Linearization of the MS response function: case study for metformin assay in plasma samples for bioequivalence purposes

Calibration data of LC-MS/MS rarely fit the pure least square regression model, especially for large concentration intervals. The response function of the MS instrument is corrected by weighted regression models or logarithms. The choice of a response linearization method is based on results produced through back-interpolation of experimental data and/or evaluation of correlation coefficients. Two bioequivalence studies carried out for pharmaceutical formulations containing metformin gave us the opportunity to appreciate the impact of the MS response linearization method (logarithm and 1/x weighted linear regression) on method quality characteristics. The sample preparation was based on protein precipitation with acetonitrile. Chromatographic separation was achieved on a Zorbax CN column (mobile phase acetonitrile and aqueous 10 m m ammonium acetate solution, pH 3.5). Tandem MS detection was performed on a triple quadrupole spectrometer equipped with an electrospray source, operated under positive-ion mode. The method was validated and used for evaluation of the bioequivalence of formulations containing 500 and 1000 mg metformin. The 500 mg metformin study used logarithms for linearization of the detector response, while the 1000 mg metformin study was based on 1/x linear weighted regression. Data resulting from validations and studies completion were compared with evaluate the impact of the response linearization on the method quality characteristics.     

Investigations on sol–gel process and structural characterization of SiO2-P2O5 powders

The purpose of the study is to investigate the influence of the precursors, pH of the solution and temperature on the gelation and structure evolution of the samples from the SiO₂-P₂O₅ system. Tetraethoxysilane (TEOS) was used as precursor for SiO₂ and triethylphosphate (TEP) or phosphoric acid for P₂O₅, together with water as reagent for hydrolysis reaction and ethylic alcohol as solvent. The pH of the sols was modified by adding hydrochloric acid, in the case of TEP and by adding ammonia, in the case of H₃PO₄. The samples have been prepared starting from P₂O₅/SiO₂ = 1/10 and 1/5 molar ratio, H₂O/TEOS = 1; 2; 3 mass ratios and C₂H₅OH/TEOS = 1 mass ratio. We prepared silico-phosphate samples in the 1.5–5 pH domain and we observed that in all the cases, the lowest gelation time was found in the 3.5–4.5 pH range. We found that for the same pH value samples prepared with H₃PO₄ had a lower gelation time (few days) by comparison with the samples prepared with TEP (weeks), explainable by the low rate of the hydrolysis and condensation reactions of TEP. When the amount of water was increased, the gelation time increased in the case of samples prepared with H₃PO₄ and it was not significantly changed in the case of the samples prepared with TEP. The increasing of the solution temperature up to 40–41 °C yielded a decreasing of the gelation time (hours), especially for the samples prepared with H₃PO₄ by comparison with those prepared using TEP. In all the cases, the increased amount of water resulted in an increasing of the gelation time, even the temperature was raised. FTIR and Raman spectroscopy characterization aimed at getting information about the structural changes in the case of the samples dried in air and also for those heated at 100 °C, 300 °C, 600 °C and 900 °C. Vibration modes specific for SiOEt, SiOH, hydrogen bonds, H₂O and combined vibrations have been observed, which are in agreement with those revealed in literature data. ³¹P and ²⁹Si MAS NMR spectra gave interesting information about first surrounding of P and Si ions meaning the type and proportion of Q species and their evolution starting from the room temperature up to 900 °C.     

Influence of the heat treatment conditions on the formation of CuFe2O4 from mechanical milled precursors oxides

Stoichiometric mixture of CuO and ??-Fe₂O₃ milled in air up to 30?h was subjected to different heat treatments. The evolution of the heat treated milled powders was investigated by X-ray diffraction (XRD). The CuFe₂O₄ was partially obtained by milling, the material consisting in a mixture of phases. By applying different heat treatments in air and in vacuum, for 2?C6?h, in 500?C800?°C temperature range the phases composition of the milled samples is changed. A heat treatment at 500?°C in vacuum favours the formation of delafossite (CuFeO₂) and tenorite (CuO) phases. If the same heat treatment is made in air, the CuFe₂O₄ phase formation with a cubic structure is favoured. Differential scanning calorimetry (DSC) investigation realised in Ar atmosphere revealed two large exothermic peaks. The first one is associated with the formation of the delafossite and tenorite phases and the second one with the formation of CuFe₂O₄. The XRD patterns of the samples subjected to the DSC measurements present maxima corresponding to the delafossite and cuprospinel (CuFe₂O₄) phases. For the heat treatment at 600?°C in air the phases present in the sample are the same as for the annealing performed at 500?°C: CuFe₂O₄, ??-Fe₂O₃ and CuO. The heat treatment in air at 800?°C leads to the complete reaction between the different phases and the formation of CuFe₂O₄ phase in whole the sample volume. The CuFe₂O₄ ferrite crystallises after this heat treatment in two crystal systems: cubic and tetragonal.     

A peridynamic formulation for transient heat conduction in bodies with evolving discontinuities

We introduce a multidimensional peridynamic formulation for transient heat-transfer. The model does not contain spatial derivatives and uses instead an integral over a region around a material point. By construction, the formulation converges to the classical heat transfer equations in the limit of the horizon (the nonlocal region around a point) going to zero. The new model, however, is suitable for modeling, for example, heat flow in bodies with evolving discontinuities such as growing insulated cracks. We introduce the peridynamic heat flux which exists even at sharp corners or when the isotherms are not smooth surfaces. The peridynamic heat flux coincides with the classical one in simple cases and, in general, it converges to it in the limit of the peridynamic horizon going to zero. We solve test problems and compare results with analytical solutions of the classical model or with other numerical solutions. Convergence to the classical solutions is seen in the limit of the horizon going to zero. We then solve the problem of transient heat flow in a plate in which insulated cracks grow and intersect thus changing the heat flow patterns. We also model heat transfer in a fiber-reinforced composite and observe transient but steep thermal gradients at the interfaces between the highly conductive fibers and the low conductivity matrix. Such thermal gradients can lead to delamination cracks in composites from thermal fatigue. The formulation may be used to, for example, evaluate effective thermal conductivities in bodies with an evolving distribution of insulating or permeable, possibly intersecting, cracks of arbitrary shapes.     

