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.
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 variation of the solution density and water activity due to the evolving solute concentration, and the diffusive interaction between neighboring droplets. 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.
Here, we describe a plug-and-play microfluidic platform, suitable for protein crystallization. The droplet factory is designed to generate hundreds of droplets as small as a few nanoliters (∼2 to 10 ...nL) for screening and optimization of crystallization conditions. Commercially available microfluidic junctions and tubing are combined to create the appropriate geometry. In addition, a “chemical library” is produced in tubing. The microfluidic geometry for a “crystallization agent-based chemical library” is validated by screening crystallization conditions of lysozyme. The microfluidic geometry for a “ligand-based chemical library” is also explored to co-crystallize the protein QR2 with a ligand, for the purposes of structure-based drug design. This platform mixes aqueous phases (containing the protein and the crystallization agent) and organic phases (containing the ligand), during the droplet generation and circulation without using any surfactant. The droplet composition is controlled by the respective flow rates of the different solutions, and checked by measuring online absorbance. The low volumes involved in the crystallization trials, the speed of execution, and the absence of a microfabrication stage make our platform a cheap, easy-to-use, and versatile tool for crystallization studies.
A multi-well setup with video-microscopy was used to study the influence of solvent on solubility, nucleation, and crystallization of an Active Pharmaceutical Ingredient (API): metformin ...hydrochloride (MET.HCl). Starting with 13 solvents covering a wide variety of polarity and proticity, we found 63 crystallization medium for MET.HCl solid generation: good solvents, good co-solvents and anti-solvent systems. For toxicological reasons, we limited the number of crystallization medium to 18: 3 good solvents (class 3), 3 good co-solvent systems and 12 anti-solvent systems. In order to study the influence of crystallization medium on nucleation temperature, crystal habit and polymorphism of MET.HCl, crystallization was studied by a cooling temperature method. Different crystal habits were observed by optical and scanning electron microscopies, and solid phase were characterized by X-ray powder diffraction, indicating that all the crystals correspond to the thermodynamic stable polymorphic form A of MET.HCl. Finally, the enthalpy of fusion and the melting temperature of MET.HCl were determined by DSC and confirmed the X-ray powder diffraction results.
•A multi-well set-up was used as a rapid tool to investigate Metformin Hydrochloride crystallization.•Solubility in 13 varied solvents was measured.•Different crystal habit appeared in five of six good solvents selected after the screening.•All crystals were characterized by MO, SEM, DSC and DRX.•Solubility data analysis and toxicity of solvents permits us to minimize the number of crystallization medium.
•Microfluidic method for the production of monodispersed hydrogel microparticles.•No use of surfactant.•Microparticle separation is simple and easy.•Microparticles of controllable sizes and ...mechanical properties are produced.
Seeking to produce microparticles that mimic red blood cells (RBCs), we present a microfluidic method of generating monodispersed hydrogel microparticles of Na-/Ca-alginate with controllable sizes (micrometer range) and mechanical properties. No surfactant is used. Transformation from Na-alginate to Ca-alginate microparticles is realized via ex situ gelation, which proves essential to obtaining desired microparticle properties, such as insolubility in water and RBC-like mechanical properties. For both Na-alginate and Ca-alginate microparticles, a smooth surface and a porous inner structure are observed under a scanning electron microscope. A platform of microgrippers is successfully developed to manipulate the microparticles. The Young’s modulus measured using an atomic force microscope on the surface of Ca-alginate microparticles is of the same order as that of RBCs.
This paper reports for the first time the crystallization of the carbamazepine (CBZ) molecule in two solvents (methanol and acetonitrile) using the non-photochemical laser-induced nucleation (NPLIN) ...technique. The metastable zone of CBZ is first determined experimentally for different temperatures in both solvents. Then, the prepared solutions are irradiated by a 532 nm wavelength nanosecond pulsed laser and permitted to obtain CBZ crystals of phases I and III. The impact of laser power and polarization (circularly (CP) and linearly (LP)) on the CBZ crystallization efficiency in both solvents is determined through experiments. According to the results, the crystallization efficiency is significantly higher in methanol than in acetonitrile, and it is higher in solutions irradiated by CP laser than those by LP laser. Moreover, the irradiation of an acetonitrile solution by a LP laser results in CBZ phases I and III, whereas irradiation by the CP laser leads to CBZ phase III crystals. An ab initio determination of the interaction energy of different pairs of CBZ has been carried-out that enables the explanation of the nucleation in acetonitrile for both polarizations. In methanol, only CBZ phase III is obtained, which is in agreement with the ability of methanol to create noncovalent interactions preventing the CBZ phase I and II nucleation.
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 repeated 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 set-up 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.
Phase diagrams of cocrystals often show a highly unsymmetrical nature. The solvent has an important impact on the overall aspect of these diagrams. In this paper, we show how the solvent affects the ...composition of the stoichiometric solid phase nucleated. Suitable conditions for nucleation and growth of a single 2:1 caffeine/maleic acid cocrystal are obtained in ethyl acetate, showing comparable solubility toward both caffeine and maleic acid. Through a full kinetic screen, we were able to identify, for the first time, reproducible conditions for the spontaneous crystallization of the 2:1 phase in solution. Furthermore, during the screening experiments, a hithertho unknown form of the 1:1 cocrystal phase was encountered. Structural X-ray diffraction analyses of both the 2:1, as well as the 1:1 polymorphic phases, show an out of plane maleic acid compound. The carboxylic acid groups are oriented in such a manner to promote intermolecular formation of hydrogen bonded synthons.
A solvent-assisted solid-to-solid polymorphic transition, which was assumed to be one of the key processes for the occurrence of preferential enrichment (PE), has been proven to occur by means of ...temperature-controlled video-microscopy (TCVM) and time-resolved in situ X-ray powder diffraction (XRPD) measurement during crystallization of two typical first-generation chiral racemic compounds (1 and 2) showing an excellent PE phenomenon.
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