Compatibility of sildenafil citrate and pharmaceutical excipients by thermal analysis and LC–UV

The evaluation of sildenafil citrate (SC), the best-selling drug for treatment of impotence, for compatibility with various excipients was investigated using thermal and isothermal stress testing. Differential scanning calorimetry (DSC), hot-stage microscopy (HSM) and liquid chromatography (LC) with ultraviolet detection were successfully employed to investigate the compatibility between SC and various excipients commonly used in solid form in the pharmaceutical industry. The studies were performed using 1:1 (m/m) drug/excipient physical mixtures and samples were stored under accelerated stability conditions (40 °C at 75% relative humidity). All excipients tested (such as colloidal silicon dioxide, croscarmellose sodium, lactose, mannitol and sucrose) showed potential incompatibilities by DSC and LC analysis after accelerated stability testing. However, some incompatibilities were not detected by the DSC method and were observed only when LC analysis was performed. HSM was able to differentiate active pharmaceutical ingredient degradation from solubilisation, supporting the interpretation of DSC in excipients where thermal events either overlapped or disappeared. The combination of both the analytical techniques (DSC and LC) and use of a stability chamber is extremely helpful in detecting incompatibilities and providing more robust and accurate approaches for pre-formulation studies.     

Direct determination of propranolol in urine by spectrofluorimetry with the aid of second order advantage

This work presented an application of the second-order advantage provided by parallel factor analysis (PARAFAC) aiming at direct determination of propranolol, a beta-blocker also used as doping agent, in human urine by spectrofluorimetry. The adopted strategy combined the use of PARAFAC, for extraction of the pure analyte signal, with the standard addition method, for a determination in the presence of an individual matrix effect caused by the quenching action of the proteins present in the urine. The urine samples were previously 100 times diluted. For each sample, four standard additions were performed, in triplicates. A specific PARAFAC model was built for each triplicate of each sample, from three-way arrays formed by 231 emission wavelengths, 8 excitation wavelengths and 5 measurements (sample plus 4 additions). The models were built with three factors and always explained more than 99.87% of the total variance. The obtained loadings were related to PRO and two background interferences. The scores related to PRO were used for a linear regression in the standard addition method. The obtained determinations in the PRO concentration range from 5.0 to 20.0 microg ml(-1) provided recoveries between 91.1 and 108.4%.     

Influence of hydration and crosslinking in transdermal delivery of nicotine from chitosan-based gels by thermal analysis

Chitosan is a biopolymer that forms hydrogels after swell in acid medium. The environment of the three-dimensional network of the chitosan-based hydrogels can be modified by its degree of swelling and crosslinking. In this way, nicotine was incorporated in the hydrogel formulations, with or without crosslinking with glutaraldehyde (0.01%), in different swollen states. Transdermal delivery of nicotine by chitosan-based hydrogels was studied in order to achieve the prolonged administration of the drug. Thermal analysis indicated a preliminary stability of these formulations, and the mechanism of drug release from hydrogels was dependent of the swelling degree and crosslinking. These formulations were able to control the transdermal flux of nicotine for up to 48 h following zero-order kinetics. The hydrogels with higher amounts of water or the partially dried crosslinked hydrogels reduced the partition of nicotine into the skin, leading to a minor transdermal flux of the drug (<3.4 µg cm⁻² h⁻¹). On the other hand, the partially dried non-crosslinked hydrogels lead to a major transdermal flux of the drug (20.19 µg cm⁻² h⁻¹) due to modifications of the environment into the hydrogel. In this way, these transdermal formulations were promising vehicles for prolonged administration of nicotine.

     

On the distribution of Laplacian eigenvalues of trees

For a tree T$T$ with n$n$ vertices, we apply an algorithm due to Jacobs and Trevisan (2011) to study how the number of small Laplacian eigenvalues behaves when the tree is transformed by a transformation defined by Mohar (2007). This allows us to obtain a new bound for the number of eigenvalues that are smaller than 2. We also report our progress towards a conjecture on the number of eigenvalues that are smaller than the average degree.     

Inflationary Phase in a Generalized Brans-Dicke Theory

We find a solution for exponential inflation in a Brans-Dicke generalized model, where the coupling “constant” is variable. While in General Relativity the equation of state is p=−ρ, here we find p=α ρ, where α<−2/3. The negativity of cosmic pressure implies acceleration of the expansion, even with Λ<0.     

Nonlinear model predicts diverse respiratory patterns of birdsong

A central aspect of the motor control of birdsong production is the capacity to generate diverse respiratory rhythms, which determine the coarse temporal pattern of song. The neural mechanisms that underlie this diversity of respiratory gestures and the resulting acoustic syllables are largely unknown. We show that the respiratory patterns of the highly complex and variable temporal organization of song in the canary (Serinus canaria) can be generated as solutions of a simple model describing the integration between song control and respiratory centers. This example suggests that subharmonic behavior can play an important role in providing a complex variety of responses with minimal neural substrate.     

Data assimilation as a nonlinear dynamical systems problem: stability and convergence of the prediction-assimilation system

We study prediction-assimilation systems, which have become routine in meteorology and oceanography and are rapidly spreading to other areas of the geosciences and of continuum physics. The long-term, nonlinear stability of such a system leads to the uniqueness of its sequentially estimated solutions and is required for the convergence of these solutions to the system's true, chaotic evolution. The key ideas of our approach are illustrated for a linearized Lorenz system. Stability of two nonlinear prediction-assimilation systems from dynamic meteorology is studied next via the complete spectrum of their Lyapunov exponents; these two systems are governed by a large set of ordinary and of partial differential equations, respectively. The degree of data-induced stabilization is crucial for the performance of such a system. This degree, in turn, depends on two key ingredients: (i) the observational network, either fixed or data-adaptive, and (ii) the assimilation method.     

Rapidity dependence of multiplicity distributions in proton-nucleus collisions at 360 GeV/c

Multiplicity distributions in various rapidity intervals for charged particles produced in collisions of 360 GeV/c protons with aluminium (Al) and gold (Au) targets are presented. The data were analysed separately for the forward and backward hemispheres. Each distribution is well described by a negative binomial distribution. The experimental distributions are compared with the predictions of the multichain model calculated by the Monte Carlo program MCMHA in which the intranuclear cascade process is included, and also with the Lund Monte Carlo FRITIOF. The results of MCMHA reproduce quite well the multiplicity distributions for various rapidity intervals.