Liquid-liquid Demixing Research Articles

Liquid–Liquid Miscibility Gaps in Drug–Water Binary Systems: Crystal Structure and Thermodynamic Properties of Prilocaine and the Temperature–Composition Phase Diagram of the Prilocaine–Water System

EMLA cream, a "eutectic mixture of local anesthetics", was developed in the early 1980s by Astra Pharmaceutical Production. The mixture of anesthetics containing lidocaine, prilocaine, and water is liquid at room temperature, which is partly due to the eutectic equilibrium between prilocaine and lidocaine at 293 K, as was clear from the start. However, the full thermodynamic background for the stability of the liquid and its emulsion-like appearance has never been elucidated. In the present study of the binary system prilocaine-water, a region of liquid-liquid demixing has been observed, linked to a monotectic equilibrium at 302.4 K. It results in a prilocaine-rich liquid containing approximately 0.7 mol fraction of anesthetic. Similar behavior has been reported for the binary system lidocaine-water (Céolin, R.; et al. J. Pharm. Sci. 2010, 99 (6), 2756-2765). In the ternary mixture, the combination of the monotectic equilibrium and the above-mentioned eutectic equilibrium between prilocaine and lidocaine results in an anesthetic-rich liquid that remains stable below room temperature. This liquid forms an emulsion-like mixture in the presence of an aqueous solution saturated with anesthetics. Physical properties and the crystal structure of prilocaine are also reported.

Homogeneous Nucleation with Parallel Pathways

An extension of the thermodynamically-based nucleation theory that has been used successfully to describe sickle cell hemloglobin polymerization is presented. (Ferrone, Hofrichter, Eaton, 1985, JMB 183:611-631) This extension accounts for the possible interference of parallel assembly pathways such as liquid-liquid demixing, or disordered cluster formation, in a mathematically simple and physically intuitive way. We illustrate this theory by application to the crystallization of lysozyme, which exhibits a well-documented liquid-liquid demixing process and thus fills the role of an alternate pathway to assembly. The theory correctly describes an observed acceleration of the nucleation rates upon intersection of the barriers for nucleation and demixing. An interesting corollary of the theory presented here is that it provides a novel explanation for assembly processes that appear to proceed via monomeric nuclei.

High‐titer n‐butanol production by clostridium acetobutylicum JB200 in fed‐batch fermentation with intermittent gas stripping

Acetone-butanol-ethanol (ABE) fermentation with a hyper-butanol producing Clostridium acetobutylicum JB200 was studied for its potential to produce a high titer of butanol that can be readily recovered with gas stripping. In batch fermentation without gas stripping, a final butanol concentration of 19.1 g/L was produced from 86.4 g/L glucose consumed in 78 h, and butanol productivity and yield were 0.24 g/L h and 0.21 g/g, respectively. In contrast, when gas stripping was applied intermittently in fed-batch fermentation, 172 g/L ABE (113.3 g/L butanol, 49.2 g/L acetone, 9.7 g/L ethanol) were produced from 474.9 g/L glucose in six feeding cycles over 326 h. The overall productivity and yield were 0.53 g/L h and 0.36 g/g for ABE and 0.35 g/L h and 0.24 g/g for butanol, respectively. The higher productivity was attributed to the reduced butanol concentration in the fermentation broth by gas stripping that alleviated butanol inhibition, whereas the increased butanol yield could be attributed to the reduced acids accumulation as most acids produced in acidogenesis were reassimilated by cells for ABE production. The intermittent gas stripping produced a highly concentrated condensate containing 195.9 g/L ABE or 150.5 g/L butanol that far exceeded butanol solubility in water. After liquid-liquid demixing or phase separation, a final product containing ~610 g/L butanol, ~40 g/L acetone, ~10 g/L ethanol, and no acids was obtained. Compared to conventional ABE fermentation, the fed-batch fermentation with intermittent gas stripping has the potential to reduce at least 90% of energy consumption and water usage in n-butanol production from glucose.

