Simultaneous determination of midazolam and 1'-hydroxymidazolam in human plasma by liquid chromatography with tandem mass spectrometry

A sensitive and simple liquid chromatography-tandem mass spectrometry method for the determination of midazolam and 1'-hydroxymidazolam in human plasma has been developed and validated with a dynamic range of 0.1-250 ng/mL. The analysis was based on semi-automated liquid-liquid extraction followed by evaporation of the extraction solvent, reconstitution and chromatography on a reversed-phase C(18) column. The mobile phase consists of 5 mm ammonium acetate and methanol and runs in gradient at a flow rate of 0.25 mL/min with column temperature of approximately 20 degrees C. The entire column effluent was transferred into the LC-MS/MS interface operated in positive electrospray ionization mode. The chromatographic run time was 4.3 min per injection, with retention times for midazolam, 1'-hydroxymidazolaml and the internal standard, triazolam, of 2.5, 2.3 and 2.1 min, respectively. The intra-day and inter-day precision (RSD %) and accuracy (bias %) of the quality control samples were <15.0% and within +/-13%, respectively. The current method has been applied to a clinical drug-drug interaction study in human.     

Determination of N-methyl-4-isoleucine-cyclosporin (NIM811) in human whole blood by high performance liquid chromatography-tandem mass spectrometry

A liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) for the determination of N-methyl-4-isoleucine-cyclosporin (NIM811) was developed and validated over the concentration range 1-2500 ng/mL in human whole blood using a 0.05 mL sample volume. NIM811 and the internal standard, d(12)-cyclosporin A (d(12)-CsA), were extracted from blood using MTBE via liquid-liquid extraction. After evaporation of the organic solvent and reconstitution, a 10 microL aliquot of the resulting extract was injected onto the LC-MS/MS system. Chromatographic separation of NIM811 and internal standard was performed using a Waters Symmetry RP-8 (50 x 4.6 mm, 3 microm particle size) column. The mobile phase consists of 10 mm ammonium acetate in water (A) and acetonitrile (B), with 45% B from 0 to 0.2 min, 45 to 85% B from 0.2 to 0.8 min and 85% B from 0.8 to 2.2 min. The total run time was 3.5 min with a flow rate of 0.8 mL/min. The method was validated for sensitivity, linearity, reproducibility, stability, dilution integrity and recovery. The precision and accuracy of quality control samples at low (2.00 ng/mL), medium (20.0 and 400 ng/mL) and high (2000 ng/mL) concentrations were in the range 1.1-4.3% relative standard deviation (RSD) and -2.5-10.0% (bias), respectively, from three validation runs. The method has been used to measure the exposure of NIM811 in human subjects.     

B-SERIES METHODS CANNOT BE VOLUME-PRESERVING

Volume preservation is one of the qualitative characteristics common to many dynamical systems. However, it has been proved by Kang and Shang that e.g. Runge–Kutta (RK) methods can not preserve volume for all linear source-free ODEs (let alone nonlinear ODEs). On the other hand, certain so-called Exponential Runge–Kutta (ERK) methods do preserve volume for all linear source-free ODEs. Do such ERK methods perhaps also preserve volume for all nonlinear ODEs? Here we prove that the answer to this question is negative; B-series methods (which include RK, ERK and several more classes of methods) cannot preserve volume for all source-free ODEs. The proof is presented via the theory of K-loops, which is an extension of the theory of classical rooted trees.     

Structure and dynamics of carbon black‐filled elastomers

The linear and nonlinear melt viscoelastic properties for a series of carbon black‐filled polymer composites were studied. Complementary tapping‐mode atomic force microscopy (AFM) studies were used to examine the dispersion and structural correlations of the filler particles in these composites. The low‐frequency dependence of the linear viscoelastic moduli gradually changes from liquidlike behavior for the unfilled polymer to pseudosolid character for composites with more than 9 vol % carbon black filler. The plateau modulus, inferred from the linear viscoelastic response, exhibits a somewhat discontinuous change at about 9 vol % filler. On the basis of the linear viscoelastic response, we postulate that the carbon black filler forms a continuous percolated network structure beyond 9 vol % filler, considerably lower than that expected from theoretical calculations for overlapping spheres and ellipsoids. We suggest that the lower threshold for percolation is due to the polymer mediation of the filler structure, resulting from the low functionality of the polymer and, consequently, few strong polymer–filler interactions, allowing for long loops and tails that can either bridge filler particles or entangle with one another. Furthermore, the strain amplitude for the transition from linear behavior to nonlinear behavior of the modulus for the composites with greater than 9 vol % filler is independent of frequency, and this critical strain amplitude decreases with increasing filler concentration. Complementary AFM measurements suggest a well‐dispersed carbon black structure with the nearest neighbor distance showing a discontinuous decrease at about 9 vol % filler, again consistent with the formation of a filler network structure beyond 9 vol % carbon black. © 2000 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 39: 256–275, 2001     

