Complex Phase Separation Research Articles

Alginate Microbeads Technology for Pharmaceutical Applications

Nowadays, microbeads are inevitable in pharmaceutical formulations with remarkable drug delivery and therapeutic outcome benefits. Usually made from biocompatible polymers, these tiny spherical particles allow for controlled and targeted delivery of APIs within the human body. Other benefits associated with microbeads include their ability to control drug release kinetics in terms of sustained or pulsatile release profiles in order to facilitate patient compliance and minimize adverse effects. This also has a minimal size and allows for adaptation for precise dosing and targeting the right sites, which augments therapeutic efficacy while cutting down systemic exposure. The need for safe and effective drug delivery systems has been a crucial aspect in the advancement of new pharmaceutical formulations. Researchers continue to seek new ways in prolonging drug release, minimizing drug wastage, and reducing the side effects of drugs. However, synthetic polymers are costly, non-biocompatible, and potentially toxic. On the other hand, sodium alginate, a natural polymer, is generally used as a matrix material because of biodegradability, low price, simplicity, and excellent biocompatibility. Sodium alginate is nontoxic when delivered orally and gives protection on the mucous membrane of the upper gastrointestinal tract. Sodium alginate is an anionic polysaccharide of natural origin wherein gelation can be obtained with the use of calcium ions to form stable microbeads. There are multiple techniques used to prepare alginate microbeads, that is, ionotropic gelation, cross-linking, emulsion gelation, spray drying, and both simple and complex coacervation phase separation methods. This review shall highlight the preparation and characterization of alginate microbeads, their therapeutic applications, and their position in the realm of controlled and novel drug delivery systems

COCOMO2: A coarse-grained model for interacting folded and disordered proteins.

Biomolecular interactions are essential in many biological processes, including complex formation and phase separation processes. Coarse-grained computational models are especially valuable for studying such processes via simulation. Here, we present COCOMO2, an updated residue-based coarse-grained model that extends its applicability from intrinsically disordered peptides to folded proteins. This is accomplished with the introduction of a surface exposure scaling factor, which adjusts interaction strengths based on solvent accessibility, to enable the more realistic modeling of interactions involving folded domains without additional computational costs. COCOMO2 was parameterized directly with solubility and phase separation data to improve its performance on predicting concentration-dependent phase separation for a broader range of biomolecular systems compared to the original version. COCOMO2 enables new applications including the study of condensates that involve IDPs together with folded domains and the study of complex assembly processes. COCOMO2 also provides an expanded foundation for the development of multi-scale approaches for modeling biomolecular interactions that span from residue-level to atomistic resolution.

Chemically reactive and aging macromolecular mixtures. I. Phase diagrams, spinodals, and gelation

Multicomponent macromolecular mixtures often form higher-order structures, which may display non-ideal mixing and aging behaviors. In this work, we first propose a minimal model of a quaternary system that takes into account the formation of a complex via a chemical reaction involving two macromolecular species; the complex may then phase separate from the buffer and undergo a further transition into a gel-like state. We subsequently investigate how physical parameters such as molecular size, stoichiometric coefficients, equilibrium constants, and interaction parameters affect the phase behavior of the mixture and its propensity to undergo aging via gelation. In addition, we analyze the thermodynamic stability of the system and identify the spinodal regions and their overlap with gelation boundaries. The approach developed in this work can be readily generalized to study systems with an arbitrary number of components. More broadly, it provides a physically based starting point for the investigation of the kinetics of the coupled complex formation, phase separation, and gelation processes in spatially extended systems.

Sensing characteristics and EPIR Studies on composite manganites: Role of nanoparticles in the micronsized matrix lattice

In the present communication, the electrical transport properties have been investigated for manganite-based composites consisting of different weight fractions of nanoparticles of LaMnO3 (LMO) and polycrystalline La0.7Ca0.3MnO3 (LCMO). A complex phase separation scenario has been proposed to understand the hysteretic resistive nature exhibited by manganite matrix composites. The role of complex phase separation has been discussed for the manganite composite resistivity and temperature coefficient of resistance (TCR) dependence on temperature, thermal cycle, current and LMO content as well as their sensitivity for voltage and current have also been examined. Observed electric pulse-induced resistance (EPIR) switching in these composites under different applied voltages and magnetic fields have been understood based on a complex phase separation scenario and the formation–rupture of conducting filamentary paths. Tuning of magnetic field-dependent resistance and magnetoresistance (MR) with the influence of different resistance states of LMO–LCMO composites has been understood in depth.

