Stability of dobutamine 500 mg in 50 ml syringes prepared using a Central Intravenous Additive Service

Objectives A pharmacy Central Intravenous Additives Service (CIVAS) provides ready to use injectable medicines. However, manipulation of a licensed injectable medicine may significantly alter the stability of drug(s) in the final product. The aim of this study was to develop a stability indicating assay for CIVAS produced dobutamine 500 mg in 50 ml dextrose 1% (w/v) prefilled syringes, and to allocate a suitable shelf life. Methods A stability indicating high performance liquid chromatography (HPLC) assay was established for dobutamine. The stability of dobutamine prefilled syringes was evaluated under storage conditions of 4°C (protected from light), room temperature (protected from light), room temperature (exposed to light) and 40°C (protected from light) at various time points (up to 42 days). Results An HPLC method employing a Hypersil column, mobile phase (pH=4.0) consisting of 82:12:6 (v/v/v) 0.05 M KH2PO4:acetonitrile:methanol plus 0.3% (v/v) triethylamine with UV detection at λ=280 nm was specific for dobutamine. Under different storage conditions only samples stored at 40°C showed greater than 5% degradation (5.08%) at 42 days and had the shortest T95% based on this criterion (44.6 days compared with 111.4 days for 4°C). Exposure to light also reduced dobutamine stability. Discolouration on storage was the limiting factor in shelf life allocation, even when dobutamine remained within 5% of the initial concentration. Conclusions A stability indicating HPLC assay for dobutamine was developed. The shelf life recommended for the CIVAS product was 42 days at 4°C and 35 days at room temperature when protected from light.

On the stability and convergence of the finite section method for integral equation formulations of rough surface scattering

We consider the Dirichlet and Robin boundary value problems for the Helmholtz equation in a non-locally perturbed half-plane, modelling time harmonic acoustic scattering of an incident field by, respectively, sound-soft and impedance infinite rough surfaces.Recently proposed novel boundary integral equation formulations of these problems are discussed. It is usual in practical computations to truncate the infinite rough surface, solving a boundary integral equation on a finite section of the boundary, of length 2A, say. In the case of surfaces of small amplitude and slope we prove the stability and convergence as A→∞ of this approximation procedure. For surfaces of arbitrarily large amplitude and/or surface slope we prove stability and convergence of a modified finite section procedure in which the truncated boundary is ‘flattened’ in finite neighbourhoods of its two endpoints. Copyright © 2001 John Wiley & Sons, Ltd.

Application of the direct Liapunov method to the problem of symmetric stability in the atmosphere

The problem of symmetric stability is examined within the context of the direct Liapunov method. The sufficient conditions for stability derived by Fjørtoft are shown to imply finite-amplitude, normed stability. This finite-amplitude stability theorem is then used to obtain rigorous upper bounds on the saturation amplitude of disturbances to symmetrically unstable flows.By employing a virial functional, the necessary conditions for instability implied by the stability theorem are shown to be in fact sufficient for instability. The results of Ooyama are improved upon insofar as a tight two-sided (upper and lower) estimate is obtained of the growth rate of (modal or nonmodal) symmetric instabilities.The case of moist adiabatic systems is also considered.

A wavenumber independent boundary element method for an acoustic scattering problem

In this paper we consider the impedance boundary value problem for the Helmholtz equation in a half-plane with piecewise constant boundary data, a problem which models, for example, outdoor sound propagation over inhomogeneous. at terrain. To achieve good approximation at high frequencies with a relatively low number of degrees of freedom, we propose a novel Galerkin boundary element method, using a graded mesh with smaller elements adjacent to discontinuities in impedance and a special set of basis functions so that, on each element, the approximation space contains polynomials ( of degree.) multiplied by traces of plane waves on the boundary. We prove stability and convergence and show that the error in computing the total acoustic field is O( N-(v+1) log(1/2) N), where the number of degrees of freedom is proportional to N logN. This error estimate is independent of the wavenumber, and thus the number of degrees of freedom required to achieve a prescribed level of accuracy does not increase as the wavenumber tends to infinity.

