A Multiscale Approach for the Characterization and Crystallization of Eflucimibe Polymorphs: from Molecules to Particles

We present in this paper a generic multiscale methodology for the characterization and crystallization of eflucimibe polymorphs. The various characterization techniques used have shown that eflucimibe polymorphism is due to a conformational change of the molecule in the crystal lattice. In addition, the two polymorphs are monotropically related in the temperature range tested and have similar structures and properties (ie. interfacial tension and solubility). Consequently, it was found that for a wide range of operating conditions, the polymorphs may crystallize concomitantly. Induction time measurements and metstable zone width determination allow to infer the origin of the concomitant appearance of the polymorphs. A predominance diagram has been established which allows to perfectly control the crystallization of the desired polymorph. However, even if the stable form can be produced in a reliable way, the crystal suspension went toward a very structured gel-like network which limits the extrapolation process. Based on microscopic observation of the crystallization events performed in a microfluidic crystallizer, we propose a range of operating conditions suitable for the production of the stable form with the desired handling properties

The study of atmospheric ice-nucleating particles via microfluidically generated droplets

Ice-nucleating particles (INPs) play a significant role in the climate and hydrological cycle by triggering ice formation in supercooled clouds, thereby causing precipitation and affecting cloud lifetimes and their radiative properties. However, despite their importance, INP often comprise only 1 in 10³–10⁶ ambient particles, making it difficult to ascertain and predict their type, source, and concentration. The typical techniques for quantifying INP concentrations tend to be highly labour-intensive, suffer from poor time resolution, or are limited in sensitivity to low concentrations. Here, we present the application of microfluidic devices to the study of atmospheric INPs via the simple and rapid production of monodisperse droplets and their subsequent freezing on a cold stage. This device offers the potential for the testing of INP concentrations in aqueous samples with high sensitivity and high counting statistics. Various INPs were tested for validation of the platform, including mineral dust and biological species, with results compared to literature values. We also describe a methodology for sampling atmospheric aerosol in a manner that minimises sampling biases and which is compatible with the microfluidic device. We present results for INP concentrations in air sampled during two field campaigns: (1) from a rural location in the UK and (2) during the UK’s annual Bonfire Night festival. These initial results will provide a route for deployment of the microfluidic platform for the study and quantification of INPs in upcoming field campaigns around the globe, while providing a benchmark for future lab-on-a-chip-based INP studies

Numerical Simulation of Droplet Formation in a Microfluidic Ice Nucleating Particle Measurement Device

Ice nucleating particles have a great impact on weather and climate by affecting the freezing process of water in the atmosphere. Therefore, INP measurements are essential to developing more accurate climate models. Despite of the importance of INP measurements, available measurement techniques are costly, which leads to scarcity of available data. Microfluidic technology offers unique features including small scales and low fabrication costs; thus, can be used to design and develop an INP instrument with lower operation costs, which can enhance the number of INP measurements. In this study, we used a microfluidic platform that can be further developed to an INP instrument. Our initial experiments showed that droplet formation in the microfluidic system can be affected by external factors, such as vibration and heat transfer. We have performed numerical simulations to derive the equations that describe droplet properties (size, generation frequency, and velocity) as a function of flow rate ratio. The derived correlation can be used in designing a future INP measurement device that features a method to keep the consistency of droplet formation. Moreover, the effect of cooling on pressure inside the channel was studied and it was found that cooling increases the pressure inside the channel due to increasing the viscosity of the fluids

Droplet-based microfluidic method for robust preparation of gold nanoparticles in axisymmetric flow focusing device

