Occurrence Of Liquid-liquid Phase Separation Research Articles

Unveiling the Factors Influencing Different Nucleation Pathways and Liquid-Liquid Phase Separation.

Exploring nucleation pathways has been a research hot spot in the fields of crystal engineering. In this work, vanillin as a model compound was utilized to explore the factors influencing different nucleation pathways with or without liquid-liquid phase separation (LLPS). A thermodynamic phase diagram of vanillin in the mixed solvent system of water and acetone from 10 to 55 °C was determined. It was found that the occurrence of LLPS might be related to different nucleation pathways. Under the guidance of a thermodynamic phase diagram, Raman spectroscopy and molecular simulation were applied to investigate the influencing factors of different nucleation paths. It was found that the degree of solvation is a key factor determining the nucleation path, and strong solvation could lead to LLPS. Additionally, the molecular self-assembly evolution during the crystallization process was further investigated by using small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS). The findings indicate that larger clusters with a diffuse transition layer may lead to LLPS during the nucleation process.

Replicating shear-mediated self-assembly of spider silk through microfluidics

The development of artificial spider silk with properties similar to native silk has been a challenging task in materials science. In this study, we use a microfluidic device to create continuous fibers based on recombinant MaSp2 spidroin. The strategy incorporates ion-induced liquid-liquid phase separation, pH-driven fibrillation, and shear-dependent induction of β-sheet formation. We find that a threshold shear stress of approximately 72 Pa is required for fiber formation, and that β-sheet formation is dependent on the presence of polyalanine blocks in the repetitive sequence. The MaSp2 fiber formed has a β-sheet content (29.2%) comparable to that of native dragline with a shear stress requirement of 111 Pa. Interestingly, the polyalanine blocks have limited influence on the occurrence of liquid-liquid phase separation and hierarchical structure. These results offer insights into the shear-induced crystallization and sequence-structure relationship of spider silk and have significant implications for the rational design of artificially spun fibers.

Inhibition of Liquid-Liquid Phase Separation for Breaking the Solubility Barrier of Amorphous Solid Dispersions to Improve Oral Absorption of Naftopidil.

Amorphous solid dispersion (ASD) is one of the most promising technologies for improving the oral absorption of poorly soluble compounds. In this study, naftopidil (NFT) ASDs were prepared using vinylpyrrolidone-vinyl acetate copolymer (PVPVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and poly(methacrylic acid-co-methyl methacrylate) L100-55 (Eudragit) to improve the dissolution and oral absorption behaviors of NFT. During the dissolution process of ASD, liquid-liquid phase separation (LLPS) may occur when certain requirements are met for providing a maximum quasi-stable concentration achievable by amorphization. The occurrence of LLPS was confirmed in the presence of PVPVA and HPMCAS; however, Eudragit inhibited LLPS owing to its molecular interaction with NFT. Although the dissolution behavior of the Eudragit ASD was found to be markedly poorer than that of other ASDs, it offered the best oral absorption in rats. The findings of the current study highlight the possibility for improving the oral absorption of poorly soluble drugs by this ASD, which should be eliminated from candidate formulations based on the conventional in vitro tests.

Effect of solvent and temperature on the phase equilibrium behavior of hydroxylamine sulfate in water-ethanol mixed solvents: Solubility and ternary liquid-liquid equilibrium diagram with liquid-liquid equilibrium

The thermodynamic properties of hydroxylamine sulfate (HAS) in binary mixed solvents of water-ethanol were investigated in this work. Experimental results indicated that a temperature above 323.15 K will bring about the occurrence of liquid-liquid phase separation in the water-ethanol-HAS system. Solubility of HAS in water and ethanol-water binary mixed solvents was experimentally determined from 283.15 to 323.15 K under atmospheric pressure (101.3 kPa) by employing a gravimetric method. As the mass fraction of water in the mixed solvent increase, there is an increase in the solubility of HAS. In addition, the solubility of HAS is positively dependent on the temperature. Furthermore, the modified van’t Hoff model, Apelblat model, van’t Hoff − Jouyban − Acree model, and Apelblat − Jouyban − Acree model were used to correlate the experimental solubility of HAS, and the Apelblat model showed the best agreement. Besides, the van't Hoff equation was utilized to evaluate the thermodynamic parameters of HAS in binary solvents, calculation results confirm that these dissolving processes are endothermic and entropy-driving. Ternary phase diagrams with liquid-liquid equilibrium at 324.15, 328.15 and 333.15 K were constructed, and the boundaries of each phase area of the ternary phase diagram were verified at 333.15 K. As for the water-ethanol-HAS system, the temperature has an influence on the phase zone of the ternary phase diagram by affecting solid-liquid phase equilibrium. However, the temperature has no effect on the liquid-liquid phase equilibrium. The nucleation process of oiling-out crystallization of HAS was determined to follow a two-step mechanism: the liquid-liquid phase separation is generated at first, and then nucleation occurred and crystals subsequently grow in the aqueous phase.