An insight into the rotational stall delay

Blade element momentum (BEM) theory which is based on the two-dimensional (2D) aerodynamic properties of airfoil blade element is the most common computational engineering method for the prediction of loads and power curves of wind turbines. Although most BEM models yield acceptable results for high tip-speed ratios where the local angles of attack are small, no generally accepted model exists up to date that consistently predicts the loads and power in stall regime for stall-controlled turbines. Understanding of the stall delay phenomenon on wind turbines remains, to this day, incomplete. The lack of a conceptual model for the complex three-dimensional (3D) flow field on the rotor blade, where stall is begins, how it progresses and where stall is practically terminated, has hindered the finding of a unanimously accepted solution. The paper aims at giving a better understanding of the delayed stall events and a reasonably simple correction model that complements the 2D airfoil characteristics used to a BEM method. (© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Nondegeneracy,from the prospect of wave-wave regular interactions of a gasdynamic type

A parallel is considered between Burnat's “algebraic” approach [restricted to a genuine nonlinearity] and Martin's “differential” approach regarding their contribution to describing some nondegenerate one-dimensional gasdynamic regular interaction solutions. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Ink‐Jet Microdispensing for the Formation of Gradients of Immobilised Enzyme Activity

Summary: The integration of gradients of enzyme activity in microstructured biosensor arrays enables intrinsic on‐line quality control of biosensor performance. Multiple sensor elements with different compositions and hence varying responses for the same analyte are evaluated as a basis for improving data reliability. The formation of glucose oxidase/polymer microstructures using a piezo microdispenser and their examination by scanning electrochemical microscopy (SECM) are used to demonstrate the feasibility of this approach.

Optical microscope image of grids obtained by dispensing of 1 mg/mL GOx and 2 mg/mL Vinnapas® mixture.     

Statistical Characterization of the Phytochemical Characteristics of Edible Mushroom Extracts

The antioxidant activity, total phenolic content, and total flavonoid content of 10 edible mushrooms species, including cultivated (Pleurotus ostreatus, Agaricus bisporus white and brown) and wild (P. ostreatus, Macrolepiota procera, Cantharellus cibarius, Russula vesca, Russula alutacea, Boletus edulis and Agaricus campestris), were determined. The extraction was performed using water and 50% water–ethanol and the caps and stipe were investigated separately. Water was the most appropriate solvent for phenolic compounds regardless of the sample. In contrast, the presence of ethanol in the solvent increased the extraction of flavonoids for cultivated P. ostreatus (caps and stipe), and wild R. alutacea, R. vesca, A. campestris, P. ostreatus (only caps) and C. cibarius, M. procera (only stipe). Significant differences between the antioxidant activities of the samples were registered in relationship with the different solvents. The antioxidant activity of water extract of dried A. bisporus brown (cultivated) showed the strongest 1,1-diphenyl-2-picrylhydrazyl radicals-scavenging assay (88.64%), while the B. edulis hydroalcoholic extract contained 74.93%. A detailed investigation into the functional group of phenolics and other organic compounds responsible with the antioxidant activity has been performed using Fourier transform infrared spectroscopy. The infrared spectra showed that the solvent-type directly influences the extraction process and, hence, the antioxidant activity. The present study contributes to information concerning mushrooms as sources of biologically active compounds. To investigate the correlations between phytochemical characteristics (i.e., phenolics, flavonoids and antioxidant activity) closely related to nature of solvents, the statistical analysis was performed.     

CO rebinding to protoheme: investigations of the proximal and distal contributions to the geminate rebinding barrier

The rebinding kinetics of CO to protoheme (FePPIX) in the presence and absence of a proximal imidazole ligand reveals the magnitude of the rebinding barrier associated with proximal histidine ligation. The ligation states of the heme under different solvent conditions are also investigated using both equilibrium and transient spectroscopy. In the absence of imidazole, a weak ligand (probably water) is bound on the proximal side of the FePPIX-CO adduct. When the heme is encapsulated in micelles of cetyltrimethylammonium bromide (CTAB), photolysis of FePPIX-CO induces a complicated set of proximal ligation changes. In contrast, the use of glycerol-water solutions leads to a simple two-state geminate kinetic response with rapid (10-100 ps) CO recombination and a geminate amplitude that can be controlled by adjusting the solvent viscosity. By comparing the rate of CO rebinding to protoheme in glycerol solution with and without a bound proximal imidazole ligand, we find the enthalpic contribution to the proximal rebinding barrier, H(p), to be 11 +/- 2 kJ/mol. Further comparison of the CO rebinding rate of the imidazole bound protoheme with the analogous rate in myoglobin (Mb) leads to a determination of the difference in their distal free energy barriers: DeltaG(D) approximately 12 +/- 1 kJ/mol. Estimates of the entropic contributions, due to the ligand accessible volumes in the distal pocket and the xenon-4 cavity of myoglobin ( approximately 3 kJ/mol), then lead to a distal pocket enthalpic barrier of H(D) approximately 9 +/- 2 kJ/mol. These results agree well with the predictions of a simple model and with previous independent room-temperature measurements of the enthalpic MbCO rebinding barrier (18 +/- 2 kJ/mol).