Tuning the low-temperature phase behavior of aqueous ionic liquids.

Water's anomalous behavior is often explained using a two-liquid model, where two types of water, high-density liquid (HDL) and low-density liquid (LDL), can be separated via a liquid-liquid phase transition (LLPT) at low temperature. Mixtures of water and the ionic liquid hydrazinium trifluoroacetate were suggested to also show an LLPT but with the advantage that there is no rapid ice crystallization hampering its observation. It remains controversial whether these solutions exhibit an LLPT or are instead associated with complex phase separation phenomena. We here show detailed low-temperature calorimetry and diffraction experiments on aqueous solutions containing hydrazinium trifluoroacetate and other similar ionic liquids, all at a solute mole fraction of x = 0.175. Hydrazinium trifluoroacetate, ammonium trifluoroacetate, ethylammonium trifluoroacetate and hydrazinium pentafluoropropionate all boast exothermic transitions unrelated to crystallization as well as remarkable structural changes upon cooling into the glassy state. We propose a model inspired by micelle formation and decomposition in surfactant solutions, which is complemented by MD simulations and allows rationalizing the rich phase behavior of our mixtures during cooling. The fundamental aspect of the model is the hydrophobic nature of fluorinated anions that enables aggregation, which is reversed upon cooling and culminates in the remarkable exothermic first-order transition observed at low temperature. That is, we assign the first-order transition not to an LLPT but to phase-separations similar to the ones when falling below the Krafft temperature. All other solutions merely show simple vitrification behavior. Still, they exhibit distinct differences in liquid fragility, which is decreased continuously with decreasing hydrophobicity of the anions. This might enable the systematic tuning of ionic liquids with the goal of designing aqueous solutions of specific fragility.

Solvent-Tailored Reversible Self-Assembly: Unveiling Ionic Transport Nanochannels in Block Copolymer Composite Electrolytes.

Block copolymer composite electrolytes have gained extensive attention for their promising performance in ionic conductivity and mechanical properties, making them valuable for future technologies. The control of the ionic conductivity through the self-assembly of block copolymers, however, remains a great challenge, especially in confined environments. In this study, we prepare block copolymer composite electrolytes using polystyrene-block-poly(ethylene oxide) (PS-b-PEO, SEO) as the polymer matrix and anodic aluminum oxide (AAO) templates as the ceramic skeleton. The self-assembly of SEO creates nanoscale ion transport pathways in the PEO regions through ionic interactions with lithium salts. The nanopores of the AAO templates provide a confined environment for complex phase separation of SEO controlled by selective solvent vapor annealing. Our findings demonstrate that transforming self-assembled SEO structures allows for precise control of ion transport pathways with cylindrical structures exhibiting 20 times higher ionic conductivities than those of helical structures. For AAO templates with pore diameters of 20 nm (SEO-LiTFSI@AAO-20), the ionic conductivities are approximately 410 times higher than those with pore diameters of 200 nm (SEO-LiTFSI@AAO-200), owing to the larger specific surface areas within the smaller nanopores. Utilizing the self-assembly of SEO not only enables the construction of vertically aligned ion transport channels on various scales but also offers a fascinating approach to tailor the conductive capabilities of composite electrolytes, enhancing the ion transport efficiency and allowing for the flexible design of block copolymer composite electrolytes.

