Microdroplet Approach for Measuring Aqueous Solubility and Nucleation Kinetics of a Metastable Polymorph: The case of KDP Phase IV

Solubility and interfacial energy are two fundamental parameters underlying the competitive nucleation of polymorphs. However, solubility measurement of metastable phases comes with a risk of solventmediated transformations which can render the results unreliable. In this work, we present a rapid microfluidic technique for measuring aqueous solubility of the metastable form using KDP Phase IV as a model system. This bracketing approach involves analyzing the dissolution behavior of crystals in contact with supersaturated microdroplets generated via evaporation. Then, with the help of our recently developed nucleation time measurement technique, together with Mersmann calculation of interfacial energies from solubilities, we were able to access the interfacial energies of both metastable and stable phases. To gain further insights into the observed nucleation behavior, we employed the Classical Nucleation Theory (CNT) to model the competition of polymorphs using our measured solubility and calculated interfacial energies. The results show that the stable form is favored at lower supersaturation while the metastable form is favored at higher supersaturation, in good agreement with our observations and experimental reports in the literature. Overall, our microfluidic approach allows access to unprecedentedly deep levels of supersaturation and reveals an interesting interplay between thermodynamics and kinetics in polymorphic nucleation. The experimental methods and insights presented herein can be of great interest, notably in the mineral processing and pharmaceutical industry

CNT effective interfacial energy and pre-exponential kinetic factor from measured NaCl crystal nucleation time distributions in contracting microdroplets

Nucleation, the birth of a stable cluster from disorder, is inherently stochastic. Yet up to date, there are no quantitative studies on NaCl nucleation that accounts for its stochastic nature. Here, we report the first stochastic treatment of NaCl-water nucleation kinetics. Using a recently developed microfluidic system and evaporation model, our measured interfacial energies extracted from a modified Poisson distribution of nucleation time show an excellent agreement with theoretical predictions. Furthermore, analysis of nucleation parameters in 0.5 pL, 1.5pL and 5.5 pL microdroplets reveals an interesting interplay between kinetic confinement and shifting of nucleation mechanisms. Overall, our findings highlight the need to treat nucleation stochastically rather deterministically to bridge the gap between theory and experiment

Development and analysis of methods for quantifying nucleation kinetics in agitated crystallizers and microfluidic systems

La nucléation est une étape essentielle dans les processus de cristallisation utilisés en industrie (pharmaceutique, cosmétique, chimie fine…). Cependant, des questions fondamentales restent sur la cinétique de nucléation, que cette thèse cherche à quantifier par des méthodes innovantes : dans des cristallisoirs agités à grande échelle industriellement pertinents, et dans des gouttes en systèmes microfluidiques (nL, pL), avec un intérêt fondamental. A l'échelle du L, nous suivons l'évolution du nombre de particules et de la concentration de la solution en utilisant la réflectance optique couplée à la spectroscopie Raman in situ. En extrapolant le nombre de particules jusqu'à une vitesse d'agitation nulle, nous obtenons la cinétique de nucléation primaire. A l’échelle du mL et du µL, l'approche de distribution du temps d'induction donne des paramètres de cinétique de nucléation qui s’écartent de sept ordres de grandeurs par rapport au L, les rendant inexploitables en industrie. Toutefois, les valeurs d'énergie interfaciale effective γeff sont cohérentes à toutes ces échelles en milieu agité. Tandis qu’au nL, en microfluidique à base de gouttes dans des capillaires, γeff est élevée due à la barrière thermodynamique. Au pL, en microfluidique à base de gouttes sessiles sur une surface, nous détectons le temps d’induction via des cycles de déliquescence-efflorescence. Un modèle d'évaporation nous donne la sursaturation au moment de la nucléation et une distribution de Poisson modifiée, la stochasticité de la nucléation. Grâce à ces trois développements, nous quantifions les paramètres de la cinétique de nucléation, avec une cohérence entre théorie et expériences.Nucleation is a key step in crystallization processes which are widely used in almost all sorts of industries (pharmaceuticals, cosmetics, fine chemicals, etc.). Thus, fundamental understanding of its nucleation kinetics is of immense importance yet it remains poorly understood from both experimental and theoretical perspective. With these motivations, this thesis seeks to develop innovative methods in quantifying nucleation kinetics both in industrially-relevant agitated crystallizers and in fundamentally-oriented microfluidic systems. Starting with agitated crystallizers, a protocol for estimating primary nucleation was developed based on laser backscattering which involves extrapolating the nucleation rates to zero agitation. To validate the approach, a multiscale investigation of nucleation kinetic parameters was performed using various techniques in L, mL, and µL scales. This sheds light into the transferability of kinetic data for engineering purposes. To focus on the fundamental aspects of nucleation, an approach to extract nucleation kinetic parameters from evaporative microcrystallizers was developed, using microdroplets at pL scale. This involves the measurement of induction time via deliquescence-efflorescence cycle, the derivation of evaporation model to accurately determine the supersaturation at nucleation, and the use of a modified Poisson distribution to model the stochastic nature of nucleation and extract nucleation kinetic parameters. The combination of these three developments have led to a successful quantification of nucleation kinetic parameters in evaporating microdroplets, demonstrating a remarkable agreement between theory and experiment

