Construction Of Phase Diagram Research Articles

Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion

Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical stability. The internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which can compromise therapeutic efficacy and limit product shelf life. A primary concern in the development of stable ASDs is the solubility of the drug in the polymeric carrier, but there is a scarcity of reliable analytical techniques for its determination. In this work, terahertz (THz) Raman spectroscopy was introduced as a novel empirical approach to determine the saturated solubility of crystalline active pharmaceutical ingredient (API) in polymeric matrices directly during hot melt extrusion. The solubility of a model compound, paracetamol, in two polymer systems, Affinisol 15LV (HPMC) and Plasdone S630 (copovidone), was determined by monitoring the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolved in the polymeric matrix. THz-Raman results enabled construction of solubility phase diagrams and highlighted significant differences in the solubilization capacity of the two polymer systems. The maximum stable API-load was 20 wt % for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanning calorimetry and XRPD studies corroborated these results. This approach has demonstrated a novel capability to provide real-time API–polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.

Skyrmion instabilities and distorted spiral states in a frustrated chiral magnet

Magnetic skyrmions are particle-like topological excitations that recently generated much interest as candidates for future spintronic devices based on skyrmion small size, enhanced topological stability, and/or mutual interaction. Here we examine the properties of isolated skyrmions in a frustrated chiral magnet with competing Dzyaloshinskii-Moriya and frustrated exchange interactions. We show that the skyrmion size drastically decreases even for small values of competing stabilization mechanisms. Skyrmion mutual interaction remains attracting as is inherent for frustrated skyrmions, but the value of the Dzyaloshinskii constant regulates the number of minima in the interaction potentials. Moreover, the constructed phase diagrams for a chiral helimagnet contain a distorted spiral state that can be considered as a buffer between the helicoidal and conical one-dimensional modulations. The formulated concepts may further enhance the functionalities of spintronic devices. In particular, the controlled instability of skyrmions with respect to the conical state allows to obtain bimeron-like structures. Moreover, our results provide physical insight into the chiral states in the magnetic systems, e.g., in MnSi$_{1-x}$Ge$_x$.

Comprehensive studies of the transformation between antiferromagnetic CeCoGe3 and heavy fermion CeFeGe3 compounds

We report extensive studies of a series of alloys CeCo1−xFexGe3 in which suppression of the antiferromagnetic order in CeCoGe3 with temperature decreasing to 0 K was observed as a result of substitution of Co with Fe. Unusual temperature dependences were observed of a number of parameters characterizing these compounds: magnetic susceptibility, specific heat, electrical resistivity, magnetoresistance and thermoelectric power, which may be indication towards non-Fermi liquid behaviour connected with quantum critical point (QCP) or can result from a quantum Griffiths phase (QGP) formation. The three AFM transitions found previously for a single crystal CeCoGe3 compound were also detected in our high quality polycrystalline samples, including the case of x>0. All measurements, especially those of magnetocaloric effect (MCE), suggest that for samples with x≥0.1 the contribution of ferromagnetic component, known already for x=0 from the neutron diffraction experiments, increases significantly, with the AFM contribution still present at low temperatures. Finally, the use of different complementary methods enabled construction of a comprehensive magnetic phase diagram of CeCo1−xFexGe3 system.

In Situ Small-Angle X-ray Scattering Studies During Reversible Addition-Fragmentation Chain Transfer Aqueous Emulsion Polymerization.

