Quantitation of donepezil and its active metabolite 6-O-desmethyl donepezil in human plasma by a selective and sensitive liquid chromatography-tandem mass spectrometric method

A sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the simultaneous determination of donepezil (D) and its pharmacologically active metabolite, 6-O-desmethyl donepezil (6-ODD) in human plasma is developed using galantamine as internal standard (IS). The analytes and IS were extracted from 500 microL aliquots of human plasma via solid-phase extraction (SPE) on Waters Oasis HLB cartridges. Chromatographic separation was achieved in a run time of 6.0 min on a Waters Novapak C18 (150 mm x 3.9 mm, 4 microm) column under isocratic conditions. Detection of analytes and IS was done by tandem mass spectrometry, operating in positive ion and multiple reaction monitoring (MRM) acquisition mode. The protonated precursor to product ion transitions monitored for D, 6-ODD and IS were at m/z 380.1-->91.2, 366.3-->91.3 and 288.2-->213.2, respectively. The method was fully validated for its selectivity, interference check, sensitivity, linearity, precision and accuracy, recovery, matrix effect, ion suppression/enhancement, cross-specificity, stability and dilution integrity. A linear dynamic range of 0.10-50.0 ng mL(-1) for D and 0.02-10.0 ng mL(-1) for 6-ODD was evaluated with mean correlation coefficient (r) of 0.9975 and 0.9985, respectively. The intra-batch and inter-batch precision (%CV, coefficient of variation) across five quality control levels was less than 7.5% for both the analytes. The method was successfully applied to a bioequivalence study of 10mg donepezil tablet formulation in 24 healthy Indian male subjects under fasting condition.     

Twist‐dependent stacking energy of base‐pair steps in B‐DNA geometry: A density functional theory approach

Stacking energy of all the 10 unique DNA base‐pair steps (bp step) are calculated using density functional theory within the ultrasoft pseudopotential plane wave method and local density approximation for the exchange‐correlation functional. We have studied the dependence of stacking energy on twist angle, an aspect found difficult to explain using classical theory. We have found that the twist angle for different bp steps at stacking energy minimum matches extremely well with the values of average twist obtained from B‐DNA crystal structure data. This indicates that the use of a proper quantum chemical method to calculate the π‐π electronic interactions may explain stacking energy without incorporating hydrophobic interaction through solvent or effect of backbone through pseudobond. From the twist angle‐dependent stacking energy profile, we have also generated the probability distributions of twist for all the bp steps and calculated the variance of the distribution. Our calculated variances show similar trend to that of the experimental data for which sufficient numbers of data are available. The TA, AT, and CG doublets show large variances among the 10 possible bp steps, indicating their maximum flexibility. This might be the case of unusual deformation observed at the TATA‐box while binding to TBP protein. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

Influence of γ-ray-induced effects on dielectric dispersion of CuO-doped calcium fluoroborophosphate glass system

γ-Ray-induced dielectric dispersion in CaF₂–B₂O₃–P₂O₅ glasses doped with different concentrations of CuO was investigated. The glass samples were exposed to γ-rays with dose varying within the range 0–10 kGy. The dielectric dispersion and spectroscopic properties were measured before and after γ-ray treatment. Additionally, thermoluminescence studies were performed on post-irradiated glass samples. The results of dielectric properties and dielectric breakdown strength indicated a substantial increase in the insulating strength of CuO containing glasses due to γ-ray irradiation. The analysis of these results together with UV-vis optical absorption, IR spectra, and thermoluminescence studies have indicated a gradual increase in the concentration of mono-valent copper ions due to γ-ray treatment of the glass network. The additional studies have confirmed that these Cu⁺ ions occupy network-forming positions, increase the polymerization of the borophosphate glass network, and facilitates for the increase of insulating strength of the titled glass.     

Relative Stanley–Reisner theory and Upper Bound Theorems for Minkowski sums

In this paper we settle two long-standing questions regarding the combinatorial complexity of Minkowski sums of polytopes: We give a tight upper bound for the number of faces of a Minkowski sum, including a characterization of the case of equality. We similarly give a (tight) upper bound theorem for mixed facets of Minkowski sums. This has a wide range of applications and generalizes the classical Upper Bound Theorems of McMullen and Stanley.Our main observation is that within (relative) Stanley–Reisner theory, it is possible to encode topological as well as combinatorial/geometric restrictions in an algebraic setup. We illustrate the technology by providing several simplicial isoperimetric and reverse isoperimetric inequalities in addition to our treatment of Minkowski sums.     

New characterizations of digraphs represented by intervals

We present new characterizations of interval digraphs, interval graphs, and indifference digraphs, using linear orderings of edges and vertices. © 1996 John Wiley & Sons, Inc.     