Phase separation promotes a highly active oligomeric scaffold of the MLL1 core complex for regulation of histone H3K4 methylation

Enzymes that regulate the degree of histone H3 lysine 4 (H3K4) methylation are crucial for proper cellular differentiation and are frequently mutated in cancer. The Mixed lineage leukemia (MLL) family of enzymes deposit H3K4 mono-, di-, or trimethylation at distinct genomic locations, requiring precise spatial and temporal control. Despite evidence that the degree of H3K4 methylation is controlled in part by a hierarchical assembly pathway with key subcomplex components, we previously found that the assembled state of the MLL1 core complex is not favored at physiological temperature. To better understand this paradox, we tested the hypothesis that increasing the concentration of subunits in a biomolecular condensate overcomes this thermodynamic barrier via mass action. Here, we demonstrate that MLL1 core complex phase separation stimulates enzymatic activity up to 60-fold but not primarily by concentrating subunits into droplets. Instead, we found that stimulated activity is largely due to the formation of an altered oligomeric scaffold that greatly reduces substrate Km. We posit that phase separation-induced scaffolding of the MLL1 core complex is a potential "switch-like" mechanism for spatiotemporal control of H3K4 methylation through the rapid formation or dissolution of biomolecular condensates within RNA Pol II transcription factories.

Active Brownian particles in random and porous environments.

The transport of active particles may occur in complex environments, in which it emerges from the interplay between the mobility of the active components and the quenched disorder of the environment. Here, we explore the structural and dynamical properties of active Brownian particles (ABPs) in random environments composed of fixed obstacles in three dimensions. We consider different arrangements of the obstacles. In particular, we consider two particular situations corresponding to experimentally realizable settings. First, we model pinning particles in (non-overlapping) random positions and, second, in a percolating gel structure and provide an extensive characterization of the structure and dynamics of ABPs in these complex environments. We find that the confinement increases the heterogeneity of the dynamics, with new populations of absorbed and localized particles appearing close to the obstacles. This heterogeneity has a profound impact on the motility induced phase separation exhibited by the particles at high activity, ranging from nucleation and growth in random disorder to a complex phase separation in porous environments.

Heterotypic electrostatic interactions control complex phase separation of tau and prion into multiphasic condensates and co-aggregates

Biomolecular condensates formed via phase separation of proteins and nucleic acids are thought to perform a wide range of critical cellular functions by maintaining spatiotemporal regulation and organizing intracellular biochemistry. However, aberrant phase transitions are implicated in a multitude of human diseases. Here, we demonstrate that two neuronal proteins, namely tau and prion, undergo complex coacervation driven by domain-specific electrostatic interactions to yield highly dynamic, mesoscopic liquid-like droplets. The acidic N-terminal segment of tau interacts electrostatically with the polybasic N-terminal intrinsically disordered segment of the prion protein (PrP). We employed a unique combination of time-resolved tools that encompass several orders of magnitude of timescales ranging from nanoseconds to seconds. These studies unveil an intriguing symphony of molecular events associated with the formation of heterotypic condensates comprising ephemeral, domain-specific, short-range electrostatic nanoclusters. Our results reveal that these heterotypic condensates can be tuned by RNA in a stoichiometry-dependent manner resulting in reversible, multiphasic, immiscible, and ternary condensates of different morphologies ranging from core-shell to nested droplets. This ternary system exhibits a typical three-regime phase behavior reminiscent of other membraneless organelles including nucleolar condensates. We also show that upon aging, tau:PrP droplets gradually convert into solid-like co-assemblies by sequestration of persistent intermolecular interactions. Our vibrational Raman results in conjunction with atomic force microscopy and multi-color fluorescence imaging reveal the presence of amorphous and amyloid-like co-aggregates upon maturation. Our findings provide mechanistic underpinnings of overlapping neuropathology involving tau and PrP and highlight a broader biological role of complex phase transitions in physiology and disease.

Miscibility, thermal degradation and rheological analysis of epoxy/MABS blends.

The effect of the addition of the methyl methacrylate acrylonitrile butadiene styrene (MABS) copolymer on the miscibility, thermal degradation and rheological properties of epoxy systems is described. Epoxy resin/MABS blends containing 5, 10, 15 and 20 phr MABS were prepared using the solution mixing technique. Homogenous blends obtained using this technique have undergone a polymerization reaction induced phase separation process by the introduction of the curing agent 4,4'-diaminodiphenyl sulfone (DDS). The isothermal rheology at four different temperatures, 150, 160, 170 and 180 °C, was used to examine the effect of MABS on the gelation and vitrification time. The evolution of storage modulus, loss modulus and tan delta was found to be closely related to the evolution of complex phase separation. The increase in the complex viscosity during curing was determined by in situ rheometry and theoretically analysed by fitting with the Williams-Landell-Ferry equation. An exponential increase in complex viscosity was observed, which was induced by cross-linking. The variation of Tg before and after curing was studied using DSC analysis and dynamic kinetic modeling of the curing process was carried out by utilizing dynamic DSC scans. Thermal stability studies of completely cured epoxy/MABS blends using thermogravimetric analysis revealed that all the blends and neat epoxy exhibited single step degradation. Thermal degradation kinetics was calculated using the Coats Redfern equation.