A high-wavenumber boundary-element method for an acoustic scattering problem

In this paper we show stability and convergence for a novel Galerkin boundary element method approach to the impedance boundary value problem for the Helmholtz equation in a half-plane with piecewise constant boundary data. This problem models, for example, outdoor sound propagation over inhomogeneous flat terrain. To achieve a good approximation with a relatively low number of degrees of freedom we employ a graded mesh with smaller elements adjacent to discontinuities in impedance, and a special set of basis functions for the Galerkin method so that, on each element, the approximation space consists of polynomials (of degree $\nu$) multiplied by traces of plane waves on the boundary. In the case where the impedance is constant outside an interval $[a,b]$, which only requires the discretization of $[a,b]$, we show theoretically and experimentally that the $L_2$ error in computing the acoustic field on $[a,b]$ is ${\cal O}(\log^{\nu+3/2}|k(b-a)| M^{-(\nu+1)})$, where $M$ is the number of degrees of freedom and $k$ is the wavenumber. This indicates that the proposed method is especially commendable for large intervals or a high wavenumber. In a final section we sketch how the same methodology extends to more general scattering problems.

Pilot study of the short-term physico-chemical stability of atenolol tablets stored in a multi-compartment compliance aid

Study objectives: There is a possibility that lower air, moisture and light protection could impact on physico-chemical stability of medicines inside multi-compartment compliance aids (MCCAs), although this has not yet been proved. The objectives of the study were to examine the physico-chemical stability of atenolol tablets stored in a compliance aid at room temperature, and at elevated temperature and humidity to simulate practice conditions. Methods: Atenolol 100 mg tablets in 28-chamber, plastic compliance aids with transparent lids were stored for four weeks at room temperature and at 40°C with 75% relative humidity. Tablets were also stored at room temperature in original packaging and Petri dishes. Physical tests were conducted to standards as laid down in the British Pharmacopoeia 2005, and dissolution to those of the United States Pharmacopoeia volume 24. Chemical stability was assessed by a validated high-performance liquid chromatography (HPLC) method. Results: Tablets at room temperature in original packaging, in compliance aids and Petri dishes remained the same in appearance and passed physico-chemical tests. Tablets exposed to 40°C with 75% relative humidity in compliance aids passed tests for uniformity of weight, friability and chemical stability but became pale and moist, softer (82 newtons ± 4; p< 0.0001) than tablets in the original packaging (118 newtons ± 6), more friable (0.14% loss of mass) compared with other tablets (0.005%), and failed the tests for disintegration (>15 minutes) and dissolution (only 15% atenolol released at 30 minutes). Conclusion: Although chemical stability was unaffected, storage in compliance aids at 40°C with 75% relative humidity softened atenolol tablets, prolonged disintegration time and hindered dissolution which could significantly reduce bioavailability. This formulation could be suitable for storage in compliance aids at 25°C, but not in hotter, humid weather.

A Nyström method for a boundary value problem arising in unsteady water wave problems

This paper is concerned with solving numerically the Dirichlet boundary value problem for Laplace’s equation in a nonlocally perturbed half-plane. This problem arises in the simulation of classical unsteady water wave problems. The starting point for the numerical scheme is the boundary integral equation reformulation of this problem as an integral equation of the second kind on the real line in Preston et al. (2008, J. Int. Equ. Appl., 20, 121–152). We present a Nystr¨om method for numerical solution of this integral equation and show stability and convergence, and we present and analyse a numerical scheme for computing the Dirichlet-to-Neumann map, i.e., for deducing the instantaneous fluid surface velocity from the velocity potential on the surface, a key computational step in unsteady water wave simulations. In particular, we show that our numerical schemes are superalgebraically convergent if the fluid surface is infinitely smooth. The theoretical results are illustrated by numerical experiments.

