics are useful templates for producing uniform microcapsules and microparticles for encapsulation and delivery of active ingredients as well as living cells. Also, droplet microfluidics have been extensively exploited as a means to enable highthroughput biological screening and assays. Despite the promise droplet-based microfluidics hold for a wide range of applications, low production rate (<<10mL/hour) of emulsion droplets has been a major hindrance to widespread utilization at the industrial and commercial scale. Several reports have recently shown that one way to overcome this challenge and enable mass production of microfluidic droplets is to parallelize droplet generation, by incorporating a large number of droplet generation units (N>>100) and networks of fluid channels that distribute fluid to each of these generators onto a single chip. To parallelize droplet generation and, at the same time, maintain high uniformity of emulsion droplets, several considerations have to be made including the design of channel geometries to ensure even distribution of fluids to each droplet generator, methods for large-scale and uniform fabrication of microchannels, device materials for mechanically robust operation to withstand high-pressure injection, and development of commercially feasible fabrication techniques for three-dimensional microfluidic devices. We highlight some of the recent advances in the mass production of highly uniform microfluidics droplets via parallelization and discuss outstanding issues.     

Microfluidic fabrication of smart microgels from macromolecular precursors

Stimuli-responsive polymer microgels can be produced with exquisite control using droplet microfluidics; however, in existing methods, the droplet templating is strongly coupled to the material synthesis, because droplet solidification usually occurs through rapid polymerization immediately after the microfluidic droplet formation. This circumstance limits independent control of the material properties and the morphology of the resultant microgel particles. To overcome this limitation, we produce sensitive polymer microgels from pre-fabricated precursor polymers. We use microfluidic devices to emulsify semidilute solutions of crosslinkable poly(N-isopropylacrylamide) and solidify the drops via polymer-analogous gelation. This approach separates the polymer synthesis from the particle gelation and allows each to be controlled independently, thus enabling us to form monodisperse, thermo-responsive microgel particles with well-controlled composition and functionality. In addition, the microfluidic templating allows us to form complex particle morphologies such as hollow gel shells, anisotropic microgels, or multi-layered microgel capsules.     

Characterizing cocoa butter seed crystals by the oil-in-water emulsion crystallization method

Unambiguous quantitative evidence for the catalytic action of seed crystals in cocoa butter is presented. We used an ultrasound velocity technique to determine the isothermal growth of solid fat content in cocoa butter oil-in-water emulsions, in which the probability of finding a seed crystal in any one droplet was around 0.37 at 14.2°C. The upper limit for the size of seed crystals in West African cocoa butter was around 0.09 μm, the Gibbs free energy for nucleation was 0.11 mj m⁻², and the concentration of seed crystals was in the range of 10¹⁶ to 10¹⁷ m⁻³. X-ray diffraction measurements showed that emulsified cocoa butter crystallizes in the α polymorph and does not appear to transform to the β′ form within the first 25 min of crystallization. Primary nucleation events in cocoa butter emulsions are accounted for by seed crystals. Collision-mediated nucleation, a secondary nucleation mechanism, in which solid droplets (containing seed crystals) catalyze nucleation in liquid droplets, is shown to account for subsequent crystallization. This secondary nucleation mechanism is enhanced by stirring.     

Microfluidic spray drying as a versatile assembly route of functional particles

Microfluidic spray drying is a versatile route to synthesize functional particles, as the technique is scalable with sufficient yields for practical use and easy product recovery, whilst allowing for subsequent processing as necessary. Here a microfluidic jet spray drier producing single trajectory droplets with identical thermal history was used to obtain monodisperse particles with precise morphology. The method employed a moderate temperature range (≤300 °C), and was able to handle multi-component precursors to form solid particles in a single step. Spray drying of a stable colloidal suspension containing iron chloride, lactose, and silica nanoparticles produced microcomposites with platelet-like morphology due to the nanoparticles in the precursor. Subsequent calcination caused the formation of iron oxide crystals of 10 nm–1 μm on the surface of the particles. Both calcination period and post-drying conditions affected the magnetic properties of the composites, with the increase in magnetization correlating well with the proportion of magnetite phase in the iron oxide crystals. The reaction pathways pertaining to the formation of different iron oxide phases are discussed.     