Polymerization-induced self-assembly (PISA) is a powerful platform technology for the rational and efficient synthesis of a wide range of block copolymer nano-objects (e.g., spheres, worms or vesicles) in various media. In situ small-angle X-ray scattering (SAXS) studies of reversible addition–fragmentation chain transfer (RAFT) dispersion polymerization have previously provided detailed structural information during self-assembly (see M. J. Derry et al., Chem. Sci.2016, 7, 5078–509030155157). However, conducting the analogous in situ SAXS studies during RAFT aqueous emulsion polymerizations poses a formidable technical challenge because the inherently heterogeneous nature of such PISA formulations requires efficient stirring to generate sufficiently small monomer droplets. In the present study, the RAFT aqueous emulsion polymerization of 2-methoxyethyl methacrylate (MOEMA) has been explored for the first time. Chain extension of a relatively short non-ionic poly(glycerol monomethacrylate) (PGMA) precursor block leads to the formation of sterically-stabilized PGMA-PMOEMA spheres, worms or vesicles, depending on the precise reaction conditions. Construction of a suitable phase diagram enables each of these three morphologies to be reproducibly targeted at copolymer concentrations ranging from 10 to 30% w/w solids. High MOEMA conversions are achieved within 2 h at 70 °C, which makes this new PISA formulation well-suited for in situ SAXS studies using a new reaction cell. This bespoke cell enables efficient stirring and hence allows in situ monitoring during RAFT emulsion polymerization for the first time. For example, the onset of micellization and subsequent evolution in particle size can be studied when preparing PGMA29-PMOEMA30 spheres at 10% w/w solids. When targeting PGMA29-PMOEMA70 vesicles under the same conditions, both the micellar nucleation event and the subsequent evolution in the diblock copolymer morphology from spheres to worms to vesicles are observed. These new insights significantly enhance our understanding of the PISA mechanism during RAFT aqueous emulsion polymerization.

Intranasal Tadalafil nanoemulsions: formulation, characterization and pharmacodynamic evaluation

This study aims at improving the bioavailability of a poorly soluble phosphodiesterase-5 inhibitor; tadalafil (TD) via developing intranasal (IN) nanoemulsions (NEs). Optimum NE ingredients were selected based on solubility studies, emulsification tests, and phase diagram construction. Both o/w and w/o NEs were selected based on their drug loading capacity. Optimum formulations were subjected to physicochemical characterization and were assessed for nasal toxicity through biochemical analysis of tumor necrosis factor-α (TNF-α) and caspase-3 in rat nasal tissues. Pharmacodynamic study was performed via biochemical analysis of cyclic guanosine monophosphate (cGMP) in rat penis 2-h post-treatment and compared with oral suspension of Cialis® tablets. Optimum o/w and w/o NEs were successfully prepared using different ratios of Capmul-MCM-EP, Labrasol:Transcutol-HP (1:1) and water. Optimized formulations exhibited more than 4000-fold increase in TD solubility compared with its aqueous solubility. Both formulations were optically isotropic with the majority of globules in the nanometric-size range. Nasal toxicity study revealed no significant difference in values of TNF-α and caspase-3 between the NE-treated groups and the control group. Both TD-NEs succeeded to achieve a significant enhancement in cGMP levels. Our findings suggested that IN administration of the developed TD-NEs could provide a safe and effective alternative to TD oral delivery.

Time-Dependent Multi-Light-Source Image Classification Combined With Automated Multidimensional Protein Phase Diagram Construction for Protein Phase Behavior Analysis.

Image-based protein phase diagram analysis is key for understanding and exploiting protein phase behavior in the biopharmaceutical field. However, required data analysis has become a notorious time-consuming task since high-throughput screening approaches were implemented. A variety of computational tools have been developed to support analysis, but these tools primarily use end point visible light images. This study investigates the combined effect of end point and time-dependent image features obtained from cross-polarized and ultraviolet light features, supplementary to visible light, on protein phase diagram image classification. In addition, external validation was performed to evaluate the classification algorithm's applicability to support protein phase diagram scoring. The predicted protein phase behavior classes were subsequently used to automatically construct multidimensional protein phase diagrams to prevent image information loss without complicating the used image classification algorithm. Combining end point and time-dependent features from 3 light sources resulted in a balanced accuracy of 86.4 ± 4.3%, which is comparable to or better than more complex classifiers reported in literature. External validation resulted in a correct formulation classification rate of 91.7%. Subsequent automated construction of the multidimensional protein phase diagrams, using predicted classes, allowed visualization of details such as crystallization rate and protein phase behavior type coexistence.

