Development and validation of a near infrared method for the analytical control of a pharmaceutical preparation in three steps of the manufacturing process

A near infrared diffuse reflectance spectroscopy (NIRS) procedure for the quantitative control analysis of the active compound (otilonium bromide) in a pharmaceutical preparation in three steps of the production process (blended product, cores and coated tablets) and a methodology for its validation are proposed. The analytical procedure is composed by two consecutive steps. First, the sample is identified by comparing its spectrum with a second derivative spectral library. If the sample is positively identified, the active compound is quantified by using a previously established partial least squares (PLS) calibration model. The procedure was validated by studying repeatability, intermediate precision, accuracy and linearity. To this end, an adaptation of ICH (International Conference on Harmonisation) validation methodology to an NIR multivariate calibration procedure is proposed. The relative standard error of prediction (RSEP) was < or = 1% and the suitability of the procedure for control analysis was confirmed by the results obtained analysing new production samples produced over a three-month period.     

Phenotyping apolipoprotein E*3-leiden transgenic mice by two-dimensional polyacrylamide gel electrophoresis and mass spectrometric identification

Apolipoprotein E (ApoE) plays an important role in cholesterol and triglyceride metabolism, being one of the major structural components of chylomicrons and very low density lipoprotein (VLDL) remnants. ApoE functions as a ligand in the receptor-mediated uptake of these remnants from the blood by the liver. A variant form of ApoE, apolipoprotein E*3-Leiden, shows reduced affinity for the low density lipoprotein (LDL) receptor, and results in the dominant expression of type III hyperlipoproteinemia. Two-dimensional electrophoresis (2-DE) has been used to characterise protein expression in serum samples from control and transgenic mice expressing the human ApoE*3-Leiden mutation, fed a cholesterol-rich diet, and transgenic mice fed a normal diet. For the identification of proteins, single silver-stained spots were excised from the 2-DE gels and subjected to in-gel enzymatic digestion. Extracted peptides were analysed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). This proteomic approach has enabled the ApoE*3-Leiden variant to be positioned in a 2-DE separation of serum proteins, and has identified changes in the expression of haptoglobin, indicating that this protein may provide a marker for the potential onset of atherosclerosis.     

The reactions of tellurium tetrahalides with triphenylphosphine under ambient conditions

The reactions of tellurium tetrahalides and triphenylphosphine in tetrahydrofuran have been carried out under ambient conditions and afford [(Ph(3)PO)(2)H](2)[Te(2)X(10)] [X = Cl (1), Br (2)] and [(Ph(3)PO)(3)(OH(3)])(2)[TeI(6)] (4). The X-ray structures of 1 and 2 show that they are isostructural and contain discrete [Te(2)X(10)](2-) anions exhibiting octahedral coordination around both tellurium atoms with one shared edge and [Ph(3)POH...OPPh(3)](+) cations that show strong hydrogen bonds (the O...O distances are 2.399 and 2.404 A for 1 and 2, respectively). The compound 4 is built up with discrete octahedral hexaiodotellurate anions and [(Ph(3)PO)(3)(OH(3))](+) cations. The reaction of TeBr(4) and PPh(3) also results in the formation of formally zwitterionic Ph(3)PO(CH(2))(4)TeBr(4) (3). This reaction involves an unprecedented THF ring opening in which the oxygen atom becomes bonded to the phosphorus atom of triphenylphosphine and the carbon atom at the other end of the five-atomic chain becomes bonded to the tellurium atom of TeBr(4). The ring opening of the solvent THF is also taking place in the reaction involving tellurium tetraiodide, as indicated by the formation of C(4)H(8)TeI(2) (5). The reaction may initially lead to Ph(3)PI(2) that reacts with THF yielding Ph(3)PO and ICH(2)(CH(2))(2)CH(2)I. The latter species reacts with elemental tellurium producing 5. Depending on the conditions upon crystallization, two polymorphs of C(4)H(8)TeI(2) (5a and 5b) are observed. While the molecular structures of the two forms are virtually identical, their packing and intermolecular contacts are different. Two further minor products (6a and 6b) were isolated in the reaction of TeI(4) and PPh(3): Both are formally 1:1 adducts of 5 and TeI(4), but they differ considerably in their structures. 6a can be formulated as [C(4)H(8)TeI(+)](2)[Te(2)I(10)(2-)] and 6b as [C(4)H(8)TeI(+)](2)(TeI(3)(+))(2)(I(-))(4). The latter compound exhibits framework similar to that of the tetramers in gamma- and delta-TeI(4).     

Tosylation of endocrine-disruptive alkylphenolic compounds in a solid-phase reaction system consisting of C18-modified silica gel and aqueous buffer solution

The tosylation reaction of endocrine-disruptive alkylphenolic compounds in a solid-phase aqueous system was investigated with the aim of developing an environment-friendly and efficient derivatization method for HPLC analyses of environmental samples. The phenols were rapidly and efficiently converted to the tosyl derivatives on a commercially available ODS solid-phase cartridge by passing an aqueous buffer solution through it. The solid-phase aqueous tosylation system has been incorporated into a preconcentration step performed by solid-phase extraction from environmental water.     

Reaction of 1-alkylthioisoquinolinium salts with active methylene compounds

2-Alkyl-1-alkylthioisoquinolinium salts were readily prepared from 2-alkyl-1(2H)-isoquinolones via 2-alkyl1(2H)-thioisoquinolones in two steps. Under mild conditions, the reaction of 2-alkyl-1-alkylthioisoquinolinium salts with active methylene compounds in the presence of sodium hydride afforded 2-alkyl-1-(substituted methylene)iso-quinolines in good yields. Pyrrolo[2,1-a]isoquinolines were synthesized by the cyclization of 2-benzyl-1-(substituted methylene)isoquinolines using acetic anhydride.     