Quantitative Analysis of Phase Separation Using the Lattice Boltzmann Method

Phase separation is widely observed in multiphase systems. In this study, it has been investigated using Shan–Chen lattice Boltzmann method. The adhesion parameter in SC model leads to the desired fluid–fluid phenomenon, which was varied to specify the strength of separation between two phases to present emulsified performance in oil production. In order to describe such behaviors quantitatively, graphical distributions were described with time and were corresponded with a statistical index–Fourier structure factor that is able to predict complex phase separation behaviors, thereby providing a measurement for calculating such random distribution during the process of separation as well as evaluating heterogeneous degrees of the entire domain. The repulsive interactions are specified as low, intermediate, and high values. Phase separations with clear boundaries have been observed and each stage of separation evolvement has been discussed in this study. Magnitudes of structure factors are increased with higher degrees of fluctuations.

Physico chemical and phase separation characterization of high molecular PLLA blended with low molecular PCL obtained from solvent cast processes

Blends of PLLA and PCL yielded by solvent casting usually exhibit phase separation and crystallization behavior which have a strong impact on their suitability for certain biomedical applications such as degradable coatings or drug carriers. Therefore, it is important to understand the underlying mechanisms. In this study, high-molecular biodegradable semi-crystalline poly(L-lactide) (PLLA) (Mw = 320 kDa) was blended with low-molecular biodegradable semi-crystalline poly(ε-caprolactone) (PCL) (Mw = 40 kDa) in various combinations (10, 50 and 90 wt.% PCL) by solvent casting. The yielded blends were subjected to annealing at 40 °C, 80 °C and 200 °C and cooled down slowly to maintain thermodynamic equilibrium. Scanning electron microscopy, atomic force microscopy, Raman images and differential scanning calorimetry were used to investigate the structure, morphology and thermal properties of the solvent cast PLLA/PCL blends. It was shown that the physico-chemical properties of PLLA/PCL blends prepared by solvent casting differ substantially compared to those accessed by melt manufacturing processes. In summary, the blends showed a complex phase separation behavior, which is completely dependent on the method of preparation and the adjusted temperature during production process.

Larvicidal activity and microencapsulation of tobacco (Nicotiana tabacum) extract on Malacosoma neustria testacea larvae

To understand and improve the stability of the insecticidal activity of tobacco extract, the 3rd instar larvae of Malacosoma neustria testacea was determined by the leaf film method. Spectrophotometry identified extract effects on activities of several enzymes. In addition, to improve the stability of the extract, microcapsules were prepared by complex coacervation and phase separation with the extract as core material, and gelatin and gum arabic as wall material. With the embedding rate as the evaluation index, the response surface method was used to optimize the preparation process of the microcapsules. The results show that the extract had a strong insecticidal activity on the larvae, with inhibitory effects on several enzymes examined of carboxylesterase, acetylcholinesterase, glutathione-S transferase, catalase, and superoxide dismutase. The inhibition rate increased with time. The best preparation process of tobacco extract microcapsules was 25% mass fraction of emulsifier, 2.05% mass fraction of gelatin, 3% mass fraction of gum arabic, 1.34 wall core ratio, 36 min of complex coacervation time. The embedding rate was 58.4% which is approximately the theoretical embedding rate (58.9%). The microcapsules prepared by this method have a smooth surface, good combining form and particle size distribution, and a median diameter of 8.6 μm. Infrared characteristic peaks of the extracts were preserved at 877.55 cm‒1 and 2922.13 cm‒1. Microencapsulation can improve the thermal stability of the tobacco extract. Indoor toxicity tests showed that LC50 of extract microcapsules was 20.2 mg·mL‒1, equivalent to the toxicity level of the tobacco extract itself, indicating that microencapsulation did not reduce extract insecticidal effects. This research may provide a reference for the optimization of the tobacco extract microcapsule preparation process.