A novel microfluidic mixing strategy was developed and used to prepare polyvinylpyrrolidone (PVP) capped gold nanoparticles (AuNPs). In this process, 1 mM tetrachloroauric acid (HAuCl4) stream containing 1% (w/v) PVP was injected through the inner capillary tube and mixed with 20 mM L-ascorbic acid solution delivered co-currently through the outer coaxial capillary. The reaction mixture was hydrodynamically flow focused by the environmentally friendly oil Miglyol 840 delivered from the opposite side of the outer capillary, which resulted in the generation of reaction droplets in a tapered collection tube. The reactants were rapidly mixed within droplets by internal circulating flows induced by hydrodynamic interactions of fluids inside the droplets with the carrier oil. The size of the prepared AuNPs was measured by both dynamic light scattering and transmission electron microscopy and was found to decrease with decreasing the droplet size and increasing the difference in velocity between the two reactant streams, which improved mixing efficiency within droplets. The smallest nanoparticles were obtained when the outlet section of the injection tube was positioned at the entry section of the collection tube due to the highest shear at the liquid interface. The carrier oil formed a hydrophobic barrier between the droplets and the reactor walls preventing deposition of the synthesised particles. As a result, the size of the AuNPs was smaller than in the co-flow mixer operated with two continuous reactant streams

Droplet Microfluidics XRD Identifies Effective Nucleating Agents for Calcium Carbonate

The ability to control crystallization reactions is required in a vast range of processes including the production of functional inorganic materials and pharmaceuticals and the prevention of scale. However, it is currently limited by a lack of understanding of the mechanisms underlying crystal nucleation and growth. To address this challenge, it is necessary to carry out crystallization reactions in well‐defined environments, and ideally to perform in situ measurements. Here, a versatile microfluidic synchrotron‐based technique is presented to meet these demands. Droplet microfluidic‐coupled X‐ray diffraction (DMC‐XRD) enables the collection of time‐resolved, serial diffraction patterns from a stream of flowing droplets containing growing crystals. The droplets offer reproducible reaction environments, and radiation damage is effectively eliminated by the short residence time of each droplet in the beam. DMC‐XRD is then used to identify effective particulate nucleating agents for calcium carbonate and to study their influence on the crystallization pathway. Bioactive glasses and a model material for mineral dust are shown to significantly lower the induction time, highlighting the importance of both surface chemistry and topography on the nucleating efficiency of a surface. This technology is also extremely versatile, and could be used to study dynamic reactions with a wide range of synchrotron‐based techniques

Design of a Monosized Droplet Generator

This dissertation focuses on the development and validation of an instrument that allows the formation of drops. This document starts by showing the design developed for this purpose. After the development of the design, the pieces were built using 3D printing. When the process was complete, the device was assembled and validated. For the validation of this instrument, it was necessary to create a test station which is shown in chapter 3. After the entire assembly process, the validation tests were carried out. In the validation phase, water was applied to be ejected by the apparatus. Six different flow rates were implemented in order to determine the effect of the flow rate on the formation and behavior of the drops. The results of these tests were obtained through visualization methods. After all the images were collected in the testing phase, they were analyzed for the extraction of diameters. After the tests of undisturbed droplet formation were completed, the disturbed generation of droplets was proceeded to test. In this testing phase, three flows were chosen from the previous phase and imposed. The flow rates chosen for the disturbed phase of the generation of droplets were: 2.5, 4 and 5 ml/min. The proceedings for these tests was the flow and signal implementation. After the flow was implemented, the electromagnetic wave was built to be implemented in the piezoelectric cell. The electromagnetic signal consists of a square wave of constant amplitude (20 Vpp), where the frequency is periodically increased. The study with several frequencies aims to investigate the influence of frequency on the forma- tion of drops for the case of this instrument. This study allows testing whether the apparatus is capable of creating consecutive drops with high repeatability in terms of diameter and spacing between drops. Like the undisturbed cases, the disturbed droplet formation was also tested through visualization and image analysis.Esta dissertação foca-se no desenvolvimento e validação de um instrumento que permite a for- mação de gotas. Este documento começa por mostrar o design desenvolvido para este propósito. Após o desenvolvimento do design, as peças foram construídas recorrendo à impressão 3D. Após a impressão das peças, procedeu-se à montagem e validação do dispositivo. Para a validação deste instrumento, foi necessário criar uma estação de testes que é mostrada no capítulo 3. Após todo o processo de montagem, realizaram-se os testes de validação. Na fase de validação, usou-se água para a validação do aparelho. Seis caudais diferentes foram implementados, de forma a determinar o efeito do caudal na formação e comportamento das gotas. Os resultados destes testes foram obtidos através de métodos de visualização. Após todas as imagens serem recolhidas na fase de testes, estas foram analisadas para a extracção de diâmetros. Depois deste processo ter sido concluido, procedeu-se a testar a geração de gotas perturbada. Nesta fase de testes, três caudais foram escolhidos de entre os im,postos na primeira fase de validação e impostos. Os caudais escolhidos para a fase perturbada da geração de gotas foram: 2.5, 4 e 5 ml/min. O procedimento para estes testes foi a implementação do caudal e do sinal. Após a implementação do caudal, a onda electromagnética foi construída para implementar na célula piezoeléctrica. O sinal electromagnético consiste numa onda quadrada de amplitude constante (20 Vpp), onde a frequência é periodicamente aumentada. O estudo com várias frequências visa a investigação da influência da frequência na formação de gotas para o caso deste instrumento. Este estudo permite testar se o aparato é capaz de criar gotas consecutivas com alta repetibilidade no que toca a diâmetros e espaçamento entre gotas. À semelhança dos casos não perturbados, a formação perturbada de gotas também foi testada através de visualização e análise de imagem