Application of a ternary phase diagram to the liquid-liquid extraction of ethanoic acid using ethyl ethanoate

This article was elaborated in an approach to the liquid-liquid equilibrium of the extraction process of ethanoic acid (C2H4O2) in aqueous phase using ethyl ethanoate as solvent. The liquid-liquid extraction was modeled by the construction of a ternary phase diagram for the water-ethanoic acid- ethyl ethanoate system with the aid of the Origin software. The equilibrium data were obtained experimentally by titration at room temperature (298.15 K) and atmospheric pressure (101325 Pa) using four mixtures of water, ethanoic acid, and ethyl ethanoate. The determination of the composition of the extract and residue portions in the equilibrium of each mixture by of the tie-lines method allowed to examine the percentages of liquid-liquid extraction achieved. The distribution coefficients and separation factors calculated made it possible an evaluation of the distribution and of the mutual solubility of the solute in the aqueous and organic phases. The results showed a good performance of ethyl ethanoate in the extraction of ethanoic acid for concentrations of solute until 16% of the feed.

Mixture of two unequally charged superfluids in a magnetic field

The artificial magnetic fields engineered for ultracold gases depend on the internal structure of the neutral atoms. Therefore the components of a mixture composed of two atomic gases can exhibit a different response to an artificial magnetic field. Such a mixture can be interpreted as a mixture of two atomic gases, carrying different synthetic charges. We consider such mixtures of two superfluids with unequal synthetic charges in a ring trap subject to a uniform artificial magnetic field. The charge imbalance in such a mixture changes the distribution of excited particles over angular momentum states compared to that of an equally charged mixture. This microscopic difference exhibits macroscopic consequences, such as the occurrence of an angular momentum transfer between two unequally charged components. Due to the interfluid atomic interactions in a ring, the angular momentum transfer can create a counterflowing persistent current in the weakly charged superfluid. Even in the limiting case of a charged and an uncharged superfluid mixture, a persistent current can be induced in the uncharged superfluid, despite the fact that it is not directly coupled to the magnetic field. The stability analysis shows that the induction depends on the interplay between the interfluid interaction and the applied magnetic field. We obtain instability boundaries of the system and construct phase diagrams as a function of the interfluid interaction and the magnetic field. We investigate these properties employing the Bogoliubov approximation.

Machine Learning Phase Diagram in the Half-filled One-dimensional Extended Hubbard Model

We demonstrate that supervised machine learning (ML) with entanglement spectrum can give useful information for constructing phase diagram in the half-filled one-dimensional extended Hubbard model. Combining ML with infinite-size density-matrix renormalization group, we confirm that bond-order-wave phase remains stable in the thermodynamic limit.

Design and development of permeation enhancer containing self-nanoemulsifying drug delivery system (SNEDDS) for ceftriaxone sodium improved oral pharmacokinetics

Ceftriaxone sodium cannot be delivered orally due to its lower permeability and gastric instability. Self-nanoemulsifying drug delivery systems (SNEDDS) spontaneously form oil-in-water nanoemulsions and are preferred for oral drug delivery owing to their enhanced permeation capabilities. This study is based on design and development of permeation enhancer containing SNEDDS for oral bioavailability of ceftriaxone sodium. Cinnamon oil, Tween 80 and propylene glycol were selected as oil, surfactant and co-surfactant respectively for the development of SNEDDS on the base of drug solubility and emulsifying ability. Region of self-nanoemulsification was selected through construction of phase diagram. Optimal formulation with best attributes consisted 43.33%, 30% and 26.77% (w/w) oil, surfactant and co-surfactant respectively. SNAC (Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) was used as permeation enhancer for the development of SNEDDS. The resultant nano-emulsion was investigated for various parameters and stabilities using zetasizer, atomic force microscope, TGA, DSC, FTIR analysis and dilution and thermodynamic stability studies. It was further screened for cellular uptake and in vivo oral bioavailability of the drug. Drug loaded nano-emulsion revealed negatively charged nano size droplets (166–208 nm) and was highly stable against dilution as well as temperature. Drug remained chemically well intact in solubilized from in oil droplets. The drug cellular uptake and in vivo oral bioavailability remarkably increased upon delivery in permeation enhancer containing SNEDDS. Findings of the study confirm the applicability of the designed SNEDDS for enhancing oral bioavailability of Ceftriaxone sodium.