Microfluidic production of liposomes through liquid--liquid phase separation in ternary droplets

Liposomes, the self-assembled phospholipid vesicles, have been extensively used in various fields such as artificial cells, drug delivery systems, biosensors and cosmetics. However, current microfluidic routes to liposomes mostly rely on water-in-oil-in-water double emulsion droplets as templates, and require complex fabrication of microfluidic devices, and tedious manipulation of multiphase fluids. Here we present a simple microfluidic approach to preparing monodisperse liposomes from oil-in-water droplets. For demonstration, we used butyl acetate-water-ethanol ternary mixtures as inner phase and an aqueous solution of surfactants as outer phase to make oil-in-water droplets, which can evolve into water-in-oil-in-water double emulsion droplets by liquid–liquid phase separation of ternary mixtures. Subsequently, the resultant water-in-oil-in-water droplets underwent a dewetting transition to form separated monodisperse liposomes and residual oil droplets, with the assistance of surfactants. The method is simple, does not require complex microfluidic devices and tedious manipulation, and provides a new platform for controllable preparation of liposomes.     

一步法制备生物相容油核微胶囊及其可控释放

一步法可控制备生物相容油核微胶囊对工业制备微胶囊及其应用具有重要意义。通过设计微流控器件,成功实现一步法制备尺寸均一可控的生物相容油核微胶囊。利用玻璃毛细管管套管的方法制备了微流控器件。通过外相水凝胶相剪切内相油相得到油核液滴,同时油核液滴和外相水凝胶相在重力作用下脱离管口,形成油核微胶囊,再通过交联水凝胶壳层得到稳定的结构。系统研究了微流控器件结构、内相流速、外相流速等参数对油核微胶囊油核数量、微胶囊直径、壁厚等性质的影响规律。生物相容油核微胶囊作为活性物质的理想载体,可以实现pH改变触发的快速释放和壁厚调节的缓慢释放,为其实际应用奠定了基础。     

Crystallization of alpha-lactose monohydrate in a drop-based microfluidic crystallizer

A microfluidic process for producing crystals of controlled size by confining the crystallization within drops is demonstrated. The process consists of a drop producing stage which segments the mother liquor into monodisperse drops followed by crystallization in a temperature controlled tubular crystallizer. The process is implemented to produce lactose crystals with significantly narrower crystal size distribution (CSD) as compared with crystals produced in a stirred bulk crystallizer. By controlling the drop size and initial supersaturation the mean crystal size can be controlled. The distribution of the number of crystals per drop and the CSD are measured as a function of supersaturation at temperatures between 20 and for 150 and drops. In the case where drops contain only one crystal, a very narrow CSD is obtained with a coefficient of variation of crystal size as low as 7%. The crystallization of lactose in a microfluidic tubular crystallizer is modeled by treating nucleation in drops as a Poisson process with a nucleation rate based on classical nucleation theory. Experimental results are in good agreement with predictions from a Poisson process model over the range of temperatures, supersaturations and drop sizes tested.     

微通道内卫星液滴生成机理与惯性分离机制

由于非线性动态特征,液液界面破裂过程常伴随卫星液滴的产生,对基于液滴的微流体技术生产液滴的均一性和精准化目标提出了挑战。阐释了微流体界面失稳的复杂动力学特征,剖析了界面失稳的影响因素,并分析了伴随界面失稳而产生的卫星液滴的现象与原理。结合惯性微流体新概念,总结了卫星液滴的惯性分离机制。展望了卫星液滴生成-惯性微流体分离一体化及其并行化数目放大的构想。相关工作的开展,有利于实现微流体技术生产单分散性液滴的精准化目标,为微流体与复杂流体相关的界面动力学行为与调控夯实基础。     

Quantitative evaluation of fractionated and homogeneous nucleation of polydisperse distributions of water-dispersed maleic anhydride-grafted-polypropylene micro- and nano-sized droplets

The nucleation processes in waterborne Maleic Anhydride-grafted-Polypropylene micro- and nano-droplet suspensions have been studied. Compared to a previous report on this topic, an extended set of samples in combination with improved particle size distribution data of the samples have been used, which are both essential for the advancement of the analysis.Self-nucleation was utilized to ensure that the observed lowered fractionated crystallization (peak) temperatures – down to the extremely low value of 34 °C – are due to a lack of seeds in the droplets, which seeds for the polypropylene system used are normally active at the heterogeneous crystallization temperature of approximately 110 °C. An unusual self-nucleation behavior was observed in case of samples having a large amount of small droplets, requiring an extremely low self-nucleation temperature in order to suppress all crystallization at the lowest temperatures. Such behavior was observed for block copolymers but has not been reported so far for droplets dispersed in an immiscible matrix, polymeric or not. Another unusual behavior was observed for some self-nucleation temperatures for which apparently two different populations of self-nuclei are created that are suggestive of the α₁ and α₂ crystal structures of isotactic polypropylene.Next, two new methods are presented to quantify various crucial parameters of the nucleation process: one estimates the density of nucleants acting at different temperatures from the combination of dynamic DSC data and particle size distribution (PSD) data, and the other one focuses on the nature of the nucleation mechanism using both isothermal DSC data and PSD data, quantifying the nucleation rate at different temperatures. For the present MA-g-PP dispersions the latter method leads to the conclusion that the lowest crystallization temperatures reflect sporadic nucleation, probably by way of volume (homogeneous) nucleation.In the field of polymer crystallization, polymer dispersions are usually treated as being monodisperse, even though that is rarely the case. This simplification is inadequate for the present calculations, which is why polydispersity has been taken into account in order to quantify the density of nucleants and the kinetics of nucleation. Though in the present study DSC data are used for the calculations, the methods developed can be easily adapted to other techniques like time-resolved X-ray, rheometry and dilatometry.     