Développement et analyse de méthodes de quantification de la cinétique de nucléation dans les cristallisoirs agités et les systèmes microfluidiques

Nucleation is a key step in crystallization processes which is a crucial unit operation in the manufacture and purification of products, occurring in almost all sorts of industries including foods, pharmaceuticals, cosmetics, fine chemicals, ceramics, metallurgy and electronics. Thus, fundamental understanding of its nucleation kinetics is of immense importance yet it remains poorly understood from both experimental and theoretical perspective. With these motivations, this thesis seeks to develop innovative methods in quantifying nucleation kinetics both in industrially-relevant agitated crystallizers and in fundamentally-oriented microfluidic systems. Starting with agitated crystallizers, a protocol for estimating primary nucleation was developed based on laser backscattering which involves extrapolating the nucleation rates to zero agitation. To validate the approach, a multiscale investigation of nucleation kinetic parameters was performed using various techniques in L, mL, and μL scales. This sheds light into the transferability of kinetic data for engineering purposes. To focus on the fundamental aspects of nucleation, an approach to extract nucleation kinetic parameters from evaporative microcrystallizers was developed, using microdroplets at pL scale. This involves the measurement of induction time via deliquescence-efflorescence cycle, the derivation of evaporation model to accurately determine the supersaturation at nucleation, and the use of a modified Poisson distribution to model the stochastic nature of nucleation and extract nucleation kinetic parameters. The combination of these three developments have led to a successful quantification of nucleation kinetic parameters in evaporating microdroplets (i.e; at variable supersaturation), demonstrating a remarkable agreement between theory and experiment.La nucleation est une etape essentielle dans le processus de cristallisation, qui est notamment utilise pour la fabrication et la purification de produits industriels (pharmaceutiques, cosme tiques, de chimie fine, alimentaires, ce ramiques, de me tallurgie et d'e lectronique). Cependant, il reste encore des questions fondamentales, notamment sur la cine tique de nucle ation qui est cruciale dans ces applications. Cette the se cherche a mieux comprendre la nucle ation des cristaux par le de veloppement de me thodes innovantes pour quantifier cette cine tique de nucle ation : dans des cristallisoirs agite s a grande e chelle (L, mL, μL) qui sont industriellement pertinents, ainsi qu’a petite e chelle (nL, pL) dans des syste mes microfluidiques a base de microgouttelettes qui pre sentent un inte re t fondamental. A l'e chelle du L, la mesure de la re flectance optique couple e a la spectroscopie Raman in situ nous a permis de suivre l'e volution du nombre de particules et de la concentration de la solution. Et par l’extrapolation du de compte des particules jusqu'a une vitesse d'agitation nulle, nous avons extrait la cine tique de nucle ation primaire. A l’e chelle du mL et du μL en syste mes agite s, les parame tres de la cine tique de nucle ation obtenus par l'approche de distribution du temps d'induction re ve lent des e carts de six a sept ordres de grandeur, par rapport a ceux obtenus dans des volumes de l’ordre du L, ce qui les rend inexploitables a l'e chelle industrielle. Toutefois, les valeurs d'e nergie interfaciale effective γeff sont relativement cohe rentes a toutes ces e chelles. Tandis qu’a l’e chelle du nL, en microfluidique a base de microgouttelettes dans des capillaires, l’e nergie interfaciale effective γeff est e leve e. Ceci est lie a la barrie re thermodynamique e leve e pour atteindre la nucle ation. Par conse quent, la sursaturation doit y e tre tre s e leve e pour nucle er, faisant ainsi de la nucle ation homoge ne le me canisme pre dominant. A l’e chelle du pL, la me thode microfluidique est base e sur la ge ne ration de microgouttelettes sessiles sur une surface. Le temps de nucle ation est de tecte par microscopie in situ et analyse d'images lors de cycles de de liquescence-efflorescence, la sursaturation au moment de la nucle ation est de termine e avec pre cision a partir d'un mode le d'e vaporation que j'ai de veloppe , et la nature stochastique de la nucle ation est analyse e a l'aide d'une distribution de Poisson modifie e. Ainsi la combinaison de ces trois de veloppements nous a permis de quantifier les parame tres de la cine tique de nucle ation dans les microgouttelettes en e vaporation, avec une cohe rence entre la the orie et l'expe rience