Rate constants for the gas-phase reaction of the hydroxyl radical with a series of dimethylbenzaldehydes and trimethylphenols at atmospheric pressure

Rate constants for three dimethylbenzaldehydes and two trimethylphenols have been determined for the OH reactions at 298±2 K and atmospheric pressure using a relative rate method. The OH reaction rate constants were placed on an absolute basis using the literature rate constant for 1,2,4-trimethylbenzene of (3.25±0.5)×10⁻¹¹ cm³ molecule⁻¹s⁻¹). The measured rate constants were (in units of cm³ molecule⁻¹ s⁻¹) 2,4-dimethyl-benzaldehyde, (4.32±0.67)×10⁻¹¹; 2,5-dimethylbenzaldehyde, (4.37±0.68)×10⁻¹¹; 3,4-dimethylbenzaldehyde, (2.14±0.34)×10⁻¹¹; and 2,3,5- trimethylphenol, (12.5±1.9)×10⁻¹¹, 2,3,6-trimethylphenol, (11.8±1.8)×10⁻¹¹. Using an average OH concentration of 8.7×10⁵ molecule cm⁻³, the estimated atmospheric lifetimes are ca. 7.5 h for 2,4- and 2,5-dimethylbenzaldehydes, ca. 15 h for 3,4-dimethylbenzaldehyde, ca. 2.5 h for 2,3,5- and 2,3,6-trimethylphenols. The reactivities of the trimethylphenols exceed those of the dimethyl-benzaldehydes by more than a factor of 3. © 1997 John Wiley & Sons, Inc. Int J Chem Kinet 29: 523–525, 1997.     

Experimental and theoretical investigation of galloping of transversely inclined slender prisms

Galloping is characterized by large and periodical oscillations which may lead to collapse of slender structures. This study is the first attempt of a comprehensive experimental and theoretical investigation of galloping of transversely inclined prisms. A modified quasi-steady model is proposed with a constant term to estimate the galloping of a transversely inclined prism, which is later experimentally investigated by conducting a static Synchronous Multi-Pressure Sensing System (SMPSS) test and an aeroelastic test in a boundary layer wind tunnel. The galloping responses of the prisms were measured in the aeroelastic test, while the aerodynamic force coefficients were determined from the SMPSS test. These experimental results were subsequently utilized to validate the quasi-steady model. Based on the proposed model, the galloping responses of the prisms were predicted and compared with the experimental results. The experimentally measured and theoretically predicted galloping responses are discussed with respect to aerodynamic damping ratios, onset galloping wind speeds, distributed pressure coefficients, point pressure spectra and vortex shedding frequencies. Interesting findings are summarized.     

Crystallographic Characterization of Dipyridylamine Derivatives

Abstract  

Dipyridylamine has been coupled with phenyl groups to yield new organic ligands. During the course of one reaction a lithium salt of dipyridylamine was isolated as the product. These new compounds were characterized by single crystal X-ray diffraction, which reveals that π–π stacking interactions as well as hydrogen bonding permeate the isolated compounds in the solid state. BrPhDPA, compound 1, crystallizes in the monoclinic P2₁ space group with cell parameters a = 5.8291(1), b = 8.8504(2), c = 13.2341(3) ? and β = 91.928(1)°. 3-ThPh(DPA)₂, compound 4, crystallizes in the orthorhombic C2/c space group with cell parameters a = 14.8033(7), b = 11.4124(4), c = 16.11780(7) ? and β = 115.911(3)°. Finally the lithium salt, [Li(HDPA)(H₂O)₂](H₂DPA)(Cl)₂(H₂O), compound 5, crystallizes in the monoclinic Cmcm space group with cell parameters a = 14.043(3), b = 12.370(3) and c = 13.389(3) ?.