Hydrodynamic control of droplets coalescence in microfluidic devices to fabricate two-dimensional anisotropic particles through boundary element method

Multicompartment and patchy particles attract much attention recently due to their great potentials in many fields such as drug delivery systems and photonic crystal materials. The controlled coalescence of droplets might be a promising approach to fabricate such particles since different droplets might be composed of distinct components or might contain diverse functional solutes. Through a two-dimensional boundary element method, we investigate the controlled adhesion of small droplets to specific locations of a main drop via careful flow control at inlets and outlets of a skillfully designed microfluidic device at low Reynolds numbers. This paper presents an original procedure to construct anisotropic particles assisted by microfluidics. By alternating extensional and rotational flow at the central cavity of the micro-device, it is possible to make small droplets adhere to the main drop one by one at expected location and thus fabricate patchy particles with multiple patches at expected angles in two dimensions.     

连续微流体在光聚合制备聚合物颗粒中的应用进展

光聚合以其对环境友好、反应条件温和、适应性广、成本低等优点备受关注。连续微流体在光聚合中的应用有助于提高反应效率并实现聚合的高度控制。连续微流体在光聚合制备聚合物颗粒中的优点包括可重复性高、合成精度高、能控制聚合物的粒径、多分散性和内部结构。在这篇综述中，总结了连续微流体在光聚合合成纳米颗粒中的应用，其中包括单相微流体光聚合和多相微流体光聚合，具有各种形态的聚合物颗粒的形成机理以及典型实例。     

Polymer crystallization and precipitation‐induced wrapping of carbon nanofibers with PBT

Carbon nanofibers (CNFs) have attracted significant interest because of their excellent mechanical, electrical, and physical properties. Recent advances in chemical functionalization strategies are anticipated to extend their utility in various applications. In this study, noncovalent methods of CNF functionalization utilizing solution crystallization and precipitation techniques were used to create hybrid nanostructures consisting of CNFs and poly(butylene terephthalate) (PBT). Key to this study is the finding that o‐chlorophenol can be used as a suitable solvent to dissolve PBT to generate these nanostructures. PBT crystallization was documented via wide‐angle X‐ray analysis and differential scanning calorimetry and was due to the nucleation effect of the CNFs. The sizes of the PBT crystals could be manipulated by altering the polymer concentration. The solution crystallization and precipitation techniques provide an alternative strategy to alter and control the nanostructure/polymer interface. The resulting nanohybrid structures may potentially find use in a broad range of applications including electronic devices, sensors, and as reinforcing agents in a polymer matrix. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

A droplet-based high-throughput tubular platform to extract rate constants of slow chemical reactions

A high-throughput tubular millifluidic platform for performing slow kinetics measurements occurring in liquid phase, using minute amounts of reactant is described. The method consists of generating periodic trains of monodisperse droplets in a capillary tube and using these droplets as micro-reactors. In contrast to microfluidic lab-on chip devices, limited to fast kinetics measurements, this setup permits to extract kinetic rate constants of slow reactions at very low cost without requiring any use of soft lithography or glass etching technique for its design, nor miniaturization of analytical tools. It therefore appears very well suited for laboratories and industrial research and development centers.     