Développement et analyse de méthodes de quantification de la cinétique de nucléation dans les cristallisoirs agités et les systèmes microfluidiques

Nucleation is a key step in crystallization processes which is a crucial unit operation in the manufacture and purification of products, occurring in almost all sorts of industries including foods, pharmaceuticals, cosmetics, fine chemicals, ceramics, metallurgy and electronics. Thus, fundamental understanding of its nucleation kinetics is of immense importance yet it remains poorly understood from both experimental and theoretical perspective. With these motivations, this thesis seeks to develop innovative methods in quantifying nucleation kinetics both in industrially-relevant agitated crystallizers and in fundamentally-oriented microfluidic systems. Starting with agitated crystallizers, a protocol for estimating primary nucleation was developed based on laser backscattering which involves extrapolating the nucleation rates to zero agitation. To validate the approach, a multiscale investigation of nucleation kinetic parameters was performed using various techniques in L, mL, and μL scales. This sheds light into the transferability of kinetic data for engineering purposes. To focus on the fundamental aspects of nucleation, an approach to extract nucleation kinetic parameters from evaporative microcrystallizers was developed, using microdroplets at pL scale. This involves the measurement of induction time via deliquescence-efflorescence cycle, the derivation of evaporation model to accurately determine the supersaturation at nucleation, and the use of a modified Poisson distribution to model the stochastic nature of nucleation and extract nucleation kinetic parameters. The combination of these three developments have led to a successful quantification of nucleation kinetic parameters in evaporating microdroplets (i.e; at variable supersaturation), demonstrating a remarkable agreement between theory and experiment.La nucleation est une etape essentielle dans le processus de cristallisation, qui est notamment utilise pour la fabrication et la purification de produits industriels (pharmaceutiques, cosme tiques, de chimie fine, alimentaires, ce ramiques, de me tallurgie et d'e lectronique). Cependant, il reste encore des questions fondamentales, notamment sur la cine tique de nucle ation qui est cruciale dans ces applications. Cette the se cherche a mieux comprendre la nucle ation des cristaux par le de veloppement de me thodes innovantes pour quantifier cette cine tique de nucle ation : dans des cristallisoirs agite s a grande e chelle (L, mL, μL) qui sont industriellement pertinents, ainsi qu’a petite e chelle (nL, pL) dans des syste mes microfluidiques a base de microgouttelettes qui pre sentent un inte re t fondamental. A l'e chelle du L, la mesure de la re flectance optique couple e a la spectroscopie Raman in situ nous a permis de suivre l'e volution du nombre de particules et de la concentration de la solution. Et par l’extrapolation du de compte des particules jusqu'a une vitesse d'agitation nulle, nous avons extrait la cine tique de nucle ation primaire. A l’e chelle du mL et du μL en syste mes agite s, les parame tres de la cine tique de nucle ation obtenus par l'approche de distribution du temps d'induction re ve lent des e carts de six a sept ordres de grandeur, par rapport a ceux obtenus dans des volumes de l’ordre du L, ce qui les rend inexploitables a l'e chelle industrielle. Toutefois, les valeurs d'e nergie interfaciale effective γeff sont relativement cohe rentes a toutes ces e chelles. Tandis qu’a l’e chelle du nL, en microfluidique a base de microgouttelettes dans des capillaires, l’e nergie interfaciale effective γeff est e leve e. Ceci est lie a la barrie re thermodynamique e leve e pour atteindre la nucle ation. Par conse quent, la sursaturation doit y e tre tre s e leve e pour nucle er, faisant ainsi de la nucle ation homoge ne le me canisme pre dominant. A l’e chelle du pL, la me thode microfluidique est base e sur la ge ne ration de microgouttelettes sessiles sur une surface. Le temps de nucle ation est de tecte par microscopie in situ et analyse d'images lors de cycles de de liquescence-efflorescence, la sursaturation au moment de la nucle ation est de termine e avec pre cision a partir d'un mode le d'e vaporation que j'ai de veloppe , et la nature stochastique de la nucle ation est analyse e a l'aide d'une distribution de Poisson modifie e. Ainsi la combinaison de ces trois de veloppements nous a permis de quantifier les parame tres de la cine tique de nucle ation dans les microgouttelettes en e vaporation, avec une cohe rence entre la the orie et l'expe rience

