Scott A. White

Rheological study of crosslinking and gelation in chlorobutyl elastomer systems

Abstract The multiple waveform rheological technique was used to study the crosslinking behaviour of a filled elastomeric system at various temperatures. The gel point could be precisely determined from a single experiment at each temperature using this technique. At the instant of gelation, the storage ( G ′) and loss ( G ″) moduli scale with frequency in an identical manner, i.e. ∼ ω n . The relaxation exponent, n was found to be approximately constant (0.14) in the temperature range studied. Reported values of n for chemically crosslinking systems are typically higher; the low value in this case can be attributed to the high molecular weight of the prepolymer and the presence of filler. The gel times at various temperatures were used to calculate an apparent activation energy of the curing reaction, which was found to be approximately 92 kJ mol −1 .

Molecular, Nanostructural and Mechanical Characteristics of Lamellar Triblock Copolymer Blends: Effects of Molecular Weight and Constraint

While theoretical and experimental efforts have thoroughly addressed microphase-ordered AB diblock copolymer blends with a parent homopolymer (hA or hB) or a second block copolymer, surprisingly few studies have considered comparable ABA triblock copolymers in the presence of hB or an AB diblock copolymer. In this study, we elucidate the roles of additive molecular weight and constraint by examining three matched series of miscible ABA/hB and ABA/AB blends. Self-consistent field theory is employed to analyze molecular characteristics, e.xa0g., segmental distributions, microdomain periods and midblock bridging fractions, as functions of blend composition. Predictions are compared to morphological characteristics discerned by transmission electron microscopy and small-angle X-ray scattering. The corresponding mechanical properties of these blends are measured by dynamic mechanical analysis. The results of this comprehensive work reveal that addition of hB swells the B-lamellae of the ABA copolymer and has a generally deleterious effect on both the dynamic elastic modulus and midblock bridging fraction. In contrast, addition of a lamellar or cylindrical AB copolymer to the same ABA copolymer can promote an increase or decrease in lamellar period and bridging fraction, depending on relative block sizes.

Modification of a thermoplastic elastomer gel through the addition of an endblock‐selective homopolymer

Addition of a midblock-selective oil to an ABA triblock copolymer with a rubbery B-midblock and thermoplastic A-endblocks yields a thermoplastic elastomer gel (TPEG) if the oil constitutes the majority blend constituent and a physically crosslinked network, responsible for solid-like mechanical properties, is retained. These blends typically exhibit a micellar morphology in which the micellar cores are composed of the oil-incompatible A-endblocks. Since the micelles serve as crosslink sites, the properties of TPEGs depend on (i) the intrinsic characteristics of the solid-state endblocks, and (ii) the degree to which the micelles interact through bridged and looped midblocks. In this work, a poly[styrene-b-(ethylene-co-butylene)-b-styrene] triblock copolymer and an aliphatic oil are used to prepare TPEGs into which poly(2,6-dimethylphenylene oxide) (PPO), a styrene-compatible homopolymer, is added. The morphologies and bulk properties of these ternary systems are examined by electron microscopy, viscometry, and dynamic rheology. A slight increase in the PPO content in these TPEGs promotes increases in micelle size, confirming that the PPO primarily resides within the micelles, and disordering temperature, signified by an abrupt change in rheological properties.

Safety and Efficacy of GSK2248761, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Treatment-Naive HIV-1-Infected Subjects

ABSTRACT GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log10 copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [Cmax], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC0-τ], and concentration at the end of the dosing interval [Cτ]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (Emax) model using Cτ (Emax = 2.0; 50% effective concentration [EC50] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.

Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects

ABSTRACT Cefiderocol is a novel parenteral siderophore cephalosporin that shows potent efficacy against various Gram-negative bacteria, including carbapenem-resistant strains, in vitro and in preclinical models of infection. The aim of the present study was to evaluate the pharmacokinetics (PK), safety, and tolerability of cefiderocol after both single and multiple dosing by intravenous infusion over 60 min in healthy adult subjects. A single-ascending-dose study at doses of 100, 250, 500, 1,000, and 2,000 mg was conducted in 40 healthy Japanese males and females (6 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). A multiple-ascending-dose study at doses of 1,000 (two groups) and 2,000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and Caucasian males (8 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). There were no serious or clinically significant adverse events (AEs) observed in either study. A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs. Dose-proportional increases in the maximum plasma concentration (Cmax), the area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration after dosing, and the area under the concentration-time curve extrapolated from time zero to infinity were observed across the dose range of 100 to 2,000 mg. The mean plasma half-life of cefiderocol was 1.98 to 2.74 h. Cefiderocol was primarily excreted unchanged in the urine (61.5% to 68.4% of the dose). There was little accumulation of Cmax and AUC by dosing q8h, and the PK of cefiderocol did not change with multiple dosing. This study indicates that single and multiple intravenous doses of cefiderocol at up to 2,000 mg are well tolerated in healthy subjects and exhibit linear PK at doses up to 2,000 mg.

Rheological investigation of shear-induced structure changes in multiblock copolymers

Styrene-butadiene multiblock copolymers were examined with both newly introduced and established rheological techniques and by transmission electron microscopy (TEM) to evaluate shear-induced structural changes in these polymers. Transient rheological tests (based on superposed flow principles) were developed which probed structural changes that occur in the copolymers during and at the cessation of steady shear. Data from these tests indicated that for the cylindrical morphology copolymer (SB1) there were structural changes occurring during steady shear that were recovered upon cessation of shear. The recovery process took place on time scales that could be significant in processing. The lamellar morphology material (SB2) did not exhibit this recovery behavior. Longer-term structure changes were investigated using established techniques and showed differences between the cylindrical and lamellar copolymers. When tested at 210°C, peaks in tan δ occurred at 30 rad/s for SB1 and at 0.5 rad/s for SB2 with saturation strain levels of 150 strain units (SU) for SB1 and 80 SU for SB2. TEM analysis of SB2 indicated that, although rheological changes are significant up to 80 SU, better alignment of the domain morphology can be achieved at moderately low strains of 7 SU. This indicates that the copolymers rheological changes, which occur as a result of steady shearing, may not be due entirely to domain alignment, but may also be due to more local molecular rearrangements (e.g., chain disentanglement).