Confined crystallization phenomena in immiscible polymer blends with dispersed micro- and nanometer sized PA6 droplets, part 3: crystallization kinetics and crystallinity of micro- and nanometer sized PA6 droplets crystallizing at high supercoolings

Crystallization kinetics and crystallinity development of PA6 droplets having sizes from 0.1 to 20 μm dispersed in immiscible uncompatibilized PS/PA6 and reactively compatibilized (PS/Styrene-maleic anhydride copolymer=SMA2)/PA6 blends are reported. These blend systems show fractionated crystallization, leading to several separate crystallization events at different lowered temperatures. Isothermal DSC experiments show that micrometer-sized PA6 droplets crystallizing in an intermediate temperature range (T_c∼175 °C) below the bulk crystallization show a different dependency on cooling rate compared to bulk crystallization, and an athermal crystallization mechanism is suggested for PA6 in this crystallization temperature region. The crystallinity in these blends decreases with PA6 droplet size. Random nucleation, characteristic for a homogeneous nucleation process, is found for sub-micrometer sized PA6 droplets crystallizing between T_c 85 and 110 °C using isothermal DSC experiments. However, crystallization in the PA6 droplets is most likely initiated at the PA6-PS interface due to vitrification of the PS matrix during crystallization. Very imperfect PA6 crystals are formed in this low temperature crystallization region, leading to a strongly reduced crystallinity. These crystals show strong reorganization effects upon heating.     

微流控技术可控制备异形微颗粒功能材料的研究进展

异形功能性微颗粒由于具有独特的散射、流变和凝结等特性,被广泛应用于工业和临床医学等领域。微流控技术作为一种新兴的微流体操控技术,能够连续可控地制备尺寸均一、结构和功能多样化的微尺度材料。近年来,利用微流控技术制备异形功能微颗粒成为研究热点。主要综述了利用微流控技术制备多面体结构、棒条状、子弹形、多腔室结构、孔-壳形和螺旋形微颗粒功能材料的研究新进展,重点介绍了基于微流控通道的尺寸和形状的限制作用、基于微流控构建层流模板的可控光刻蚀、基于表面活性剂的种类或含量辅助诱导多重乳液反浸润过程和对利用微流控技术制备的单分散液滴进行二次操作制备异形微颗粒功能材料等方面的研究现状。     

Application of flow-focusing to the break-up of an emulsion jet for the production of matrix-structured microparticles

Powder behaviour and performances are intimately related to particle attributes defined by the size, shape and structure of the individual particles making up the powder. The heterogeneous nature of the vast majority of powders reflected in the broad distribution of these particle attributes gives rise to the well-known difficulties in the prediction of powder behaviours. To achieve a better predictability and ultimate control of the performances, significant research efforts have recently been made towards the production of particles with controlled attributes, i.e. structured particles with a very narrow size distribution. This paper presents a new method for the production of monodisperse matrix-structured microcapsules using a simple in-house designed and fabricated macroscopic flow cell. The method combines flow-focusing with laminar jet break-up of a water-in-oil emulsion jet in a bulk water phase that produces monodisperse water-in-oil-in-water dispersion templates. The templates are then converted into solid microcapsules with a matrix structure by solvent evaporation. Results presented in the paper confirm a transition of flow regime from jetting to dripping when the outer to inner flow rate ratio reaches a critical value, accompanied by an increase in the size of the resultant droplets from the break-up. Importantly, the transition imposes a limit to the smallest size of monodisperse droplets each flow cell can produce through flow-focusing. The smallest monodisperse microcapsules produced from the flow cell used in this study through flow-focusing are in diameter.     

Customized Design of Scalable Microfluidic Droplet Generators Using Step‐Emulsification Methods

Customized monodisperse microparticles and microcapsules can be produced by combining microfluidic droplet generation with subsequent particle solidification. Established microfluidic devices for droplet formation like flow‐focusing structures or T‐junctions provide high reproducibility and controllability, but are often limited in terms of throughput or variability. A higher throughput by means of simple numbering‐up can be achieved by applying alternative droplet formation mechanisms like step emulsification. Using laser‐ablated glass reactors designed in‐house, comprehensive studies with varied step geometry and process parameters were performed in order to provide fundamental data for general calculation methods allowing the fast design of customized microfluidic droplet generators.     

Nucleation and crystallization of PET droplets dispersed in an amorphous PC matrix

The present work compares the nucleation and crystallization process of poly(ethylene terephthalate) (PET) in bulk and when it is finely dispersed in a polycarbonate (PC) matrix. Two types of 80/20 PC/PET immiscible blends were prepared by twin-screw extrusion at different screw rotation rates in order to produce fine dispersions of PET. The results indicate that the finer the dispersion, the greater the inhibition of the crystallization of the PET droplets. These results are explained by demonstrating (through self-nucleation experiments) that a fractionated crystallization process was developed in the dispersed PET, since the number of PET particles was much greater than the number of heterogeneities originally present in the bulk polymer. The dispersion of PET into droplets also affects its crystallization rate during isothermal crystallization at high temperatures and its reorganization capacity during heating. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 70: 1725–1735, 1998