Solvent influence on the phase behavior and glass transition of Amorphous Solid Dispersions

Understanding the long-term stability of amorphous solid dispersions (ASDs) is important for their successful approval for market. ASD stability does not only depend on the interplay between the active pharmaceutical ingredient (API) and the polymer in the final formulation but may already be disadvantageously influenced by process steps during the production (e.g. selection of inappropriate solvent for spray drying). Residual solvent can affect the API solubility in the polymer, molecular mobility (by influencing the glass-transition temperature) and induce liquid-liquid phase separation. Enhanced mobility in the ASD due to residual solvent can promote recrystallization in ASDs.The removal of residual solvent can be expensive, time-consuming, and usually requires secondary drying procedures to fulfil the regulatory requirements. The aim of this work is to predict the API solubility in polymer-solvent mixtures, solvent influence on the glass transition, and the occurrence of liquid-liquid phase separation of solvent-loaded ASDs using the thermodynamic model PC-SAFT and to experimentally validate these predictions. ASDs containing the APIs ritonavir or naproxen and the polymers poly(vinylpyrrolidone), poly (vinylpyrrolidone-co-vinyl acetate), or hydroxypropyl methylcellulose acetate succinate were spray-dried using the solvents acetone, ethanol, and dichloromethane. API solubility, sorption behavior, liquid-liquid phase separation and glass transition in the ternary API/polymer/solvent mixtures were predicted based on the binary phase behavior between API/solvent, API/polymer, and polymer/solvent and successfully validated experimentally using dynamic vapor sorption (DVS), and Raman spectroscopy. Thus, the presented methodology allows for an in-silico selection of appropriate solvent systems for solvent-based ASD preparation based on a limited amount of experimental data for binary systems only.

Congruent release of drug and polymer: A “sweet spot” in the dissolution of amorphous solid dispersions

Liquid-liquid phase separation (LLPS) occurs following amorphous solid dispersion (ASD) dissolution when the drug concentration exceeds the “amorphous solubility”, and is emerging as an important characteristic of formulations that may enhance the oral bioavailability of poorly soluble drugs. The purpose of this research was to identify criteria that impact the rate and extent of drug release and hence the occurrence or not of LLPS upon ASD dissolution. Specifically, the effect of drug log P, phase behavior of the hydrated but undissolved ASD matrix and the relative dissolution rates of drug and polymer were studied as a function of drug loading, using nilvadipine (Nil) (ClogP = 3.04) and cilnidipine (Cil) (ClogP = 5.54) as model drugs. The model polymer was poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA). Nil-PVPVA and Cil-PVPVA ASDs with different drug loadings were prepared. Surface area normalized dissolution rates of both the drug and the polymer from ASD tablets were studied. At a similar and relatively low drug loading (<20% w/w drug), dissolution of both Nil-PVPVA and Cil-PVPVA ASDs was found to switch from rapid, congruent (i.e., simultaneous) release of drug and polymer to incongruent release with slow release of drug. Only ASDs showing congruent release underwent LLPS, with the formation of amorphous drug-rich aggregates (~300nm). Scanning electron microscopy (SEM) and micro-computed tomography (micro-CT) showed the presence of characteristic “pits” on the surface of partially dissolved, incongruently releasing ASD tablets. These most likely arise due to faster polymer release in comparison to drug, whereby the drug-rich composition around these pits was confirmed by energy-dispersive X-ray (EDX) analysis and the surface drug enrichment on the compacts was confirmed by X-ray photoelectron spectroscopy (XPS). This study demonstrates two important findings, firstly, a link between congruent release of drug and polymer and the occurrence of LLPS and secondly, the switch between congruent and incongruent release of drug and polymer is a result of competitive kinetics between phase separation and the release rate of ASD components with minimal influence from drug hydrophobicity for two structural analogues.