Monte Carlo simulations of crystallization in heterogeneous copolymers: The role of copolymer fractions with intermediate comonomer content

Abstract

Conductive behavior in relation to domain morphology and phase diagram of Nafion/poly(vinylidene-co-trifluoroethylene) blends

Electron and proton conductive properties of Nafion/poly(vinylidene fluroride)-co- trifluoroethylene (PVDF-TrFE) blends were investigated in relation to domain morphology guided by phase diagram using differential scanning calorimetry, polarized optical microscopy, and AC impedance analyzers. A theoretical phase diagram was established by self-consistently solving the combined free energy density of Flory–Huggins theory for liquid-liquid demixing and the phase field theory for crystal solidification. Nafion/PVDF-TrFE blends revealed an hourglass type phase diagram, consisted of single phase crystal (Cr1), liquid + liquid (L1 + L2) and crystal + liquid (Cr1 + L2) coexistence regions. Guided by the phase diagram, the co-continuous or dispersed droplet domains were produced via phase separation induced either by solvent evaporation or thermal quenching. Fourier transformed infrared spectroscopy and water uptake measurements revealed swelling reduction in the Nafion/PVDF-TrFE blends. Accompanying the ferroelectric to paraelectric transition, the PVDF-TrFE copolymer exhibited a change of capacitor to insulator behavior with increasing temperature. Neat Nafion is poor electron conductor, but it becomes an ion conductor when hydrated. Electron/ion and proton conductivities of the 60/40 Nafion/PVDF-TrFE blend were discussed in relation to the comingled percolated morphology of the membrane.

Eutectic Mesophase Transitions and Induced Crystalline Phase in Mixtures of Hexagonal Columnar Liquid Crystal and Mesogenic Diacrylate

Eutectic behavior and the induced crystalline phase in mixtures of hexagonal columnar liquid crystal, 2, 3, 6, 7, 10, 11-hexakis-(pentyloxy) triphenylene (HPTP)/reactive mesogenic diacrylate monomer, 4-(3-acryloyloxypropyloxy)-benzoic acid 2-methyl-1, 4-phenylene ester (RM257) have been investigated both experimentally and theoretically. To determine the theoretical phase boundaries, we combined the free energy of Flory-Huggins free energy for liquid-liquid demixing, Maier-Saupe free energy of nematic ordering, and Chandrasekhar-Clark free energy of hexagonal ordering. The calculated phase diagram of the HPTP/RM257 blend is essentially of a eutectic type that consists of isotropic (I), nematic (N), and hexagonal columnar (Col(h)) regions, and nematic + isotropic (N+I), hexagonal columnar + isotropic (Col(h)+I), and hexagonal columnar + nematic (Col(h)+N) coexistence regions, bound by the liquidus and solidus lines. Of particular interest is the formation of an induced crystalline phase (Cr(in)) in the intermediate compositions of the HPTP/RM257 mixtures, exhibiting Cr(2) (RM257) + Cr(in) in the RM257-rich and Cr(in) + Cr(1) (HPTP) in the HPTP-rich regions.

New Insight into Phase Equilibria Involving Imidazolium Bistriflamide Ionic Liquids and Their Mixtures with Alcohols and Water

The fluid phase equilibria (liquid-liquid demixing behavior (LLE)) of mixtures of ionic liquids of the 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide family, [C(n)mim][NTf(2)], with 2-methylpropanol or n-octanol were investigated. Binary mixtures of [C(4)mim][NTf(2)] + alcohol and [C(6)mim][NTf(2)] + alcohol were compared to pseudobinary mixtures of (0.5[C(2)mim] + 0.5[C(6)mim])[NTf(2)] + alcohol and (0.5[C(2)mim] + 0.5[C(10)mim])[NTf(2)] + alcohol, respectively. Additionally, the presence of water in the studied alcohols or as a third component in the system was analyzed in order to check any possible deviation from the LLE observed for the anhydrous systems. Systems containing small fractions of ionic liquid show similar LLE between the corresponding binary and pseudobinary systems; however, large differences are observed in the presence of water when the IL mass fraction is increased.