Nanostructuring, compositional fluctuations, and atomic ordering in the thermoelectric materials AgPb(m)SbTe(2+m). The myth of solid solutions

The nature of the thermoelectric materials Ag(1-x)Pb(m)SbTe(m+2) or LAST-m materials (LAST for Lead Antimony Silver Tellurium) with different m values at the atomic as well as nanoscale was studied with powder/single-crystal X-ray diffraction, electron diffraction, and high-resolution transmission electron microscopy. Powder diffraction patterns of different members (m = 0, 6, 12, 18, infinity) are consistent with pure phases crystallizing in the NaCl-structure-type (Fmm) and the proposition that the LAST family behaved as solid solutions between the PbTe and AgSbTe2 compounds. However, electron diffraction and high resolution transmission electron microscopy studies suggest the LAST phases are inhomogeneous at the nanoscale with at least two coexisting sets of well-defined phases. The minority phase which is richer in Ag and Sb is on the nanosized length scale, and it is endotaxially embedded in the majority phase which is poorer in Ag and Sb. Moreover, within each nanodomain we observe extensive long range ordering of Ag, Pb, and Sb atoms. The long range ordering can be confirmed by single crystal X-ray diffraction studies. Indeed, data collections of five different single crystals were successfully refined in space groups of lower symmetry than Fmm including P4/mmm and Rm. The results reported here provide experimental evidence for a conceptual basis that could be employed when designing high performance thermoelectric materials and dispel the decades long belief that the systems (AgSbTe2)(1-x)(PbTe)x are solid solutions.     

Aromatic-aromatic interactions in crystal structures of helical peptide scaffolds containing projecting phenylalanine residues

Aromatic-aromatic interactions between phenylalanine side chains in peptides have been probed by the structure determination in crystals of three peptides: Boc-Val-Ala-Phe-Aib-Val-Ala-Phe-Aib-OMe, I; Boc-Val-Ala-Phe-Aib-Val-Ala-Phe-Aib-Val-Ala-Phe-Aib-OMe, II; Boc-Aib-Ala-Phe-Aib-Phe-Ala-Val-Aib-OMe, III. X-ray diffraction studies reveal that all three peptides adopt helical conformations in the solid state with the Phe side chains projecting outward. Interhelix association in the crystals is promoted by Phe-Phe interactions. A total of 15 unique aromatic pairs have been characterized in the three independent crystal structures. In peptides I and II, the aromatic side chains lie on the same face of the helix at i/i + 4 positions resulting in both intrahelix and interhelix aromatic interactions. In peptide III, the Phe side chains are placed on the opposite faces of the helix, resulting in exclusive intermolecular aromatic interactions. The distances between the centroids of aromatic pair ranges from 5.11 to 6.86 A, while the distance of closest approach of ring carbon atoms ranges from 3.27 to 4.59 A. Examples of T-shaped and parallel-displaced arrangements of aromatic pairs are observed, in addition to several examples of inclined arrangements. The results support the view that the interaction potential for a pair of aromatic rings is relatively broad and rugged with several minima of similar energies, separated by small activation barriers.     

The modulating possibilities of dicarbollide clusters: optimizing the Kharasch catalysts

exo-Cluster dicarbollides substitution has allowed tuning of the E degrees (Ru(II)/Ru(III)) potential to obtain the best-performing Kharasch catalyst. We postulate that this is possible through the to-and-fro electron movement between the boron cluster and the sulfonium moieties.     

Prenylated xanthones from Garcinia xanthochymus

A new prenylated xanthone, 1,3,5,6-tetrahydroxy-4,7,8-tri(3-methyl-2-butenyl)xanthone (1), was isolated from the wood of Garcinia xanthochymus together with a known xanthone, garciniaxanthone E (2). Their structures were determined by spectroscopic analysis. Compounds 1 (3 microM) and 2 (10 microM) elicited marked enhancement of nerve growth factor-mediated neurite outgrowth in PC12D cells.     

Development of a high-performance liquid chromatographic system with enzyme reactors for the determination of N-acetyl branched-chain amino acids

Immobilized enzymes were used as column reactors in a high-performance liquid chromatographic system for the specific detection of N-acetyl branched-chain amino acids (AcBCAs) such as N- acetyl- l -valine (AcVal), N- acetyl- l -leucine (AcLeu) and N- acetyl- l -isoleucine (AcIle). Aminoacylase and leucine dehydrogenase were immobilized onto poly(vinyl alcohol) beads. The AcBCAs were separated as three peaks on a Capcell C(1) SG120 column with 0.03M phosphate buffer (pH 8.0). Aminoacylase was capable of hydrolysing the AcBCAs to amino acids, which react with beta-nicotinamide adenine dinucleotide (NAD(+)) in the presence of leucine dehydrogenase. The reduced nicotinamide adenine dinucleotide (NADH) produced was monitored fluorimetrically. The calibration graphs were linear from 4 to 200muM for AcVal and AcLeu, and from 5 to 300muM for AcIle; detection limits for AcVal, AcLeu and AcIle were 2, 2 and 3muM, respectively. The immobilized aminoacylase reactor should be renewed every 5 days owing to a poor stability of aminoacylase.