A coarse grained simulation study on the morphology of ABA triblock copolymers

The Dissipative Particle Dynamics (DPD) simulation technique was used to elucidate the composition-dependent equilibrium morphological behavior of three different symmetric ABA triblock copolymers, which were; poly(ε-caprolactone)-poly(dimethylsiloxane)-poly(ε-caprolactone) (PCL-PDMS-PCL), poly(ε-caprolactone)-poly(ethylene oxide)-poly(ε-caprolactone) (PCL-PEO-PCL) and poly(L-lactide)-poly(dimethylsiloxane)-poly(L-lactide) (PLLA-PDMS-PLLA). These polymers were chosen due to their biomedical and biotechnological importance. Polymeric A and B blocks were modeled as connected chain of beads with varying incompatibility. The impact of the block incompatibilities on the microphase separation as well as on the equilibrium phase behaviors were investigated at the mesoscopic scale. A detailed visual analysis of the DPD images and constructed phase diagram showed that quite different equilibrium morphologies were attainable by controlling the molecular weights of the blocks and the strength of the intermolecular interaction between them. More compatible A and B blocks underwent lamellar to cylindrical and cylindrical to spherical phase transitions at lower B block concentrations. Our results clearly showed that, Flory–Huggins interaction parameter (χ) and degree of polymerization (N) were the only control parameters, which determined the shape and size of the phase domains, as well as the extent of equilibrium nanophase separation. Our DPD simulated morphologies were compared with experimental images obtained by Atomic Force Microscopy (AFM).

Experimental and Predictive Description of the Morphology of Wet-Spun Fibers

The prediction of the morphology of wet-spun fibers has so far been only possible by complex and experimentally-intensive approaches that include the construction of ternary phase diagrams. Ultimately, however, the available models give approximate information. Here we propose an alternative predictive approach that uses design principles based on the combination of (1) Relative Energy Difference (RED) of Hansen solubility and, (2) a kinetic parameter ‘T’ that considers mass transfer effects. Such model is applied and experimentally validated for a priori determination of the diameter and internal morphology of wet-spun fibers. Remarkably, only three variables relevant to wet-spinning are needed, namely, the choice of polymer, solvent, and non-solvent types. A combination of systems are tested and the morphology of the obtained fibers determined via electron microscopy. Aspects related to demixing, internal specific surface area (BET) and layer formation on the fibers are described qualitatively. The faci...

Transdermal fennel essential oil nanoemulsions with promising hepatic dysfunction healing effect: in vitro and in vivo study

Fennel (Foeniculum vulgare Mill.) is a member of family Apiaceae. Trans-anethole, the major component of Fennel essential oil (FEO), possesses antioxidant and hepatoprotective effects. Transdermal nanoemulsions (NEs) are advanced colloidal systems for systemic and controlled drug delivery through the stratum corneum barrier. FEO NEs were prepared using the oil Lauroglycol™ 90, as it provides a larger NE existence zone than Captex® 300, in the constructed phase diagrams. Six systems were prepared using Tween20/propylene glycol (S/CoS) in the ratios 2:1 and 3:1 with oil to S/CoS mass ratios 1:9, 2:8 and 3:7. Physicochemical characterization revealed optimum properties regarding thermodynamic stability, droplet size and pH with a Newtonian flow pattern. In vitro permeation study in rat skin revealed the highest cumulative amount permeated (µg/cm2), flux and permeability coefficient values for F4 made up of 2% FEO, 4.67% Lauroglycol™ 90, 60% S/CoS in the ratio 3:1. Results of the in vivo hepatic dysfunction study in rats indicate promising significant amelioration of liver function reflected in ALT, AST, ALP, bilirubin, albumin, malondialdehyde and ammonia plasma levels. The results signify the promising approach of FEO NEs in achieving remedy of liver toxicity. The most promising effect is inherent to F4 which imparts a more positive effect than FEO.