MODELLING AND SIMULATION OF THE MICROSTRUC- TURE FORMATION IN A STRIP CAST Al-Pb ALLOY

When a single-phase liquid is cooled into the miscibility gap,it decomposes into two liquid phases.Generally the liquid-liquid phase transformation causes the formation of a solidification microstructure with serious phase segregation.Many efforts have been made to use the liquid-liquid demixing phenomenon for the production of the finely dispersed metal-metal composite materials. It is demonstrated that the only effective method of preventing the formation of the microstructure with heavy phase segregation in monotectic alloys is using the rapid solidification processing techniques. Strip casting may have great potentials in the manufacturing of the bulk materials of this kind of alloys. In this paper,a model was developed to describe the microstructure formation in a strip cast monotectic alloy based on the population dynamic method.The model takes into account the concurrent actions of the nucleation,diffusional growth and motions of the minority phase droplets.The model was numerically solved together with the controlling equations for the heat transfer,mass transport and momentum transfer to study the microstructure development in the strip cast Al-Pb alloys.The effects of alloy composition,solidification velocity and melting temperature on the microstructure formation were investigated.The results indicate that with the increase of the solidification velocity, the nucleation position of the minority phase droplets moves towards the solidification interface,the nucleation rate and number density of droplets increase and the average droplet size decreases.All these are favorable for the formation of a well dispersed microstructure.With the increase of the Pb content,the nucleation position of the minority phase droplets moves away form the solidification interface,the nucleation rate decreases,and the average droplet size increases.These are against the formation of a well dispersed microstructure.With the increase of the melting temperature, the nucleation rate and number density of droplets increase and the average droplet size decreases. These are favorable for the formation of a well dispersed microstructure.But the velocity of the minority phase droplets decreases with the increase of the melting temperature.When the velocity of droplets is negative,samples can not obtain steady state solidification and result in the formation of a microstructure with massive segregation.

Determination of the Thickness and Composition Profiles for a Film of Binary Mixture on a Solid Substrate

We determine the steady-state structures that result from liquid-liquid demixing in a free surface film of binary liquid on a solid substrate. The considered model corresponds to the static limit of the diffuse interface theory describing the phase separation process for a binary liquid (model-H), when supplemented by boundary conditions at the free surface and taking the influence of the solid substrate into account. The resulting variational problem is numerically solved employing a Finite Element Method on an adaptive grid. The developed numerical scheme allows us to obtain the coupled steady-state film thickness profile and the concentration profile inside the film. As an example we determine steady state profiles for a reflection-symmetric two- dimensional droplet for various surface tensions of the film and various preferential attraction strength of one component to the substrate. We discuss the relation of the results of the present diffuse interface theory to the sharp interface limit and determine the effective interface tension of the diffuse interface by several means.

Poly(vinyl alcohol) Membranes Having an Integrally Skinned Asymmetric Structure

Poly(vinyl alcohol) membranes, having integrally skinned asymmetric structures, were prepared by using 2-propanol and cosolvent composed of N-methyl-2-pyrrolidone and water, by phase inversion processes. In this work, the effects of cosolvent on the formation of integrally skinned structure of the asymmetric poly(vinyl alcohol) membranes were investigated and discussed from the morphological point of view. Experimental result indicated that the resulting membranes exhibited closely overall morphology change from a uniform cell structure to an asymmetric structure with a dense skin layer and a nonporous structure, by increasing the N-methyl-2-pyrrolidone ratio in the cosolvent. For this phenomenon, it was considered that as the N-methyl-2-pyrrolidone ratio in polymer solutions increased, due to a poor miscibility in between them, the inflow rate of 2-propanol decreased gradually, while the overall liquid-liquid demixing pattern between a cosolvent and 2-propanol depended on the outflow rate of the cosolvent during phase inversion.

Morphology and Formation Mechanism of Poly(Vinylidene Fluoride) Membranes Prepared with Immerse Precipitation: Effect of Dissolving Temperature

Poly(vinylidene fluoride) (PVDF) membranes were prepared by the immersion precipitation method. The effects of polymer dissolving temperature for the dopes on the morphology, crystallization and performance of prepared membranes were examined. Polymer dissolving temperature was varied from 50 to 120°C. N,N-dimethylacetamide (DMAc) and de-ionized water were used as solvent and non-solvent, respectively. Based on the membrane morphology and the schematic phase diagram of the ternary system, the membrane formation mechanism was analyzed theoretically. The binodal liquid-liquid demixing took place first for the nucleation and growth of droplets in the polymer poor phase; then consequently the spinodal liquid-liquid demixing occurred in the polymer rich phase. The demixings together resulted in the prepared membranes having a cross-section composed of interconnected globule-like particulates with bi-continuous structured surfaces. The dissolving temperature of the dopes had a remarkable effect on the morphology of the cross-section, even when the solution underwent a long time cooling before the demixing. The increase of the diameter of the particulates with the dissolving temperature was theoretically analyzed according to the conditions of the polymeric solution.

