Thermal properties and eutectic behaviour of dapivirine in combination with steroid hormones and other antiretrovirals

Background: Combination drug products can display thermal behaviour that is more complex than for the corresponding single drug products. For example, the contraceptive vaginal ring (VR) Nuvaring contains a eutectic (lowest melting) composition of etonogestrel (ETN) and ethinyl estradiol. Here we report the predisposition of dapivirine (DPV) to form reduced melting/eutectic mixtures when combined with other contraceptive hormones and antiretrovirals, and discuss the implications for development of combination microbicide and multipurpose prevention technology (MPT) products.
Methods: Binary mixtures of DPV with darunavir (DRV), levonorgestrel (LNG), ETN or maraviroc (MVC) were prepared either by physical mixing or by solvent evaporation. Selected binary mixtures were also incorporated into silicone elastomer (SE) VR devices. Thermal behavior of the mixtures was analyzed using differential scanning calorimetry (DSC) operating in standard heating ramp mode (10 °C/min). DSC data were used to construct two component phase diagrams for each binary system.
Results: Drug mixtures typically showed reduced melting transitions for both drug components, with clear evidence for a eutectic mixture at a well-defined intermediate composition. Eutectic temperatures and compositions for the various mixtures were: 40% DPV / 60% ETN - 170°C; 25% DPV / 75% MVC - 172°C; 65% DPV / 35% LNG - 192°C. In each case, the eutectic composition was also detected when the drug mixtures were incorporated into SE VRs. For the DPV/DRV system, the thermal behaviour is complicated by desolvation from the darunavir ethanolate polymorph.
Conclusions: When DPV is combined with small molecular weight hydrophobic drugs, the melting temperature for both drugs is typically reduced to a degree dependent on the composition of the mixture. At specified compositions, a low melting eutectic system results. The formation of eutectic behavior in binary drug systems needs to be carefully characterised in order to define product performance and drug release.

Controlling the materials properties and nanostructure of a single-component dendritic gel by adding a second component

This paper reports a dendritic system which is capable of forming both one-component and two-component gels interestingly the addition of the second component can either increase or decrease the degree of gelation, depending on dendritic generation.

Effect of Nanosilica on Rheology, Fresh Properties, and Strength of Cement-Based Grouts

The effect of colloidal nanosilica on the fresh and rheological parameters, plastic shrinkage, heat of hydration, and compressive strength of cement-based grouts is investigated in this paper. The fresh and rheological properties were evaluated by the minislump flow, Marsh cone flow time, Lombardi plate cohesion meter, yield value, and plastic viscosity. The key parameters investigated were the dosages of nanosilica and superplasticizer and temperature of mixing water. Statistical models and isoresponse curves were developed to capture the significant trends. The dosage of nanosilica had a significant effect on the results. The increase in the dosage of nanosilica led to increasing the values of flow time, plate cohesion meter, yield stress, plastic viscosity, heat of hydration at 1 day and 3 days, and compressive strength at 1 day, while reducing the minislump, plastic shrinkage up 24 h, and compressive strength at 3, 7, and 28 days. Conversely, the increase in the dosage of superplasticizer led to decreasing the values of flow time, plate cohesion meter, yield stress, plastic viscosity, heat of hydration at 1 day and 3 days, and compressive strength at 1 day, while increasing the minislump, plastic shrinkage, and compressive strength at 3 and 7 days. Increasing the temperature of mixing water led to a notable increase in the results of minislump, flow time, plastic viscosity, heat of hydration at 3 days, and compressive strength at 1 day, while it reduced the plate cohesion, compressive strength at 3, 7, and 28 days. The statistical models developed in this study can facilitate optimizing the mixture proportions of grouts for target performance by reducing the number of trial batches needed.

Microstructure, mechanical properties and fractography of heat-treated manganese steel

A Fe-8.46%Mn-0.24%Nb-0.038%C (wt.%) manganese steel was investigated. The steel has a 100% bcc structure after heat treatment at 850°C for 1.5 h, water quenching or air cooling. Martensite interlocked microstructure consisting of fine martensite plates/needles with different spatial orientations was found. Austenite forms, in small amounts, after a 600°C reheating treatment. Scanning electron microscopy images and energy dispersive spectrometry of the fracture surfaces revealed both ductile and brittle types of failure and precipitates. Deep quenching after the heat treatments does not change the phase composition or the hardness. NbC is formed in the steel, in high number densities. It plays a role in the impact fracture process, by acting as void nucleation sites, facilitating ductile fracture with dimples appearing on the fracture surface.

Microstructure, properties and application of YAl2 intermetallic compound as particle reinforcements

An yttrium aluminum (YAl2) intermetallic compound ingot was prepared in an induction furnace under vacuum. The microstructure of YAl2 ingot was characterized by optical microscopy, scanning electron microscopy, and X-ray diffraction. The load bearing response of YAl2 intermetallic was investigated and compared with SiC ceramic by indentation combined with optical microscopy and scanning electron microscopy. Additionally, the tensile properties of the Mg–Li matrix composites reinforced with ultrafine YAl2 particles fabricated by planet ball milling were tested. The results show that the intermetallic compound ingot in this experiment is composed of a main face-centered-cubic structure YAl2 phase, a small amount of YAl phase, and minor Y and Al-rich phases. YAl2 intermetallic compound has excellent stability and shows better capability in crack resistance than SiC ceramic. The YAl2 intermetallic compound has better deformation compatibility with the Mg–14Li–3Al matrix than SiC reinforcement with the matrix, which leads to the superior resistance to crack for YAl2p/Mg–14Li–3Al composite compared to SiCp/Mg–14Li–3Al composite.

Kuznetsov independence for interval-valued expectations and sets of probability distributions: Properties and algorithms

Kuznetsov independence of variables X and Y means that, for any pair of bounded functions f(X) and g(Y), E[f(X)g(Y)]=E[f(X)] *times* E[g(Y)], where E[.] denotes interval-valued expectation and *times* denotes interval multiplication. We present properties of Kuznetsov independence for several variables, and connect it with other concepts of independence in the literature; in particular we show that strong extensions are always included in sets of probability distributions whose lower and upper expectations satisfy Kuznetsov independence. We introduce an algorithm that computes lower expectations subject to judgments of Kuznetsov independence by mixing column generation techniques with nonlinear programming. Finally, we define a concept of conditional Kuznetsov independence, and study its graphoid properties.

Degradation of 4-fluorobiphenyl by mycorrhizal fungi as determined by 19F nuclear magnetic resonance spectroscopy and 14C radiolabelling analysis

The pathways of biotransformation of 4-fluorobiphenyl (4FBP) by the ectomycorrhizal fungus Tylospora fibrilosa and several other mycorrhizal fungi were investigated by using ¹⁹F nuclear magnetic resonance (NMR) spectroscopy in combination with ¹⁴C radioisotope-detected high-performance liquid chromatography (¹⁴C- HPLC). Under the conditions used in this study T. fibrillosa and some other species degraded 4FBP. ¹⁴C-HPLC profiles indicated that there were four major biotransformation products, whereas ¹⁹F NMR showed that there were six major fluorine-containing products. We confirmed that 4-fluorobiphen-4'-ol and 4-fluorobiphen-3'-ol were two of the major products formed, but no other products were conclusively identified. There was no evidence for the expected biotransformation pathway (namely, meta cleavage of the less halogenated ring), as none of the expected products of this route were found. To the best of our knowledge, this is the first report describing intermediates formed during mycorrhizal degradation of halogenated biphenyls.