Development and Validation of an In‐Line API Quantification Method Using AQbD Principles Based on UV‐Vis Spectroscopy to Monitor and Optimise Continuous Hot Melt Extrusion Process

open access journalA key principle of developing a new medicine is that quality should be built in, with a thorough understanding of the product and the manufacturing process supported by appropriate process controls. Quality by design principles that have been established for the development of drug products/substances can equally be applied to the development of analytical procedures. This paper presents the development and validation of a quantitative method to predict the concentration of piroxicam in Kollidon® VA 64 during hot melt extrusion using analytical quality by design principles. An analytical target profile was established for the piroxicam content and a novel in‐line analytical procedure was developed using predictive models based on UV‐Vis absorbance spectra collected during hot melt extrusion. Risks that impact the ability of the analytical procedure to measure piroxicam consistently were assessed using failure mode and effect analysis. The critical analytical attributes measured were colour (L* lightness, b* yellow to blue colour parameters—in‐process critical quality attributes) that are linked to the ability to measure the API content and transmittance. The method validation was based on the accuracy profile strategy and ICH Q2(R1) validation criteria. The accuracy profile obtained with two validation sets showed that the 95% β‐expectation tolerance limits for all piroxicam concentration levels analysed were within the combined trueness and precision acceptance limits set at ±5%. The method robustness was tested by evaluating the effects of screw speed (150–250 rpm) and feed rate (5–9 g/min) on piroxicam content around 15% w/w. In‐line UV‐Vis spectroscopy was shown to be a robust and practical PAT tool for monitoring the piroxicam content, a critical quality attribute in a pharmaceutical HME process

A study of possible sea state information in the sample and hold gate statistics for the GEOS-3 satellite altimeter

The statistical variations in the sample gate outputs of the GEOS-3 satellite altimeter were studied for possible sea state information. After examination of a large number of statistical characteristics of the altimeter waveforms, it was found that the best sea predictor for H-1/3 in the range of 0 to 3 meters was the 75th percentile of sample and hold gate number 11

Structure and binding in crystals of cage-like molecules: hexamine and platonic hydrocarbons

In this paper, we show that first-principle calculations using a van der Waals density functional (vdW-DF), [Phys. Rev. Lett. $\mathbf{92}$, 246401 (2004)] permits determination of molecular crystal structure. We study the crystal structures of hexamine and the platonic hydrocarbons (cubane and dodecahedrane). The calculated lattice parameters and cohesion energy agree well with experiments. Further, we examine the asymptotic accounts of the van der Waals forces by comparing full vdW-DF with asymptotic atom-based pair potentials extracted from vdW-DF. The character of the binding differ in the two cases, with vdW-DF giving a significant enhancement at intermediate and relevant binding separations. We analyze consequences of this result for methods such as DFT-D, and question DFT-D's transferability over the full range of separations

Stress-Particle Smoothed Particle Hydrodynamics: an application to the failure and post-failure behaviour of slopes

We present a new numerical approach in the framework of Smooth Particle Hydrodynamics (SPH) to solve the zero energy modes and tensile instabilities, without the need for the fine tuning of non-physical artificial parameters. The method uses a combination of stress-points and nodes and includes a new stress-point position updating scheme that also removes the need to implement artificial repulsive forces at the boundary. The model is validated for large deformation geomechanics problems, and is able to simulate strain localisation within soil samples and slopes. In particular, the new model produces stable and accurate results of the failure and post-failure of slopes, consisting of both cohesive and cohesionless materials, for the first time

Auto-calibration of ultrasonic lubricant-film thickness measurements

The measurement of oil film thickness in a lubricated component is essential information for performance monitoring and design. It is well established that such measurements can be made ultrasonically if the lubricant film is modelled as a collection of small springs. The ultrasonic method requires that component faces are separated and a reference reflection recorded in order to obtain a reflection coefficient value from which film thickness is calculated. The novel and practically useful approach put forward in this paper and validated experimentally allows reflection coefficient measurement without the requirement for a reference. This involves simultaneously measuring the amplitude and phase of an ultrasonic pulse reflected from a layer. Provided that the acoustic properties of the substrate are known, the theoretical relationship between the two can be fitted to the data in order to yield reflection coefficient amplitude and phase for an infinitely thick layer. This is equivalent to measuring a reference signal directly, but importantly does not require the materials to be separated. The further valuable aspect of this approach, which is demonstrated experimentally, is its ability to be used as a self-calibrating routine, inherently compensating for temperature effects. This is due to the relationship between the amplitude and phase being unaffected by changes in temperature which cause unwanted changes to the incident pulse. Finally, error analysis is performed showing how the accuracy of the results can be optimized. A finding of particular significance is the strong dependence of the accuracy of the technique on the amplitude of reflection coefficient input data used. This places some limitations on the applicability of the technique. © 2008 IOP Publishing Ltd

Detecting Scale Recalibration in Survey Research: A Laboratory Investigation

The accurate detection of scale recalibration is an issue that should not be ignored by organizational researchers and practitioners concerned with the accurate assessment of change interventions. In an effort to more effectively operationalize one methodology that is designed to detect scale recalibration (using ideal scales), three research questions were developed and investigated in a laboratory study utilizing videotape technology. It was concluded that ideal scale methodology can be used to accurately detect the presence of scale recalibration in survey research data. The implications of these findings for both researchers and practitioners are discussed.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Transition phenomena in unstably stratified turbulent flows

We study experimentally and theoretically transition phenomena caused by the external forcing from Rayleigh-Benard convection with the large-scale circulation (LSC) to the limiting regime of unstably stratified turbulent flow without LSC whereby the temperature field behaves like a passive scalar. In the experiments we use the Rayleigh-B\'enard apparatus with an additional source of turbulence produced by two oscillating grids located nearby the side walls of the chamber. When the frequency of the grid oscillations is larger than 2 Hz, the large-scale circulation (LSC) in turbulent convection is destroyed, and the destruction of the LSC is accompanied by a strong change of the mean temperature distribution. However, in all regimes of the unstably stratified turbulent flow the ratio $\big[(\ell_x \nabla_x T)^2 + (\ell_y \nabla_y T)^2 + (\ell_z \nabla_z T)^2\big] /$ varies slightly (even in the range of parameters whereby the behaviour of the temperature field is different from that of the passive scalar). Here $\ell_i$ are the integral scales of turbulence along x, y, z directions, T and \theta are the mean and fluctuating parts of the fluid temperature. At all frequencies of the grid oscillations we have detected the long-term nonlinear oscillations of the mean temperature. The theoretical predictions based on the budget equations for turbulent kinetic energy, turbulent temperature fluctuations and turbulent heat flux, are in agreement with the experimental results.Comment: 14 pages, 14 figures, REVTEX4-1, revised versio

Semisimplicity of the quantum cohomology for smooth Fano toric varieties associated with facet symmetric polytopes

The degree zero part of the quantum cohomology algebra of a smooth Fano toric symplectic manifold is determined by the superpotential function, W, of its moment polytope. In particular, this algebra is semisimple, i.e. splits as a product of fields, if and only if all the critical points of W are non-degenerate. In this paper we prove that this non-degeneracy holds for all smooth Fano toric varieties with facet-symmetric duals to moment polytopes.Comment: 16 pages; corrected version, published in Electron. Res. Announc. Math. Sc