Encapsulation of Food Components and Bioactive Ingredients and Targeted Release

The potential utilization of encapsulation techniques in food, pharmaceutical and agricultural products preparation, presents a new alternative for complementary technologies such as targeting delivery vehicles and carriers for active food ingredients. Encapsulation could be accomplished by different techniques like: simple or complex coacervation, emulsification technique, phase separation, spray drying, spray chilling or spray cooling, extrusion coating, freeze drying, fluidized-bed coating, liposomal entrapment, centrifugal suspension separation, co-crystallization and molecular inclusion complexation. Encapsulation is a method by which one bioactive material or mixture of materials is coated by the other material. It is designed for protection, isolation, assists in the storage and controlled release. A timely and targeted release improves the effectiveness of ingredients, broadens the application and ensures optimal dosage, thereby improving cost-effectiveness process for manufacturers. This review highlights recent innovations in encapsulation and controlled release technologies. In addition, design principle of novel peppermint oil delivery systems which displays the new structured biomaterials for capsules fabrication by complex coacervation technique, besides microemulsification method for bioactive material, Lactobacillus encapsulation and targeted release studies reported.

Morphology, dynamics, and order development in a thermoplastic polyurethane with melt blended POSS

ABSTRACTA top‐down approach is applied for the production of polyurethane (PU)–polyhedral oligomeric silsesquioxane (POSS) nanocomposites, namely melt blending. As opposed to the typical chemical incorporation during synthesis, a POSS moiety with two hydroxyl groups is melt blended into a commercial thermoplastic polyurethane with mass fraction up to 2 wt %. POSS disperses in the matrix in submicrometer‐sized crystals, as well as in length scale of few tens of nanometers, in the bulk. Phase separation of the produced composites was studied by both standard dynamic and isothermal annealing experiments. In an approach rare in the literature, the dynamics of phase separation is discussed based on isothermal differential scanning calorimetry curves recorded during annealing. The blended‐in nanoparticles affect the micromorphology in a complicated manner, dependent on the intrinsically complex phase separation mechanism of PU. At higher temperatures, POSS slows down the phase separation, whereas at lower ones, it enhances and accelerates it. POSS decreases the mechanical modulus of the final material, presumably as a result of changes in the microphase separation. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019, 57, 1133–1142

Nanoscopic hydrophilic/hydrophilic phase-separation well below the LCST of polyphosphoesters.

The complex phase separation process of thermoresponsive polyphosphoesters (PPEs) with an identical side-group structure but different copolymer compositions is characterized by electron paramagnetic resonance (EPR) spectroscopy. In water these PPEs show LCST-type behavior, in which water-rich and slightly polymer-enriched nanoscopic regions are highly water swollen, and nanoscopic inhomogeneities with the lowest polarity contrast measured so far develop 8 °C below the macroscopic cloud point.

Polycation–PEG Block Copolymer Undergoes Stepwise Phase Separation in Aqueous Triflate Solution

A block copolymer poly(ethylene glycol)-b-poly(vinylbenzyltrimethylammonium triflate), PEG–PVBTMA-OTf, and a homopolymer PVBTMA-OTf were synthesized through RAFT reactions. The polymers were studied in aqueous triflate solutions with varying temperatures, changing also the polymer and salt concentrations. The hydrophobic triflate anion turns polycations thermoresponsive, and they show an UCST. In the block copolymer, the interaction between the PEG and the cationic block makes the phase separation occur in distinct steps. Upon cooling, transparent solutions first turn turbid and then partially clear at TcL. The TcL is not observed in a mixed solution of PVBTMA-OTf and PEG macro-CTA. By considering the interplay between ionic, hydrogen bonding, and hydrophobic interactions, an overall picture of the complex phase separation processes is suggested.