Analysis of void volumes in proteins and application to stability of the p53 tumour suppressor protein

We have developed a new method for the analysis of voids in proteins (defined as empty cavities not accessible to solvent). This method combines analysis of individual discrete voids with analysis of packing quality. While these are different aspects of the same effect, they have traditionally been analysed using different approaches. The method has been applied to the calculation of total void volume and maximum void size in a non-redundant set of protein domains and has been used to examine correlations between thermal stability and void size. The tumour-suppressor protein p53 has then been compared with the non-redundant data set to determine whether its low thermal stability results from poor packing. We found that p53 has average packing, but the detrimental effects of some previously unexplained mutations to p53 observed in cancer can be explained by the creation of unusually large voids. (C) 2004 Elsevier Ltd. All rights reserved.

Fast and accurate SCFT calculations for periodic block-copolymer morphologies using the spectral method with Anderson mixing

We study the numerical efficiency of solving the self-consistent field theory (SCFT) for periodic block-copolymer morphologies by combining the spectral method with Anderson mixing. Using AB diblock-copolymer melts as an example, we demonstrate that this approach can be orders of magnitude faster than competing methods, permitting precise calculations with relatively little computational cost. Moreover, our results raise significant doubts that the gyroid (G) phase extends to infinite $\chi N$. With the increased precision, we are also able to resolve subtle free-energy differences, allowing us to investigate the layer stacking in the perforated-lamellar (PL) phase and the lattice arrangement of the close-packed spherical (S$_{cp}$) phase. Furthermore, our study sheds light on the existence of the newly discovered Fddd (O$^{70}$) morphology, showing that conformational asymmetry has a significant effect on its stability.

A new method for evaluating regional air quality forecasts

A Kriging interpolation method is combined with an object-based evaluation measure to assess the ability of the UK Met Office's dispersion and weather prediction models to predict the evolution of a plume of tracer as it was transported across Europe. The object-based evaluation method, SAL, considers aspects of the Structure, Amplitude and Location of the pollutant field. The SAL method is able to quantify errors in the predicted size and shape of the pollutant plume, through the structure component, the over- or under-prediction of the pollutant concentrations, through the amplitude component, and the position of the pollutant plume, through the location component. The quantitative results of the SAL evaluation are similar for both models and close to a subjective visual inspection of the predictions. A negative structure component for both models, throughout the entire 60 hour plume dispersion simulation, indicates that the modelled plumes are too small and/or too peaked compared to the observed plume at all times. The amplitude component for both models is strongly positive at the start of the simulation, indicating that surface concentrations are over-predicted by both models for the first 24 hours, but modelled concentrations are within a factor of 2 of the observations at later times. Finally, for both models, the location component is small for the first 48 hours after the start of the tracer release, indicating that the modelled plumes are situated close to the observed plume early on in the simulation, but this plume location error grows at later times. The SAL methodology has also been used to identify differences in the transport of pollution in the dispersion and weather prediction models. The convection scheme in the weather prediction model is found to transport more pollution vertically out of the boundary layer into the free troposphere than the dispersion model convection scheme resulting in lower pollutant concentrations near the surface and hence a better forecast for this case study.

Interpretation bias and anxiety in childhood: stability, specificity and longitudinal associations

Background: Biases in the interpretation of ambiguous material are central to cognitive models of anxiety; however, understanding of the association between interpretation and anxiety in childhood is limited. To address this, a prospective investigation of the stability and specificity of anxious cognitions and anxiety and the relationship between these factors was conducted. Method: Sixty-five children (10–11 years) from a community sample completed measures of self-reported anxiety, depression, and conduct problems, and responded to ambiguous stories at three time points over one-year. Results: Individual differences in biases in interpretation of ambiguity (specifically “anticipated distress” and “threat interpretation”) were stable over time. Furthermore, anticipated distress and threat interpretation were specifically associated with anxiety symptoms. Distress anticipation predicted change in anxiety symptoms over time. In contrast, anxiety scores predicted change in threat interpretation over time. Conclusions: The results suggest that different cognitive constructs may show different longitudinal links with anxiety. These preliminary findings extend research and theory on anxious cognitions and their link with anxiety in children, and suggest that these cognitive processes may be valuable targets for assessment and intervention.

