We design and implement a simple and versatile droplet-based millifluidic method for investigating nucleation and growth processes in crystal-forming aqueous systems. It consists in generating and storing in a transparent capillary a train of identical and regularly-spaced droplets of an aqueous phase in a carrier oil phase, and then in video-monitoring crystal nucleation and subsequent growth and melting events as temperature and/or pressure are varied. Compared to previous investigations, the novelty is the possibility of working with aqueous solutions containing dissolved gas under controlled pressure, thus opening the way to gas hydrate studies. In the absence of dissolved gas, i.e., at ambient pressure, we observe ice nucleation to be weakly promoted by titanium oxide and montmorillonite particles, and strongly promoted by silver iodide, in agreement with literature results. Ice nucleation is also promoted when the carrier oil is more wetting towards the capillary, which is the case for fluorinated oil as compared to n-hexane. With cyclopentane, a hydrate-former, as the carrier oil, and dissolved CO2, also a hydrate-former and a "help gas" for cyclopentane hydrate formation, we find evidence for hydrate nucleation along with that of ice, and monitor the different solid phases as temperature varies. (C) 2018 Published by Elsevier Ltd.

This chapter presents different practical ways to address nucleation stochasticity. The methods use either statistical studies on spontaneous nucleation or local control of nucleation. Techniques developed in our laboratory are described: droplet-based microfluidics, microinjectors in oil, and external electrical or mechanical fields in confined systems. Results of nucleation kinetics obtained on various molecules are presented in terms of metastable zone, critical supersaturation, nucleation rate, induction time, interfacial energy of the critical nucleus, polymorphism, and detection of the critical nucleus. These practical approaches show considerable potential to increase understanding and control of the nucleation mechanism.

Droplet-based nucleation experiments reveal discrepancies in kinetic and thermodynamic factors. Here we examine how the chemical nature of the water-oil interface, and not the type of the device, used in different set-ups by three different groups impacts nucleation rate and explain discrepancies among lysozyme interfacial energies and pre-exponential factors encountered in the literature.

The nucleation mechanisms behind crystallized products remain mysterious. In this communication, we describe experiments performed using small volumes, microdroplets, to control nucleation and thus product properties. The effect of small-volume systems on nucleation is discussed. (C) 2012 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.

Le but de cette thèse est de développer un outil microfluidique d'étude de la cristallisation (et plus particulièrement de la nucléation) le plus adapté aux contraintes de l'industrie. C'est-à-dire un outil permettant de réaliser un grand nombre d'expériences de cristallisation tout en utilisant le moins de produits possible et en restant simple à mettre en place expérimentalement. Seule la microfluidique permet, en utilisant des volumes de l'ordre du nL, de répondre simultanément à ces deux contraintes. Les systèmes microfluidiques permettent en effet de générer des gouttes de quelques nanolitres qui sont autant de microcristallisoires permettant l'étude de la nucléation. Ce travail présente la mise au point de systèmes microfluidiques et des méthodes analytiques associées dédiés à l'étude de la nucléation de principes actifs pharmaceutiques. Un système microfluidique existant a été adapté afin de répondre dans un premier temps aux problèmes posés par la cristallisation de protéines dans l'eau. Ce système a permis de mesurer la limite de zone métastable ainsi que la fréquence de nucléation d'une protéine modèle, le lysozyme, également utilisée comme principe actif. Puis ce système a été à nouveau adapté afin de permettre l'étude de la nucléation dans des solvants organiques variés et donc l'étude d'un grand nombre de principes actifs pharmaceutiques. À l'occasion de cette nouvelle adaptation, des méthodes plus polyvalentes d'études de la nucléation ont dû être mises au point afin de résoudre les nouveaux problèmes soulevés.

This paper highlights the work of our group on the control and the observation of nucleation with techniques using nanotechnologies. This control is performed either by triggering nucleation in time with an external field or by localising it spatially in a microdroplet. Localisation in time using light irradiation induces nucleation by forming radicals; the use of electric field acts locally on the density of the solution. Localisation in space with a microfluidic device produces hundreds of nanovolume crystallisers where concentration and temperature are easily monitored. Thus, accurate statistical studies lead to the nucleation parameters (metastable zone, nucleation rate and polymorphism). Lastly, confinement with a microdroplet generator permits to reach very high supersaturations in fL to pL volumes allowing nucleation of a single crystal per microdroplet. All these methods clearly enhance nucleation in the metastable zone. Finally, they use small quantities of products offering potentialities for the screening of crystallisation conditions and phases (polymorphism).

We present an easy-to-use microfluidic set-up, easily transferable to the laboratory and determine an accurate method for metastable zone width measurement. We clearly define a zone in the phase diagram where nucleation is mononuclear. We nucleate a single crystal of metastable phase, which turns out to be stable. This approach holds promise for the control and the study of crystallization processes.

Microfluidic devices are increasingly used for the screening of crystallization conditions. Their advantage is the generation of droplets, every droplet being an independent crystallizer with volumes in the nanoliter range. This enables a large number of experiments to be carried out under identical conditions necessitating only small quantities of materials. However, classic microfluidic crystallization devices are made of poly(dimethylsiloxane), only compatible with an aqueous medium. In addition, they generally involve very complicated setups, often inaccessible to nonmicrofluidics specialists. In this paper, we overcome these drawbacks, presenting a cheap and universally applicable microfluidic crystallization tool. This thermostatted device makes it possible to study nucleation in both aqueous and organic solvents, rendering microfluidic devices applicable to organic molecules such as APIs, explosives, and metal oxide nanoparticles.

SessionsC282 this is the first structure with these ligands based on Fe, one of the most important metals in porphyrin biosystems.

Here we measure lysozyme nucleation kinetics using an easy-to-use and simply constructed microfluidics setup previously described. We confirm that microfluidics is a direct, accurate, and fast method to measure nucleation frequency using only a few milligrams of molecules, Moreover, our microfluidics setup, by diminishing crystallizer volumes, increases the experimental supersaturation range accessible and can be applied to all water-soluble molecules.

Thanks to an improved control of the nucleation, an original crystal growth method operating in stationary thermodynamic conditions has been developed. It allows rapid growth of crystals at constant temperature and supersaturation. As a case study, large KH2PO4 (KDP) crystals of high purity have been reproducibly obtained at constant temperatures and growth rates of 1 cm/day. Recorded X-ray diffraction topographs of as-grown crystals showed high crystal quality. This method opens the way for the rapid growth of high quality crystals for homogeneous intermediate compositions of solid solutions, doped crystals, and compounds exhibiting a weak solubility.