Nature of the magnetic interaction between Fe-porphyrin molecules and ferromagnetic surfaces

We have investigated computationally the magnetic spin state of free metalloporphyrins and how magnetic ordering in metalloporphyrins can be induced through contact with the metallic surface and what the origin of the exchange interaction is. To this end, we performed density functional theory (DFT) and DFT + U studies for a series of isolated, ligated as well as unligated Fe-porphyrin (FeP) molecules as well as various FeP molecules on surfaces. Our calculations for isolated FePs clearly demonstrate that the usual DFT-based exchange-correlation functionals (such as the generalized gradient approximation) cannot predict the experimental high-spin ground state of these molecules. Instead, one has to resort to DFT + U calculations with a Coulomb U of about 4 eV on the Fe atoms, to obtain the correct single-molecule spin state. The magnetic interaction between FeP and a Co surface has been studied computationally with the DFT and DFT + U approaches. Our total energy DFT and DFT + U calculations predict an optimal Fe – substrate distance of 3.5 Å and a ferromagnetic exchange coupling of FeP to the substrate, in accordance with recent experiments. For Fe-porphyrin chloride (FePCl), on the other hand, an antiferromagnetic coupling is computed to be more favorable. Our study demonstrates that due to an indirect exchange interaction, which is mediated through the four nitrogen atoms, ferromagnetic ordering on the FeP is stabilized.     

An extensive study on isosorbide-5-mononitrate acid adducts for quantification in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry and its application to bioequivalence sample analysis

A rapid and sensitive liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for the determination of isosorbide-5-mononitrate (5-ISMN), used in the treatment of angina pectoris, in human plasma is described. The quantification of 5-ISMN was performed via stable acetate adduct formation with a high relative abundance. The plasma filtrate obtained after solid-phase extraction (SPE), using a polymer based, hydrophilic-lipophilic balanced (HLB) cartridge, was submitted directly to reversed-phase high-performance liquid chromatography separation followed by ESI and detection of the resulting ions using triple-quadrupole mass spectrometry in selected reaction monitoring (SRM) mode. There was no significant matrix effect on the analysis. For validation of the method, the recovery of the free analyte response was compared to that obtained from an optimized extraction method. The analyte stability was examined under conditions mimicking the sample storage, handling, and analytical procedures. The extraction procedure yielded extremely clean extracts with a recovery of 95.51% and 93.98% for iossorbide-5-mononitrate and topiramate (internal standard (IS)), respectively. The calibration curves were linear for the dynamic range of 10.0 to 1000.0 ng/mL with a correlation coefficient r > or = 0.9985. The intra-assay and inter-assay precision for the samples at the lower limit of quantification (LLOQ) were 9.02 and 13.30%, respectively. The intra-assay accuracies at LLOQ, LQC, MQC and HQC levels varied from 98.13 to 118.15, 102.34 to 105.21, 100.69 to 109.68, and 95.76 to 102.92%, respectively, while the inter-assay accuracies ranged from 93.10 to 118.15, 93.03 to 107.04, 86.97 to 109.68 and 86.18 to 105.85%, respectively, at these levels. The method is rugged and fast with a total run time of 2 min. The method was successfully applied for a bioequivalence study in 24 human subject samples after oral administration of 60 mg extended release (ER) formulations.     

Theoretical investigation on first-principles electronic and thermal properties of some CdRE intermetallics

Ab initio calculation on B2-cadmium rare earth (RE), CdRE (RE=La, Ce and Pr) intermetallics has been performed at T=0 K with respect to their structural, electronic and thermal properties. The structural and electronic properties are derived using self-consistent tight binding linear muffin tin orbital method at ambient and at high pressure. Other properties like lattice parameter, bulk modulus, density of states, electronic specific heat coefficient, cohesive energy, heat of formation, Debye temperature and Grüneisen constant for CdRE are also estimated. The RE-f effect can be seen in CdPr in terms of variation in the density of states and opens a possibility of structural instability. A pressure induced variation of Debye temperature is also presented for three cadmium rare earth intermetallics.     

First principles calculations of magnetism, dielectric properties and spin-phonon coupling in double perovskite Bi(2)CoMnO(6)

First principles electronic structure calculations have been performed for the double perovskite Bi(2)CoMnO(6) in its non-centrosymmetric polar state using the generalized gradient approximation plus the Hubbard U approach. We find that the ferromagnetic state is more favored compared to the ferrimagnetic state with both Co and Mn in high spin states. The calculated dynamical charge tensors are anisotropic reflecting a low-symmetry structure of the compound. The magnetic structure dependent phonon frequencies indicate the presence of a weak spin-phonon coupling. Using the Berry phase method, we obtain a spontaneous ferroelectric polarization of 5.88?μC?cm(-2), which is close to the experimental value observed for a similar compound, Bi(2)NiMnO(6).