The oscillatory testing of pharmaceutical semi-solids using a transfer function analyser

Summary The rheological investigation of pharmaceutical materials such as pastes and creams has been limited to continuous shear experiments although it is known that complex rheological behaviour (visco-elasticity) is present and that analysis of hysteresis loops can only give a qualitative estimate of structure and rheological properties. Oscillatory testing has been avoided largely due to the lengthy measurements involved in calculation of amplitudes and phase angle and the difficulty in obtaining a clean wave form. Solartron Electronic Group Ltd. have recently introduced an apparatus that overcomes these objections: the transfer function analyser J. M. 1600 and mechanical reference synchroniser J. X. 1606. Electronic noise can be filtered out and the results are available almost instantaneously.This apparatus has been used in conjunction with aWeissenberg rheogoniometer to study the rheological properties of a variety of pharmaceutical materials, including emulsions, creams and ointment bases. The change in phase angle and amplitude has been studied over the frequency range 25 Hz to 7.9 × 10^–3 Hz for parallel plate and concentric cylinder geometries. The systems examined have demonstrated a large range of rheological behaviour ranging from essentially linear Newtonian liquid to very non linear plastic solid.It is concluded that the Solartron apparatus will provide a rapid and accurate method for the rheological analysis of complex pharmaceutical materials.

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Zusammenfassung Rheologische Untersuchung von pharmazeutischen Produkten wie Pasten und Cremen war bisher auf Experimente mit kontinuierlicher Scherbeanspruchung beschränkt. Man weiß jedoch, daß es komplexes rheologisches Verhalten gibt und daß die Untersuchung der Hysteresisschleife nur ein qualitatives Erfassen von Strukturen und Theologischen Eigenschaften ermöglicht. Untersuchungen unter oszillierenden Bedingungen wurden vermieden, hauptsächlich wegen der zeitverbrauchenden Messungen, die die Berechnung von Amplitude und Phasenwinkel mit sich bringen und wegen der Schwierigkeiten, eine saubere Wellenform zu erhalten. Die Solartron Electronic Group Ltd. hat vor kurzem ein Gerät entwickelt, das diese Schwierigkeiten überwindet: den transfer function analyser JM 1600 und den mechanical reference synchroniser JX 1606.Unschärfe wegen Interferenz kann durch Filtern vermieden werden und Ergebnisse können fast augenblicklich erhalten werden.Dieses Gerät wurde in Verbindung mit demWeissenberg-Rheogoniometer benützt, um das rheologische Verhalten von pharmazeutischen Produkten wie Emulsionen, Cremen und Salbengrundlagen zu testen. Die Änderung von Phasenwinkel und Amplitude wurde mit parallelen Platen und konzentrischen Zylindern im Bereich von 25 Hz bis 7,9 · 10^–3 Hz untersucht. Das rheologische Verhalten der untersuchten Systeme wurde über einen weiten Bereich variiert, von linearen newtonischen Flüssigkeiten zu nichtlinearen plastischen Festprodukten.Man kann daraus schließen, daß das Solartrongerät ein schnelles und genaues Verfahren bietet, um rheologische Bestimmungen von komplexen pharmazeutischen Produkten durchzuführen.

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Paper presented at the Conference on Experimental Rheology, University of Bradford, April 17–19, 1968.     

Flow and Thermal Convection in Full-Zone Liquid Bridges of Wide-Ranging Aspect Ratio

Flow and thermal effects concerned with liquid crystal growth are studied nonlinearly for low Prandtl numbers, in an axisymmetric steady configuration with end walls present. Full solutions are obtained by finite-element simulation to examine the influences of aspect ratio, Marangoni number and Rayleigh number. In particular, a lemonhead phenomenon is found in which the velocity profiles acquire a very localised bell-shaped form as jet-like flow starts to emerge, when the relative size of the Marangoni number increases above a finite critical value which is identified. Wide-domain and narrow-domain analyses are then presented, showing favourable agreement with the full solutions and explaining the impact of the end walls on the motion, especially through slender flow modelling in the narrow-domain context. Sensitive scalings for the relative effects of the Marangoni and Rayleigh numbers emerge, and the lemonhead phenomenon is also accounted for as a substantial change in the convective flow structure.     

Synthesis of a trimeric gp120 epitope mimic conjugated to a T-helper peptide to improve antigenicity

A fully synthetic trivalent mimotope of gp120 conjugated to pan allelic HLA DR binding epitope was prepared using solid-phase peptide synthesis and optimized copper-catalyzed azide-alkyne cycloaddition. The methodology efficiently provides chemically uniform heteromultimeric peptide constructs with enhanced binding, avidity, and specificity toward an established HIV-neutralizing human antibody, MAb b12. The versatile synthetic strategy serves as a powerful platform for the development of synthetic peptides as potential HIV-1 vaccine candidates.     

Three-dimensional electronic spectroscopy of excitons in asymmetric double quantum wells

We demonstrate three-dimensional (3D) electronic spectroscopy of excitons in a double quantum well system using a three-dimensional phase retrieval algorithm to obtain the phase information that is lost in the measurement of intensities. By extending the analysis of two-dimensional spectroscopy to three dimensions, contributions from different quantum mechanical pathways can be further separated allowing greater insight into the mechanisms responsible for the observed peaks. By examining different slices of the complete three-dimensional spectrum, not only can the relative amplitudes be determined, but the peak shapes can also be analysed to reveal further details of the interactions with the environment and inhomogeneous broadening. We apply this technique to study the coupling between two coupled quantum wells, 5.7 nm and 8 nm wide, separated by a 4 nm barrier. Coupling between the heavy-hole excitons of each well results in a circular cross-peak indicating no correlation of the inhomogeneous broadening. An additional cross-peak is isolated in the 3D spectrum which is elongated in the diagonal direction indicating correlated inhomogeneous broadening. This is attributed to coupling of the excitons involving the two delocalised light-hole states and the electron state localised on the wide well. The attribution of this peak and the analysis of the peak shapes is supported by numerical simulations of the electron and hole wavefunctions and the three-dimensional spectrum based on a density matrix approach. An additional benefit of extending the phase retrieval algorithm from two to three dimensions is that it becomes substantially more reliable and less susceptible to noise as a result of the more extensive use of a priori information.     