Liquid-liquid phase separation and core-shell structure of ternary Al-In-Sn immiscible alloys

In this study, the liquid-liquid phase separation of four kinds of ternary immiscible Al-In-Sn melts was investigated with resistivity and thermodynamics method. The nonlinear changes in ρ-T and DSC curves of Al-In-Sn immiscible alloys above monotectic reaction temperature revealed the occurrence of liquid-liquid phase separation of Al-In-Sn melts. The monotectic temperature, liquid phase separation temperature and immiscible gap of ternary Al-In-Sn alloys were lower than those of binary Al-In alloy. With the Al content decreasing, the immiscible gap of Al-In-Sn alloy decreased. The composition of Al80In10Sn10, Al70In15Sn15, Al60In20Sn20 and Al50In25Sn25 was located in the immiscible zone of Al-In-Sn system. Due to the differences of Stokes effect, Marangoni convection and immiscible gap, the solidification morphology of four kinds of Al-In-Sn monotectic alloy was different. The core–shell structure of Al-In-Sn monotectic alloy can form within a certain range of composition.

Liquid-liquid phase separation and solidification behavior of Al-Bi-Sn monotectic alloy

In this study, the liquid-liquid phase separation of four kinds of Al-Bi-Sn immiscible melts and the formation mechanism of core-shell structure were studied using electrical resistivity and thermodynamics method. The thermodynamic characteristics and micromorphology were analyzed by DSC, XRD, SEM and EDS. The resistivity results showed that the non-linear change of ρ-T curve above the monotectic reaction temperature reveals the occurrence of liquid-liquid phase separation. Solidification microstructure and the core-shell structure of Al-Bi-Sn immiscible alloy can be controlled by adjusting the composition of alloy. The core/shell structure of Al-rich phase/Sn-Bi-rich phase can be obtained in the Al60Bi24Sn16 alloy cast in the copper mold.

In Vitro Characterization of Ritonavir Drug Products and Correlation to Human in Vivo Performance

Ritonavir (RTV) is a weakly basic drug with a pH-dependent solubility. In vitro dissolution and supersatuation behaviors of three Norvir oral products including the tablet, powder, and solution were investigated by two biorelevant dissolution methods with pH alteration: a two-stage dissolution test and a biphasic dissolution-partition test. The two-stage dissolution test revealed a high degree of supersaturation of RTV from these products accompanied by the occurrence of liquid-liquid phase separation (LLPS) in biorelevant dissolution media. Higher, stable apparent RTV concentrations were observed in the FeSSIF-V2 as compared to those in the FaSSIF-V2, which suggested a food effect with higher exposure in the fed state. This is inconsistent with the evaluation in vivo. The biphasic test revealed significantly lower degrees of supersaturation of RTV in the aqueous media from these dosage forms as compared to results of the two-stage dissolution test. RTV concentrations in octanol at 6 h obtained from the tablet and powder with the use of the biorelevant media are consistent with corresponding in vivo AUC and Cmax under the fasting and moderate fat fed (MFF) states and predict the food effect. The underlying mechanisms responsible for the food effect are also proposed. Fractional partition profiles of RTV obtained in octanol from these three Norvir oral products are in agreement with the corresponding fractional absorption profiles in vivo under both the fasting and MFF states. This study reveals a complex interplay among the dissolution, precipitation, and partition processes from these formulations that dictate the oral exposure of RTV.

Liquid–liquid phase separation in particles containing secondary organic material free of inorganic salts

Abstract. Particles containing secondary organic material (SOM) are ubiquitous in the atmosphere and play a role in climate and air quality. Recently, research has shown that liquid–liquid phase separation (LLPS) occurs at high relative humidity (RH) (greater than ∼ 95 %) in α-pinene-derived SOM particles free of inorganic salts, while LLPS does not occur in isoprene-derived SOM particles free of inorganic salts. We expand on these findings by investigating LLPS at 290 ± 1 K in SOM particles free of inorganic salts produced from ozonolysis of β-caryophyllene, ozonolysis of limonene, and photo-oxidation of toluene. LLPS was observed at greater than ∼ 95 % RH in the biogenic SOM particles derived from β-caryophyllene and limonene while LLPS was not observed in the anthropogenic SOM particles derived from toluene. This work combined with the earlier work on LLPS in SOM particles free of inorganic salts suggests that the occurrence of LLPS in SOM particles free of inorganic salts is related to the oxygen-to-carbon elemental ratio (O : C) of the organic material. These results help explain the difference between the hygroscopic parameter κ of SOM particles measured above and below water saturation in the laboratory and field, and have implications for predicting the cloud condensation nucleation properties of SOM particles.

