Synthesis of novel 1-methyl-1H-pyridazino[3,4-b]indoles

New synthetic pathways have been elaborated to 1-methyl-1H-pyridazino[3,4-b]indoles starting from halopyridazin-3(2H)-ones. Suzuki cross-coupling reaction of chloro, iodo, dichloro, and dibromo substituted pyridazin-3(2H)-ones with 2-pivaloylaminophenylboronic acid followed by hydrolysis of the amide and subsequent ring closure via condensation gave fused indoles. Some of these compounds showed biological activity as antitrypanosomal agents.     

Evaluation of a dedicated gas chromatography-mass spectrometry method for the analysis of phenols in water

The increasing need to routinely analyse phenolic hydrocarbons in aqueous samples was addressed by the development and implementation of a state-of-the-art, though relatively straightforward, analytical procedure. The proposed method is based on acetic anhydride derivatisation of the native phenols, liquid-liquid extraction of the corresponding phenyl acetate esters and subsequent analysis by GC-MS. The key feature and main strength of the method is located at the injection step which applies 'at-once' large volume injection with a programmable temperature vaporizer (PTV)-type injector. In the proposed method, the sensitivity gain inherent to the higher injection volume was used entirely to proportionally miniaturize, considerably accelerate and effectively simplify the otherwise tedious and time-consuming derivatisation/extraction step. Method performance, as expressed in terms of repeatability, reproducibility, linearity and accuracy, was found to be excellent. R.S.D. values, determined in the framework of an extensive reproducibility study, ranged between 1.47 and 9.02%. Detection limits were in the low ng/L range for all compounds with linear ranges extending up to two orders of magnitude. Method accuracy was determined by analyzing a certified reference material (PH- 1JM), spiked water samples and participating in a series of round robin tests and did not reveal any significant bias for the different compounds under investigation.     

Characterization of the Mode of Incorporation of Lipophilic Compounds in Solid Dispersions at the Nanoscale Using Fluorescence Resonance Energy Transfer (FRET)

Summary: Efficient engineering of solid dispersions stagnates by the current inability to establish the mode of drug distribution on a molecular level at a low drug load. This study describes the application of fluorescence resonance energy transfer (FRET) to characterize the mode of incorporation of dispersed lipophilic molecules in a solid matrix. Two different lipophilic fluorophores (donor and acceptor) were used as model substances and were incorporated in polyvinylpyrrolidone to form solid dispersions using two different production processes: lyophilization and fusion. The efficiency of the resonance energy transfer from donor to acceptor was measured by confocal microscopy. We show that the method can be used to compare the modes of drug incorporation of solid dispersions at the nanoscale.

Absorption and emission spectra of Bodipy R6G (donor) and Bodipy 650/665 (acceptor).     

Capabilities of laboratories to determine melamine in food—results of an international proficiency test

A proficiency test to assess the capabilities of laboratories to determine melamine in a milk powder and a baking mix, representing starch-containing foods like bread and biscuits, was carried out in January 2009. The need for such an interlaboratory comparison arose from a health scare in China about melamine-tainted powdered milk in the second half of 2008. Laboratories in 31 countries, including Australia, China, India, Japan, New Zealand and the USA, and 21 of the 27 Member States of the European Union participated and reported back 114 results for the milk powder and 112 for the baking mix test materials. The reported results were compared to reference values determined by exact-matching double isotope dilution mass spectrometry. The so-determined assigned values were 10.0 ± 0.6 mg/kg melamine in the milk powder and 3.18 ± 0.17 mg/kg melamine in the baking mix. A coverage factor k of 2 was applied to calculate the expanded uncertainties. Three quarters of all reported results for both materials had associated z scores which were satisfactory (z ≤ |2|). Of the reported results, 90% was accompanied by a measurement uncertainty statement, and the majority of the measurement uncertainty ranges were reasonable. A number of laboratories were found to underestimate their measurement uncertainties. Methods that involved the use of stable-isotope-labelled melamine were shown to be clearly advantageous with regard to the accuracy of the results. However, no significant influence by other method parameters could be identified.     