The Preparation of New C(α)-Dianions

For more than a decade, Hauser et. al. carried out rather extensive investigations on the preparation and reactions of the multiple anions of β -diketones and related materials. Once the conditions for the preparation of a particular multiple anion seemed established, three reactions were usually attempted with the new multiple anion: alkylations with reagents such as benzyl chloride², Aldol-type condensations with aldehydes or ketones³ such as benzaldehyde and benzophenone, and Claisen-type condensations with esters such as methyl benzoate⁴. Other electrophilic reagents, such as nitriles⁵ and isocyanates⁶, were also condensed with certain of these multiple anions in selective situations; however, the alkylations, acylations, and carbonyl additions received the greatest amount of attention⁷. In some cases only one of the three types of reactions (Aldol) worked well⁸; however this did not mean that conditions could not be found for the other two reaction types. In addition, the synthetic potential of these multiple anion reactions was quite extensive (Scheme 1).     

Tricarbamate of 1,3,5‐Triaminobenzene via Curtius Rearrangement of Trimesic Acid and Subsequent Nitration

The triethyl tricarbamate of 1,3,5‐triaminobenzene was prepared from trimesic acid in five steps with 70% overall yield. The tricarbamate underwent nitration to give the mono‐, di‐, or trinitro analogs in excellent yield.     

Radiation propagation in random media: From positive to negative correlations in high-frequency fluctuations

We survey research on radiation propagation or ballistic particle motion through media with randomly variable material density, and we investigate the topic with an emphasis on very high spatial frequencies. Our new results are based on a specific variability model consisting of a zero-mean Gaussian scaling noise riding on a constant value that is large enough with respect to the amplitude of the noise to yield overwhelmingly non-negative density. We first generalize known results about sub-exponential transmission from regular functions, which are almost everywhere continuous, to merely “measurable” ones, which are almost everywhere discontinuous (akin to statistically stationary noises), with positively correlated fluctuations. We then use the generalized measure-theoretic formulation to address negatively correlated stochastic media without leaving the framework of conventional (continuum-limit) transport theory. We thus resolve a controversy about recent claims that only discrete-point process approaches can accommodate negative correlations, i.e., anti-clustering of the material particles. We obtain in this case the predicted super-exponential behavior, but it is rather weak. Physically, and much like the alternative discrete-point process approach, the new model applies most naturally to scales commensurate with the inter-particle distance in the material, i.e., when the notion of particle density breaks down due to Poissonian—or maybe not-so-Poissonian—number-count fluctuations occur in the sample volume. At the same time, the noisy structure must prevail up to scales commensurate with the mean-free-path to be of practical significance. Possible applications are discussed.     

Observation of two-neutrino double-beta decay in 136Xe with the EXO-200 detector

We report the observation of two-neutrino double-beta decay in (136)Xe with T(1/2) = 2.11 ± 0.04(stat) ± 0.21(syst) × 10(21) yr. This second-order process, predicted by the standard model, has been observed for several nuclei but not for (136)Xe. The observed decay rate provides new input to matrix element calculations and to the search for the more interesting neutrinoless double-beta decay, the most sensitive probe for the existence of Majorana particles and the measurement of the neutrino mass scale.     

Markov chain formalism for vector radiative transfer in a plane-parallel atmosphere overlying a polarizing surface

We report on a way of building bidirectional surface reflectivity into the Markov chain formalism for polarized radiative transfer through a vertically inhomogeneous atmosphere. Numerical results are compared to those obtained by the Monte Carlo method, showing the accuracy of the Markov chain method when 90 streams are used to compute the radiation from a Rayleigh-plus-aerosol atmosphere that overlies a surface with a bidirectional reflection function consisting of both depolarizing and polarizing parts.     

Molecular tensile machines: intrinsic acceleration of disulfide reduction by dithiothreitol

Significant tension on the order of 1 nN is self-generated along the backbone of bottlebrush macromolecules due to steric repulsion between densely grafted side chains. The intrinsic tension is amplified upon adsorption of bottlebrush molecules onto a substrate and increases with grafting density, side chain length, and strength of adhesion to the substrate. These molecules were employed as miniature tensile machines to study the effect of mechanical force on the kinetics of disulfide reduction by dithiothreitol (DTT). For this purpose, bottlebrush macromolecules containing a disulfide linker in the middle of the backbone were synthesized by atom transfer radical polymerization (ATRP). The scission reaction was monitored through molecular imaging by atomic force microscopy (AFM). The scission rate constant increases linearly with the concentration of DTT and exponentially with mechanical tension along the disulfide bond. Moreover, the rate constant at zero force is found to be significantly lower than the reduction rate constant in bulk solution, which suggests an acidic composition of the water surface with pH = 3.7. This work demonstrates the ability of branched macromolecules to accelerate chemical reactions at specific covalent bonds without applying an external force.