Source splitting via the point source method

We introduce a new algorithm for source identification and field splitting based on the point source method (Potthast 1998 A point-source method for inverse acoustic and electromagnetic obstacle scattering problems IMA J. Appl. Math. 61 119–40, Potthast R 1996 A fast new method to solve inverse scattering problems Inverse Problems 12 731–42). The task is to separate the sound fields uj, j = 1, ..., n of sound sources supported in different bounded domains G1, ..., Gn in from measurements of the field on some microphone array—mathematically speaking from the knowledge of the sum of the fields u = u1 + + un on some open subset Λ of a plane. The main idea of the scheme is to calculate filter functions , to construct uℓ for ℓ = 1, ..., n from u|Λ in the form We will provide the complete mathematical theory for the field splitting via the point source method. In particular, we describe uniqueness, solvability of the problem and convergence and stability of the algorithm. In the second part we describe the practical realization of the splitting for real data measurements carried out at the Institute for Sound and Vibration Research at Southampton, UK. A practical demonstration of the original recording and the splitting results for real data is available online.

CLSM method for the dynamic observation of pH change within polymer matrices for oral delivery

If acid-sensitive drugs or cells are administered orally, there is often a reduction in efficacy associated with gastric passage. Formulation into a polymer matrix is a potential method to improve their stability. The visualization of pH within these materials may help better understand the action of these polymer systems and allow comparison of different formulations. We herein describe the development of a novel confocal laser-scanning microscopy (CLSM) method for visualizing pH changes within polymer matrices and demonstrate its applicability to an enteric formulation based on chitosan-coated alginate gels. The system in question is first shown to protect an acid-sensitive bacterial strain to low pH, before being studied by our technique. Prior to this study, it has been claimed that protection by these materials is a result of buffering, but this has not been demonstrated. The visualization of pH within these matrices during exposure to a pH 2.0 simulated gastric solution showed an encroachment of acid from the periphery of the capsule, and a persistence of pHs above 2.0 within the matrix. This implies that the protective effect of the alginate-chitosan matrices is most likely due to a combination of buffering of acid as it enters the polymer matrix and the slowing of acid penetration.

Some numerical experiments on the effect of the variation of static stability in two-layer quasi-geostrophic models

A method to solve a quasi-geostrophic two-layer model including the variation of static stability is presented. The divergent part of the wind is incorporated by means of an iterative procedure. The procedure is rather fast and the time of computation is only 60–70% longer than for the usual two-layer model. The method of solution is justified by the conservation of the difference between the gross static stability and the kinetic energy. To eliminate the side-boundary conditions the experiments have been performed on a zonal channel model. The investigation falls mainly into three parts: The first part (section 5) contains a discussion of the significance of some physically inconsistent approximations. It is shown that physical inconsistencies are rather serious and for these inconsistent models which were studied the total kinetic energy increased faster than the gross static stability. In the next part (section 6) we are studying the effect of a Jacobian difference operator which conserves the total kinetic energy. The use of this operator in two-layer models will give a slight improvement but probably does not have any practical use in short periodic forecasts. It is also shown that the energy-conservative operator will change the wave-speed in an erroneous way if the wave-number or the grid-length is large in the meridional direction. In the final part (section 7) we investigate the behaviour of baroclinic waves for some different initial states and for two energy-consistent models, one with constant and one with variable static stability. According to the linear theory the waves adjust rather rapidly in such a way that the temperature wave will lag behind the pressure wave independent of the initial configuration. Thus, both models give rise to a baroclinic development even if the initial state is quasi-barotropic. The effect of the variation of static stability is very small, qualitative differences in the development are only observed during the first 12 hours. For an amplifying wave we will get a stabilization over the troughs and an instabilization over the ridges.