Unraveling the Composition of Rembrandt's Impasto through the Identification of Unusual Plumbonacrite by Multimodal X‐ray Diffraction Analysis

Rembrandt (1606–1669) is renowned for his impasto technique, involving his use of lead white paint with outstanding rheological properties. This paint was obtained by combining lead white pigment (a mixture of cerussite PbCO₃ and hydrocerussite Pb₃(CO₃)₂(OH)₂) with an organic binding medium, but the exact formulation used by Rembrandt remains a mystery. A powerful combination of high‐angle and high‐lateral resolution x‐ray diffraction was used to investigate several microscopic paint samples from four Rembrandt masterpieces. A rare lead compound, plumbonacrite (Pb₅(CO₃)₃O(OH)₂), was detected in areas of impasto. This can be considered a fingerprint of Rembrandt's recipe and is evidence of the use of an alkaline binding medium, which sheds a new light on Rembrandt's pictorial technique.     

Photocatalytic growth of dendritic silver nanostructures as SERS substrates

We report a one-step photocatalytic synthesis method of dendritic silver nanostructures. These self-organised structures show an excellent Raman enhancement enabling the detection of analytes from dilute solutions by surface-enhanced Raman spectroscopy.     

Capillary and nano-liquid chromatography-tandem mass spectrometry for the quantification of small molecules in microdialysis samples: comparison with microbore dimensions

Enhanced sensitivity is a well known benefit of miniaturised LC-electrospray (ESI)-MS/MS methods. The suitability of miniaturised LC-MS/MS for quantification of small molecules in dialysates was investigated using the anti-epileptic drug oxcarbazepine, its active metabolite, 10,11-dihydro-10-hydroxycarbamazepine, and the internal standard for microdialysis probe calibration, 2-methyl-5H-dibenz(b,f)azepine-5-carboxamide, as test compounds. ESI-MS detection is sensitive to matrix effects. Therefore, dialysate matrix effects were investigated by comparing the responses of standards made in water, Ringer's solution (salt solution used as perfusion fluid) and blank dialysate matrix. Due to the occurrence of ion suppression or enhancement, direct injection of dialysis samples onto the analytical column could not be applied for quantification of small molecules in dialysis samples. Column switching was necessary for desalting and preconcentration of the dialysates. However, this approach was not able to completely eliminate salt effects when the injection volume exceeded 1 microL. No differences in response between Ringer's solution and dialysate matrix were detected at capillary and nano-dimensions. Calibration standards should be prepared with Ringer's solution instead of water for quantitative analysis of microdialysates. A microbore, capillary and nano-LC-ESI-MS/MS method were compared in terms of method feasibility, linearity, sensitivity, accuracy and precision. Downscaling to capillary and nano-dimensions resulted in a gain in detection sensitivity of 5 and 50, respectively. Miniaturised LC-MS/MS was found to be fit for quantification of small molecules in dialysates with acceptable accuracy and method precision.     

Analysis of collaborative savings and cost allocation techniques for the cooperative carrier facility location problem

Transport companies may cooperate to increase their efficiency levels by, for example, the exchange of orders or vehicle capacity. In this paper a new approach to horizontal carrier collaboration is presented: the sharing of distribution centres (DCs) with partnering organisations. This problem can be classified as a cooperative facility location problem and formulated as an innovative mixed integer linear programme. To ensure cooperation sustainability, collaborative costs need to be allocated fairly to the different participants. To analyse the benefits of cooperative facility location and the effects of different cost allocation techniques, numerical experiments based on experimental design are carried out on a UK case study. Sharing DCs may lead to significant cost savings up to 21.6%. In contrast to the case of sharing orders or vehicles, there are diseconomies of scale in terms of the number of partners and more collaborative benefit can be expected when partners are unequal in size. Moreover, results indicate that horizontal collaboration at the level of DCs works well with a limited number of partners and can be based on intuitively appealing cost sharing techniques, which may reduce alliance complexity and enforce the strength of mutual partner relationships.