On the Role of the Dipole and Quadrupole Moments of Aromatic Compounds in the Solvation by Ionic Liquids

The diverse dipole and quadrupole moments of benzene and its 12 fluorinated derivatives are correlated to their solubility in the ionic liquid 1-ethyl-3-methyl-imidazolium bis(trifluoromethanesulfonyl)imide. Albeit empirical, the correlation was built taken into account molecular insights gained from ab initio calculations of the isolated aromatic solute molecules and molecular dynamics simulations of all 13 aromatic solute plus ionic liquid solvent binary mixtures. This type of molecular-assisted approach unveiled a simple correlation between the dipole and quadrupole moments of the solutes and the ionic liquid solvent. It also revealed the complex nature of the interactions between aromatic compounds and ionic liquids, with the charge density functions of the former acting as a sort of molecular template that promotes the segregation of the ions of the latter and defines the fluid phase behavior (liquid-liquid demixing) of the corresponding binary mixtures. Such an approach can be extended to other systems involving the interactions of different types of solutes with ionic liquid solvents.

Effects of photointensity gradient on directional crystal growth in blends of crystalline polymer and photoreactive monomer undergoing photopolymerization-induced phase transformation

Effects of light intensity gradient on development of intricate hierarchical morphology of semicrystalline polyethylene oxide (PEO) and photoreactive diacrylate (DA) blends undergoing photopolymerization-induced crystallization have been demonstrated experimentally and theoretically. The melting temperature of PEO was found to decline upon addition of DA monomer. A solid-liquid phase diagram has been established by self-consistently solving the combined phase field free energy of crystal solidification and Flory-Huggins (FH) free energy of liquid-liquid demixing. Dynamic calculations were performed using time-dependent Ginzburg-Landau (model C) equations by incorporating the combined phase field and FH free energy densities coupled with the photopolymerization kinetics. The spatiotemporal development of gradient morphology was computed under various intensity gradient profiles including linear, cylindrical, and Gaussian profiles. The observed seaweed or dense lamellar branching morphology of the PEO/DA blend is strikingly similar to the directionally grown interface structures observed in metals driven by external thermal gradients.

Theory and computation of photopolymerization-induced phase transition and morphology development in blends of crystalline polymer and photoreactive monomer

A hypothetical phase diagram of a crystalline polymer/photoreactive monomer mixture has been calculated on the basis of phase field (PF) free energy of crystal solidification in conjunction with Flory-Huggins (FH) free energy of liquid-liquid demixing to guide the morphology development during photopolymerization of poly(ethylene oxide)/triacrylate blend. The self-consistent solution of the combined PF-FH theory exhibits a crystalline-amorphous phase diagram showing the coexistence of solid+liquid gap bound by the liquidus and solidus lines, followed by an upper critical solution temperature at a lower temperature. When photopolymerization was triggered in the isotropic region, i.e., slightly above the crystal melting transition temperatures, the depressed melting transition line moves upward. When it surpasses the reaction temperature, both crystallization and phase separation occur. The temporal evolution of phase morphology is examined in the context of time-dependent Ginzburg-Landau equations coupled with the energy balance (heat conduction) equation using the aforementioned PF-FH free-energy densities. Of particular interest is that the emerged morphology in the crystalline blends depends on the competition between dynamics of liquid-liquid phase separation and/or liquid-solid phase transition (i.e., crystallization) and photopolymerization rates.

A Unified Theory of Liquid-Liquid Demixing and Polymer Formation Kinetics

Sickle hemoglobin is a natural hemoglobin mutation with a hydrophobic replacement of a charged aminoacid on the molecular surface. This leads to aggregation into rigid helical structures (“polymerization”), the underlying cause of sickle cell disease. It has also been shown that polymerization occurs in close correspondence with the phase transition of liquid-liquid demixing , or with the critically diverging fluctuations of local concentration occurring in its proximity. Due to this correspondence, polymerization kinetics remarkably appear to exhibit, with respect to demixing temperature, the same universal scaling features shown by amplitudes and lifetimes of fluctuations occurring in proximity of phase transitions. Thus, it is important to understand the relation between polymer formation and liquid-liquid demuxing (LLD). Nucleation kinetics have been described by a relatively complete theory, that until now does not include LLD. We present here a way to incorporate LLD seamlessly into such theory, so as to have a description in terms of the concurrence and interaction of the two processes. In addition, we present new light scattering data supporting the theory. The theory provides a more in-depth understanding of aggregation and crystallization.

Critical Behavior of Symmetrical Fluid Mixtures in Random Pores

We study the liquid-liquid demixing of a binary mixture with a symmetrical coupling to the quenched disorder by means of computer simulation. The critical point in the thermodynamic limit is estimated both by assuming the knowledge of the critical exponents and independently of them. The finite-size scaling analysis of the susceptibilities and the values of the critical amplitudes show that the universality class of the fluid mixture is compatible with the diluted quenched-Ising model. Our findings extend the class of systems exhibiting the same critical behavior of diluted antiferromagnets.