Microdroplet Approach for Measuring Aqueous Solubility and Nucleation Kinetics of a Metastable Polymorph: The case of KDP Phase IV

Solubility and interfacial energy are two fundamental parameters underlying the competitive nucleation of polymorphs. However, solubility measurement of metastable phases comes with a risk of solventmediated transformations which can render the results unreliable. In this work, we present a rapid microfluidic technique for measuring aqueous solubility of the metastable form using KDP Phase IV as a model system. This bracketing approach involves analyzing the dissolution behavior of crystals in contact with supersaturated microdroplets generated via evaporation. Then, with the help of our recently developed nucleation time measurement technique, together with Mersmann calculation of interfacial energies from solubilities, we were able to access the interfacial energies of both metastable and stable phases. To gain further insights into the observed nucleation behavior, we employed the Classical Nucleation Theory (CNT) to model the competition of polymorphs using our measured solubility and calculated interfacial energies. The results show that the stable form is favored at lower supersaturation while the metastable form is favored at higher supersaturation, in good agreement with our observations and experimental reports in the literature. Overall, our microfluidic approach allows access to unprecedentedly deep levels of supersaturation and reveals an interesting interplay between thermodynamics and kinetics in polymorphic nucleation. The experimental methods and insights presented herein can be of great interest, notably in the mineral processing and pharmaceutical industry

Microdroplet Approach for Measuring Aqueous Solubility and Nucleation Kinetics of a Metastable Polymorph: The Case of KDP Phase IV

Solubility and interfacial energy are two fundamental parameters underlying the competitive nucleation of polymorphs. However, solubility measurement of metastable phases comes with a risk of solvent-mediated transformations, which can render the results unreliable. In this work, we present a rapid microfluidic technique for measuring the aqueous solubility of the metastable form using KDP Phase IV as a model system. This bracketing approach involves analyzing the dissolution behavior of crystals in contact with supersaturated microdroplets generated via evaporation. Then, with the help of our recently developed nucleation time measurement technique, together with Mersmann calculation of interfacial energies from solubilities, we were able to access the interfacial energies of both the metastable and stable phases. To gain further insights into the observed nucleation behavior, we employed Classical Nucleation Theory (CNT) to model the competition of polymorphs using our measured solubility and calculated interfacial energies. The results show that the stable form is favored at lower supersaturation, while the metastable form is favored at higher supersaturation, in good agreement with our observations and experimental reports in the literature. Overall, our microfluidic approach allows access to unprecedentedly deep levels of supersaturation and reveals an interesting interplay between thermodynamics and kinetics in polymorphic nucleation. The experimental methods and insights presented herein can be of great interest, notably in the mineral processing and pharmaceutical industry

Microdroplet Approach for Measuring Aqueous Solubility and Nucleation Kinetics of a Metastable Polymorph: The Case of KDP Phase IV

Solubility and interfacial energy are two fundamental parameters underlying the competitive nucleation of polymorphs. However, solubility measurement of metastable phases comes with a risk of solvent-mediated transformations, which can render the results unreliable. In this work, we present a rapid microfluidic technique for measuring the aqueous solubility of the metastable form using KDP Phase IV as a model system. This bracketing approach involves analyzing the dissolution behavior of crystals in contact with supersaturated microdroplets generated via evaporation. Then, with the help of our recently developed nucleation time measurement technique, together with Mersmann calculation of interfacial energies from solubilities, we were able to access the interfacial energies of both the metastable and stable phases. To gain further insights into the observed nucleation behavior, we employed Classical Nucleation Theory (CNT) to model the competition of polymorphs using our measured solubility and calculated interfacial energies. The results show that the stable form is favored at lower supersaturation, while the metastable form is favored at higher supersaturation, in good agreement with our observations and experimental reports in the literature. Overall, our microfluidic approach allows access to unprecedentedly deep levels of supersaturation and reveals an interesting interplay between thermodynamics and kinetics in polymorphic nucleation. The experimental methods and insights presented herein can be of great interest, notably in the mineral processing and pharmaceutical industry