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Romain Grossier

Publications and source records attributed to Romain Grossier.

10 recordsLinked to original sources
arXiv2025

Biomolecular crystallization in microfluidic devices

This chapter presents an overview of microfluidic devices reported in the literature, used to develop methodologies for nucleation of biomolecules, with crystal size control, and for collecting thermodynamic and kinetic data. Part I is dedicated to the properties of microfluidic devices through materials used for their fabrication and for crystals analysis. Part II describes the variety of microfluidic devices available and how to handle them to produce flows, droplets and/or wells of micrometer size. These devices use crystallization methods inspired by batch processes and they are mainly used for protein crystallization. Part III focuses on fundamental properties of biomolecule crystallization determined using droplet-based microfluidics: nucleation kinetics, nucleation rate and effective interfacial energy crystal/solution. Part IV explains how the kinetic effect of confinement due to micrometer size, and so nanovolumes, leads to isolation of different phases. These latter are characterized by X-Ray Diffraction (XRD) and methods to minimize manual handling of crystals for XRD are also presented, with appropriate equipment to store the crystals.

cond-mat.soft↗
arXiv2024

Rapid Polymorphic Screening using Sessile Microdroplets: Competitive Nucleation of Mannitol Polymorphs

We developed a rapid polymorphic screening approach based on contracting sessile microdroplets which offers several advantages: (1) achieves very high supersaturation to facilitate formation of metastable forms (2) allows systematic labeling of samples (3) gives access to statistical distribution of polymorphic selectivity as a function of experimental conditions (4) ensures the formation of crystal for each droplet, addressing the problem of uncrystallized droplets in traditional microfluidics. We studied the competitive nucleation of D-mannitol polymorphs and investigated the effect of droplet volume on polymorphic selectivity. We showed that our observed polymorph distributions at different volumes are qualitatively consistent with the predictions of classical nucleation theory except for very small volumes where thermodynamic confinement or surface effects could play a substantial role. Overall, our microfluidic approach can be a promising tool not only for routine screening of pharmaceutical polymorphs in the industrial context but also in the fundamental understanding of the mechanisms underlying the competitive nucleation of polymorphs.

cond-mat.soft↗
arXiv2023

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.

cond-mat.mtrl-sci↗
arXiv2023

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.

cond-mat.mtrl-sci↗
arXiv2022

Modular microfluidic platform for solubility measurement, nucleation statistics and polymorph screening of active pharmaceutical ingredients: Irbesartan, Rimonabant, Aripiprazole and Sulfathiazole

Drug efficacy strongly relies on the solid state of the active pharmaceutical ingredient. Classical solid-state screening methods involve different solvent compositions and supersaturations. Moreover, the many repeat experiments needed to address the stochasticity of nucleation make this approach costly. This paper presents a newly developed modular microfluidic platform that provides a universal and flexible plug-and-play tool for crystallisation studies without use of surfactants. By dissolving a powder, our setup generates saturated solutions that can be used for solubility measurements or distributed in microdroplets. Here, we describe solubility measurements performed on different forms, stable and metastable, of pharmaceutical molecules (Irbesartan, Rimonabant and Aripiprazole) in organic and aqueous solvents. In addition, we provide nucleation statistics obtained for Sulfathiazole in water and in acetonitrile. Reporting polymorph screening on Sulfathiazole and statistics for nucleated forms, we find that the cooling rate influences both nucleation and polymorphism results, reflecting the competition between thermodynamics and kinetics. Three unknown forms were discovered, with XRD patterns and Raman spectra that do not match any referenced form. We also demonstrate the limitations of microfluidics for crystallisation by cooling: reducing the crystalliser volume considerably increases nucleation induction time.

physics.app-ph↗
arXiv2022

Nucleation in Sessile Saline Microdroplets: Induction Time Measurement via Deliquescence-Recrystallization Cycling

Induction time, a measure of how long one will wait for nucleation to occur, is an important parameter in quantifying nucleation kinetics and its underlying mechanisms. Due to the stochastic nature of nucleation, efficient methods for measuring large number of independent induction times are needed to ensure statistical reproducibility. In this work, we present a novel approach for measuring and analyzing induction times in sessile arrays of microdroplets via deliquescence/recrystallization cycling. With the help of a recently developed image analysis protocol, we show that the interfering diffusion-mediated interactions between microdroplets can be eliminated by controlling the relative humidity, thereby ensuring independent nucleation events. Moreover, possible influence of heterogeneities, impurities, and memory effect appear negligible as suggested by our 2-cycle experiment. Further statistical analysis (k-sample Anderson-Darling test) reveals that upon identifying possible outliers, the dimensionless induction times obtained from different datasets (microdroplet lines) obey the same distribution and thus can be pooled together to form a much larger dataset. The pooled dataset showed an excellent fit with the Weibull function, giving a mean supersaturation at nucleation of 1.61 and 1.85 for the 60pL and 4pL microdroplet respectively. This confirms the effect of confinement where smaller systems require higher supersaturations to nucleate. Both the experimental method and the data-treatment procedure presented herein offer promising routes in the study of fundamental aspects of nucleation kinetics, particularly confinement effects, and are adaptable to other salts, pharmaceuticals, or biological crystals of interest.

cond-mat.mtrl-sci↗
arXiv2021

Evaporation Dynamics of Sessile Saline Microdroplets in Oil

The occurrence of concentration and temperature gradients in saline microdroplets evaporating directly in air makes them unsuitable for nucleation studies where homogeneous composition is required. This can be addressed by immersing the droplet in oil under regulated humidity and reducing the volume to the picoliter range. However, the evaporation dynamics of such a system is not well understood. In this work, we present evaporation models applicable for arrays of sessile microdroplets with dissolved solute submerged in a thin layer of oil. Our model accounts for the variable diffusion distance due to the presence of the oil film separating the droplet and air, the diffusive interaction of neighboring droplets, as well as the variation of the solution density and water activity due to the evolving solute concentration. Our model shows excellent agreement with experimental data for both pure water and NaCl solution. With this model, we demonstrate that assuming a constant evaporation rate and neglecting the diffusive interactions can lead to severe inaccuracies in the measurement of droplet concentration particularly during nucleation experiments. Given the significance of droplet evaporation in a wide array of scientific and industrial applications, the models and insights presented herein would be of great value to many fields of interest.

cond-mat.mtrl-sci↗
arXiv2020

Microfluidics platform for polymorph screening directly from powder

We describe a microfluidic platform for solid phase screening using extremely small quantities of raw materials. Based on our previous setup for solubility measurement that generates saturated solutions directly from powder, the platform requires no solution in excess of that used for the droplet-crystallization experiment. The setup is compatible with most solvents and molecules without using surfactant. Using this microfluidic platform, we first measured the solubility of Sulfathiazole in water, isopropanol, and acetonitrile. Second, we performed a polymorph screening of Sulfathiazole using as little as 30 mg of raw material, for numerous identical cooling crystallization experiments from 80 to 10{\textdegree}C. In the experiments presented, we obtained the 3 usual polymorphs of Sulfathiazole. We show that this economical approach yields reliable information on the probability of nucleation of a given polymorph, useful in pharmaceutical development.

physics.app-ph↗