Chern-number spectrum of ultracold fermions in optical lattices tuned independently via artificial magnetic, Zeeman, and spin-orbit fields

We discuss the Chern number spectrum of ultra-cold fermions in square optical lattices as a function of artificial magnetic, Zeeman and spin-orbit fields that can be tuned independently. We show the existence of topological quantum phase transitions induced by Zeeman and spin-orbit fields, where the total number and chirality of edge states change for fixed magnetic flux ratio, thus leading to topological-insulator phases which are different from those found at zero Zeeman and spin-orbit fields. We construct phase diagrams of chemical potential versus Zeeman field or spin-orbit coupling and characterize all insulating phases by their topological invariants. Lastly, we obtain a staircase structure in the filling factor versus chemical potential for various Zeeman and spin-orbit fields, showing the existence of incompressible states at rational filling factors derived from a generalized Diophantine equation.

Phase Diagrams, Densities, and Refractive Indexes of Aqueous Two-Phase Systems Comprising (F68, L64, or PEO1500) + (Ammonium, Sodium, or Potassium Thiocyanate Salts) + Water: Effect of Cation and Type of Macromolecule

In extraction procedures, the more commonly used aqueous two-phase systems (ATPS) comprise mainly water, salt, and macromolecule, particularly the macromolecule poly(ethylene oxide) (PEO). However, one limitation of such ATPS is their capacity to separate compounds that are more hydrophobic. One possible solution to overcome this restriction is the use of ATPS formed with triblock copolymers, which are more hydrophobic and therefore enable the extraction of hydrophobic solutes. In addition, the range of applications of ATPS formed with thiocyanate salts can be broader, mainly to extract metal ions. In view of this, equilibrium data were acquired in this work by constructing phase diagrams for ATPS comprising macromolecules [poly(ethylene oxide), PEO, or (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymers, F68 or L64] + thiocyanate salts (ammonium, sodium, or potassium) + water at 25.0 °C. The influence of the nature of the cation on the formation of the ATPS was inves...

Formulation evaluation of ketoconazole microemulsion-loaded hydrogel with nigella oil as a penetration enhancer.

Onychomycosis is an opportunistic fungal infection often infecting people with compromised immune system. Currently available treatment interventions such as physical, surgical, and chemical-based approaches are successful in treating the condition, however, are painful and nonpatient complaint. Moreover, dermal creams with antifungal agents do not penetrate nail plate as required; hence, there is a necessity of developing a novel formulation with enhanced penetration. The aim of the present research work was to develop ketoconazole microemulsion-loaded hydrogel formulation containing nigella oil as permeation enhancer for the treatment of onychomycosis. Screening of oils, surfactants, and cosurfactants were done based on solubility studies followed by the construction of pseudo-ternary phase diagrams with 2% ketoconazole. The microemulsion was characterized for globule size, zeta potential, viscosity, and thermodynamic stability. Ex-vivo studies were carried out using Franz diffusion cells using porcine skin membrane. The antifungal activity of microemulsion-loaded hydrogel was evaluated using cup plate method using Candida albicans and Aspergillus niger. The optimized microemulsion had a composition of 54.97% Capryol:Nigella (2:1), 36.07% Transcutol:Propylene glycol (2:1), and 7.13% water and was later incorporated into polymeric gel base. The microemulsion-loaded hydrogel exhibited a 10hours sustained release profile as compared to the marketed cream and an enhanced activity against marketed ketoconazole cream and compared with marketed ketoconazole formulation. The thermodynamic stability, sustained drug release with greater permeation, and enhanced activity due to the presence of nigella oil in microemulsion-loaded hydrogel warrant its application as an excellent vehicle for treating fungal infections.

Salt effect on bilayer phase transitions of dipalmitoylphosphatidylglycerol in saline water under high pressure

ABSTRACTThe phase transitions of dipalmitoylphosphatidylglycerol (DPPG) bilayer membrane at high NaCl concentrations under high pressure were investigated to construct the temperature–pressure phase diagram and to determine phase-transition properties. The constructed phase diagrams exhibited qualitative resemblance to that of the dipalmitoylphosphatidylcholine (DPPC) bilayer membrane: they showed the gel-phase polymorphism including the pressure-induced bilayer interdigitation. The phase-transition properties of the DPPG bilayer membrane changed in a salt concentration-dependent manner. We discussed the salt effect on the DPPG bilayer membrane from the variation in interactions between the polar head groups of the PG molecules.