Structural Characterization and Analysis of Glasses in the Al2O3-B2O3-Fe2O3-Na2O-SiO2 System

ABSTRACTGlasses in the Al2O3-B2O3-Fe2O3-Na2O-SiO2 system were produced at a temperature of 1150 °C, annealed, and examined using XRD and SEM/EDX. Surfaces of same samples were additionally heat-treated and etched with HCl. The pristine samples were X-ray amorphous and rather homogeneous except the B1 sample that contained trace crystalline phases of carnegieite/nepheline and spinel. Corrosion of these glasses via an etching treatment proceeds by a conventional mechanism with damage of their surface layers, however, the B2 glass exhibits a “drop-type” microstructure after etching that suggests occurrence of liquid-liquid phase separation.

Phase behavior of PCBM blends with different conjugated polymers

In this work the phase behavior of [6,6]-phenyl C(61)-butyric acid methyl ester (PCBM) blends with different poly(phenylene vinylene) (PPV) samples is investigated by means of standard and modulated temperature differential scanning calorimetry (DSC and MTDSC) and rapid heat-cool calorimetry (RHC). The PPV conjugated polymers include poly(2-methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylene vinylene) (MDMO-PPV), High T(g)-PPV which is a copolymer, and poly((2-methoxy-5-phenethoxy)-1,4-phenylene vinylene) (MPE-PPV). Comparisons of these PPV:PCBM blends with regioregular poly(3-hexyl thiophene) (P3HT):PCBM blends are made to see the different component miscibilities among different blends. The occurrence of liquid-liquid phase separation in the molten state of MDMO-PPV:PCBM and High T(g)-PPV:PCBM blends is indicated by the coexistence of double glass transitions for blends with a PCBM weight fraction of around 80 wt%. This is in contrast to the P3HT:PCBM blends where no phase separation is observed. Due to its high cooling rate (about 2000 K min(-1)), RHC proves to be a useful tool to investigate the phase separation in PPV:PCBM blends through the glass transition of these crystallizable blends. P3HT is found to have much higher thermal stability than the PPV samples.

Time-Resolving Analysis of Cryotropic Gelation of Water/Poly(vinyl alcohol) Solutions via Small-Angle Neutron Scattering

The structural transformations occurring in initially homogeneous aqueous solutions of poly(vinyl alcohol) (PVA) through application of freezing (-13 degrees C) and thawing (20 degrees C) cycles is investigated by time resolving small-angle neutron scattering (SANS). These measurements indicate that formation of gels of complex hierarchical structure arises from occurrence of different elementary processes, involving different length and time scales. The fastest process that could be detected by our measurements during the first cryotropic treatment consists of the crystallization of the solvent. However, solvent crystallization is incomplete, and an unfrozen liquid microphase more concentrated in PVA than the initial solution is also formed. Crystallization of PVA takes place inside the unfrozen liquid microphase and is slowed down because of formation of a microgel fraction. Water crystallization takes place in the early 10 min of the treatment of the solution at subzero temperatures, and although below 0 degrees C the PVA solutions used for preparation of cryogels should be below the spinodal curve, occurrence of liquid-liquid phase separation could not be detected in our experiments. Upon thawing, ice crystals melt, and transparent gels are obtained that become opaque in approximately 200 min, due to a slow and progressive increase of the size of microheterogeneities (dilute and dense regions) imprinted during the fast freezing by the crystallization of water. During the permanence of these gels at room temperature (for hours), the presence of a high content of water (higher than 85% by mass) prevents further crystallization of PVA. Crystallization of PVA, in turn, is resumed by freezing the gels at subzero temperatures, after water crystallization and consequent formation of an unfrozen microphase. The kinetic parameters of PVA crystallization during the permanence of these gels at subzero temperatures are the same shown by PVA during the first freezing step of the solutions.

Phase separation in amorphous chalcogenides

Systematic variations of electrical and optical properties of amorphous chalcogenides can be obtained by forming multicomponent solutions with elements of other periodic groups. A limitation on the preparation and stability of such solutions is the occurrence of liquid-liquid phase separation in the stable and metastable melts. This paper examines the effect of such phase separation on glass formation and stability in chalcogenide systems, giving particular emphasis to the BiSe and SbSe systems which display stable and incipient immiscibility, respectively.