Studies on transport properties of manganite based nano–micro particles–matrix composites

In this communication, low resistive bulk La0.7Ca0.3MnO3 (LCMO) was prepared by solid state reaction (SSR) route whereas high resistive nanoparticles of LaMnO3 (LMO) was prepared by cost effective sol–gel technique. Composites of LMO and LCMO were prepared by mixing them in different weight ratios, i.e. LMO = 10%, 20% and 30% in LCMO manganite matrix. In the present study, LMO have been used as nanoparticle fillers in the LCMO matrix lattice to study the transport properties of the composites. X–ray diffraction (XRD) measurement reveals the single phasic nature of the composites without any detectable impurity within the measurement range studied. XRD pattern of higher LMO content based composite possesses slightly different structural phases of LMO and LCMO. Resistivity measurement reveals that all the composites exhibit metal to insulator electronic phase transition at respective TP, wherein values of resistivity and TP get modified due to the cooling or heating cycles performed, measurement current used and LMO nanoparticle filler content in the composites. These variations have been discussed in the context of scattering centres created due to the presence of LMO fillers and complex phase separation scenario of the composites. A clear phase separation in higher filler content based composite has been displayed in its resistivity behaviour. To understand the charge transport mechanisms responsible for metallic and insulating (or semiconducting) regions in resistivity behaviours of the composites, most suitable zener double exchange polynomial law and Mott type variable range hopping mechanism were fitted theoretically to the obtained experimental results. Fittings show that spin fluctuations in the composites are highly dependent on the cycles performed, current applied and LMO nanoparticle filler content in the composites. Applied negative and positive current and voltage dependent resistance of the composites reveal the negative electroresistance. Both, resistance of the composites as well as electroresistance are highly affected by the cycles performed, current applied and LMO nanoparticle filler content in the composites understudy. Temperature dependent electroresistance was studied for better insight into an active role of phase separation near electronic phase transition temperatures for all manganite based composites.

Drop formation at nozzles submerged in quiescent continuous phase: an experimental study with TBP-dodecane and nitric acid system

Solvent extraction is an important process in the nuclear fuel cycle. Tributyl phosphate (TBP) diluted with dodecane is commonly used as a solvent for extracting heavy metals from nitric acid medium. Studies on hydrodynamics of a single drop, which is the smallest mass transfer entity, are required for better understanding of the complex mass transfer and phase separation phenomena that occur in extraction equipment. In this study, drop formation at nozzles is studied using 30% TBP-dodecane as the dispersed phase and dilute nitric acid as the quiescent continuous phase. Experiments are carried out to determine the drop diameter, jetting velocity, drop detachment height and drop detachment time for various dispersed phase velocities, nozzle diameters (1.91, 3.04, and 4.88 mm), and nitric acid concentrations (0.01, 1, 3 N). Drop formation is captured using high-speed imaging, which enables quantification of drop size, onset of jetting, drop detachment height, and drop detachment time. Experimental data are used to propose correlations for predicting drop diameter and minimum jetting velocity. The correlations are found to be very accurate with average absolute relative errors being 5.23 and 2.97%, respectively.

Exchange bias training effect in phase separated polycrystalline Sm0.1Ca0.7Sr0.2MnO3

Magnetic properties of antiferromagnetic (AFM) electron doped manganite Sm0.1Ca0.7Sr0.2MnO3 have been investigated, focusing mainly on the exchange bias (EB) effect and associated training effect. The studied compound exhibits the ground state with heterogeneous spin configuration, consisting of the C-type antiferromagnetic phase with the Néel temperature TN-C ≈ 120 K, the G-AFM phase with the Néel temperature TN-G ≈ 60 K, and ferromagnetic-like phase with a very weak spontaneous magnetic moment. Measurements of hysteresis loops have shown that the exchange bias field monotonously decreases with increasing temperature and vanishes above 40 K, while the coercivity disappears only above 70 K. The temperature variation of the exchange bias field has been successfully described by an exponential decay form. The stability of EB has been evaluated in the studies of the training effect, which has been discussed in the frame of the spin relaxation model, elucidating the important role of the AFM domain rearrangement at the interface. The complex phase separation and possible contributions from different interfaces between coexisting magnetic phases to the EB effect have also been discussed.