Computational Investigation and Experimental Realization of Disordered High-Capacity Li-Ion Cathodes Based on Ni Redox

In cation-disordered rocksalt Li-ion cathode materials, an excess of Li with respect to the transition metal content is necessary for the creation of percolating pathways for Li transport. Because of the lower amount of redox-active transition metal, a substantial part of the charge transfer must occur via less reversible oxygen redox. Fluorination can be used to minimize this dependence on oxygen redox by increasing the amount of low-valent transition metal in the compound, but it adds complexity to materials design. Here, we investigate the feasibility of using computationally constructed phase diagrams to facilitate the search for optimal oxyfluorides. We use the phase diagram of LiF–Li3NbO4–NiO to identify Li1.13Ni0.57Nb0.3O1.75F0.25 and Li1.19Ni0.59Nb0.22O1.46F0.54 as two promising compositions and demonstrate that they can be successfully synthesized. These compounds exhibit significantly reduced hysteresis and higher energy density than the previously reported Li1.3Ni0.27Nb0.43O2 compound in this s...

Formulation and evaluation of norcanthridin nanoemulsions against the Plutella xylostella (Lepidotera: Plutellidae)

BackgroundNorcantharidin (NCTD), a demethylated derivative of cantharidin (defensive toxin of blister beetles), has been reported to exhibit insecticidal activity against various types of agricultural pests. However, NCTD applications are limited by its poor water solubility and high dosage requirement. Nanoemulsions have attracted much attentions due to the transparent or translucence appearance, physical stability, high bioavailability and non-irritant in nature. In general, nanoemulsions with small droplet size can enhance the bioavailability of drugs, whereas this phenomenon is likely system dependent. In present study, NCTD nanoemulsions were developed and optimized to evaluate and improve the insecticidal activity of NCTD against Plutella xylostella (Lepidotera: Plutellidae) by a spontaneous emulsification method.ResultsTriacetin, Cremophor EL and butanol were selected as the constituents of NCTD nanoemulsions via solubility determination, emulsification efficiency and ternary phase diagram construction. Insecticidal activity of NCTD nanoemulsion was associated with the content of surfactant and cosurfactant: (1) Higher effective toxicity exhibited at Smix (surfactant to cosurfactant mass ratio) = 3:1 that may be associated with the changes in interfacial tension; (2) NCTD nanoemulsion at 3:7 < SOR (surfactant to oil mass ratio) < 6:4 was more effective at lower surfactant level, which was attributed to the relatively slow diffusion rate of NCTD hindering by excess surfactant. Interestingly, nanoemulsions with smaller droplets were not found to be more effective in our study.ConclusionsThe optimized NCTD nanoemulsion (triacetin/Cremophor EL/butanol (60/20/20, w/w)) exhibited effective insecticidal activity (LC50 60.414 mg/l, LC90 185.530 mg/l, 48 h) than the NCTD acetone solution (LC50 175.602 mg/L, LC90 303.050 mg/L, 48 h). Spontaneous emulsifying nanoemulsion employed to formulate this poor water-soluble pesticide is a potential system for agriculture application.

Efficient construction method for phase diagrams using uncertainty sampling

We develop a method to efficiently construct phase diagrams using machine learning. Uncertainty sampling (US) in active learning is utilized to intensively sample around phase boundaries. Here, we demonstrate constructions of three known experimental phase diagrams by the US approach. Compared with random sampling, the US approach decreases the number of sampling points to about 20%. In particular, the reduction rate is pronounced in more complicated phase diagrams. Furthermore, we show that using the US approach, undetected new phase can be rapidly found, and smaller number of initial sampling points are sufficient. Thus, we conclude that the US approach is useful to construct complicated phase diagrams from scratch and will be an essential tool in materials science.