Protein crystallization: universal thermodynamic vs. specific effects of PEG

The interest of nucleation of protein crystals and aggregates (including oligomerization) spans from basic physics theory all the way to biophysics, nanophysics, clinical sciences, biotechnologies, food technologies and polymer-solvent interactions. Understanding nucleation within a theoretical framework capable of providing quantitative predictions and control of nucleation rates, or even the very occurrence of crystallization, is a long-sought goal of remarkable relevance to each of the above fields. A large amount of work has been aimed at such goal, but success has been so far rather limited. Work at our laboratory has more recently highlighted a direct link between nucleation rates and the universal scaling properties of concentration fluctuations occurring in the vicinity of a phase transition. The phase transition here concerned is that of non nucleated liquid-liquid demixing of the solution. This novel universality feature allows viewing nucleation processes within one and the same frame, and to capture all normalized nucleation rates on one and the same "master curve" for different proteins, as a function of one parameter only. The quantitative value of the latter is the result of the joint, non additive effects of protein composition, conformation and state (e.g. oligomers), as well as of the temperature of non nucleated liquid-liquid demixing of the solution at the given protein concentration and at the given conditions of the solution. The present work was undertaken for the purpose of ascertaining if (and if so, in what way) the universality feature can allow the quantitative prediction of nucleation rates changes caused by the addition to the solvent of additives empirically known for their strong effect on such rates, as well as the very occurrence of crystallization. To this purpose we have used PEG (polyethylene glycol), which is perhaps the most familiar and most-used additive, and have measured by static and dynamic light scattering the properties of concentration fluctuation of the system as a function of temperature, for various PEG concentration and polymerisation degrees. Experiments have shown that the action of PEG can in no way be accounted for in terms of changes of specific local contacts or of a one-to-one chaperone-like action. Instead, the effect of PEG is seen to be due to alteration of the thermodynamic properties of the solution. This leaves unchanged the universality features and consequently also the validity and predictive power of the master curve in the various conditions.

Structure and permeability of fluoroplastic membranes cast from polymer-solvent-precipitator ternary systems

The effects of various precipitators (inorganic and organic acids and mono-and polyatomic alcohols) on the solution behavior of the vinylidene fluoride copolymer with tetrafluroethylene (fluoroplastic F-42) and the characteristics of the related porous films have been studied. The used precipitators may be divided into two groups differing in precipitation numbers, namely, hard and soft. When hard precipitators initiating liquid-liquid demixing are introduced into solutions, relatively high-flux porous films may be cast. Soft precipitators cause gelation of the system owing to a partial crystallization of the polymer and afford films lacking hydraulic permeability.

Dynamics and morphology development in electrospun fibers driven by concentration sweeps

The present article describes the modeling and simulation of the dynamics of the electrospinning process coupled with the spatio-temporal evolution of fiber morphology driven by concentration sweeps. The electrospinning process has been modeled based on an array of beads connected by Maxwell’s elements in a cylindrical shell to describe the force balance between Coulombic and viscoelastic forces at the surface of the jet. The phase separation dynamics has been calculated in the framework of the Cahn-Hilliard time-evolution equation by incorporating Flory-Huggins free energy for liquid-liquid demixing in conjunction with solvent evaporation through the fiber surface. The simulations based on the coupling of these two processes have revealed in situ morphology development registering all structural forming processes such as polymer droplets, interconnected spinodal structure, and the porous structure along the spinline. The simulated porous fiber shows a striking resemblance to the experimental finding.

Salting-out in Aqueous Solutions of Ionic Liquids and K3PO4: Aqueous Biphasic Systems and Salt Precipitation

The salting-out effect produced by the addition of potassium phosphate, K3PO4to aqueous solutions of water-miscible ionic liquids, viz. 1-ethyl-3-methylimidazoliumethyl sulfate, 1-butyl-3-methylimidazolium methyl sulfate, or 1-alkyl-3-methylimidazolium chloride (alkyl = butyl, octyl or decyl) is investigated. The effects areanalyzed using both the corresponding temperature–composition pseudo-binary andcomposition ternary phase diagrams. Different regions of liquid-liquid and solid-liquidphase demixing are mapped. The phase behavior is interpreted taking into account thecomplex and competing nature of the interactions between the ionic liquid, the inorganicsalt and water. In the case of solutions containing 1-octyl- or 1-decyl-3-methylimidazoliumchloride, the smaller magnitude of the salting-out effects is explained in terms of thepossibility of self-aggregation of the ionic liquid.