Applications of CFD Simulations on Microfluidic Systems for Nanoparticle Synthesis

Microfluidics has been extensively investigated as a unique platform to synthesize nanoparticles with desired properties, e.g., size and morphology. Compared to the conventional batch reactors, wet-chemical synthesis using continuous flow microfluidics provides better control over addition of reagents, heat and mass transfer, and reproducibility. Recently, millifluidics has emerged as an alternative since it offers similar control as microfluidics. With its dimensions scaled up to millimeter size, millifluidics saves fabrication efforts and potentially paves the way for industrial applications. Good designs and manipulations of microfluidic and millifluidic devices rely on solid understanding of fluid dynamics. Fluid flow plays an important role in heat and mass transfer; thereby, it determines the quality of the synthesized nanoparticles. Computational fluid dynamics (CFD) simulations provide an effective approach to understand various effects on fluid flows without carrying out complicated experiments. The goal of this project is to utilize CFD simulations to study flow behaviors inside microfluidic and millifluidic. Residence time distribution (RTD) analysis coupled with TEM characterization was applied to investigate the effect of reagent flow rates on particle sizes distribution. Droplet-based microfluidics, as a solution to intrinsic drawbacks associated with single-phase microfluidics, depends on proper manipulation of the flow to generate steady droplet flow. The droplet / slug formation process inside a millifluidic reactor was investigated by both experiments and numerical simulations to understand the hydrodynamics of slug breaking. Geometric optimization was carried out to analyze the dependency of slug sizes on geometric dimensions. Numerical simulations were also performed to quantify the mixing efficiency inside slugs. This work provides insight to understand fluid flow inside microfluidic and millifluidic systems. It may benefit the design and operations of novel microfluidic and millifluidic systems

Protein Crystallization in Droplet-based Microsystems

The central focus of protein crystallization has been on the production of high quality (large well diffracting) protein crystals for protein structure determination by X-ray crystallography, being a complex and multiparametric process. The successful crystallization of a protein is determined both by thermodynamic and kinetic considerations, involving the optimization of several variables. In this context, the main goal of this work is to improve our understanding of protein crystallization, namely study the influence of some parameters on the process. For this, we propose a more rational screening strategy to the traditional trial-and-error approach. The latter is based in the use of phase diagrams at an early stage to analyse protein solubility. Further, an easy-to-use and cheap droplet-based microreactor will be explored to perform multiple protein crystallization trials. In fact, microreactors have been reported to provide a unique platform for investigating fundamental protein crystallization mechanisms, since they permit a large number of experiments under identical conditions, using small quantities of samples.status: accepte