Warfarin Sodium Stability in Oral Formulations

Warfarin sodium is a low-dose pharmaceutical blood thinner that exists in two forms: the clathrate form and the amorphous form. In commercially available warfarin sodium oral suspension, the active pharmaceutical ingredient (API) is added in the amorphous state. This study investigates the apparent instability of the commercially available warfarin liquid oral formulation using Raman and IR spectroscopy, X-ray diffraction, differential scanning calorimetry, UV spectroscopy, and optical microscopy. Warfarin, not its sodium salt, was identified as the undissolved solid existing in the suspension. This was found to be due to the dissociation of sodium salt and the protonation of the warfarin ion in the liquid phase, which triggered the crystallization of the sparingly soluble unsalted form. The coexistence of protonated and unprotonated warfarin ions in the supernatant, as detected by Raman and UV spectroscopy, confirmed this assumption. Study of the dissolution of warfarin sodium amorphous salt and crystalline sodium clathrate in the placebo and pure water verified the results. The effect of pH and temperature on warfarin precipitation was also explored.     

Femtomolar Zn(II) affinity in a peptide-based ligand designed to model thiolate-rich metalloprotein active sites

Metal-ligand interactions are critical components of metalloprotein assembly, folding, stability, electrochemistry, and catalytic function. Research over the past 3 decades on the interaction of metals with peptide and protein ligands has progressed from the characterization of amino acid-metal and polypeptide-metal complexes to the design of folded protein scaffolds containing multiple metal cofactors. De novo metalloprotein design has emerged as a valuable tool both for the modular synthesis of these complex metalloproteins and for revealing the fundamental tenets of metalloprotein structure-function relationships. Our research has focused on using the coordination chemistry of de novo designed metalloproteins to probe the interactions of metal cofactors with protein ligands relevant to biological phenomena. Herein, we present a detailed thermodynamic analysis of Fe(II), Co(II), Zn(II), and[4Fe-4S]2(+/+) binding to IGA, a 16 amino acid peptide ligand containing four cysteine residues, H2N-KLCEGG-CIGCGAC-GGW-CONH2. These studies were conducted to delineate the inherent metal-ion preferences of this unfolded tetrathiolate peptide ligand as well as to evaluate the role of the solution pH on metal-peptide complex speciation. The [4Fe-4S]2(+/+)-IGA complex is both an excellent peptide-based synthetic analogue for natural ferredoxins and is flexible enough to accommodate mononuclear metal-ion binding. Incorporation of a single ferrous ion provides the FeII-IGA complex, a spectroscopic model of a reduced rubredoxin active site that possesses limited stability in aqueous buffers. As expected based on the Irving-Williams series and hard-soft acid-base theory, the Co(II) and Zn(II) complexes of IGA are significantly more stable than the Fe(II) complex. Direct proton competition experiments, coupled with determinations of the conditional dissociation constants over a range of pH values, fully define the thermodynamic stabilities and speciation of each MII-IGA complex. The data demonstrate that FeII-IGA and CoII-IGA have formation constant values of 5.0 x 10(8) and 4.2 x 10(11) M-1, which are highly attenuated at physiological pH values. The data also evince that the formation constant for ZnII-IGA is 8.0 x 10(15) M-1, a value that exceeds the tightest natural protein Zn(II)-binding affinities. The formation constant demonstrates that the metal-ligand binding energy of a ZnII(S-Cys)4 site can stabilize a metalloprotein by -21.6 kcal/mol. Rigorous thermodynamic analyses such as those demonstrated here are critical to current research efforts in metalloprotein design, metal-induced protein folding, and metal-ion trafficking.     

The interaction of diphosphonates with calcitic surfaces: understanding the inhibition activity in marble dissolution

The rates of dissolution of calcitic Carrara marble have been reported to be significantly reduced in alkaline pH (pH 8.25) at 25 degrees C in the presence of (1-hydroxyethylidene)-1,1 diphosphonic acid (HEDP). The adsorption takes place at the calcite/water interface at the double layer through the interaction of charged surface species with the charged solution species of the adsorbate. The present work focused on obtaining a better understanding of the interaction of the calcite surface with HEDP. Calculations were performed according to the triple layer model, assuming the formation of surface complexes between the charged surface species of calcite and the species of HEDP dominant at pH 8.25. According to the model, the adsorbed species are located at the inner Helmholtz plane of the electrical double layer. Strong lateral interactions between the adsorbed species were suggested and were corroborated from the calculation of the respective energy, which was equal to 69 kJ mol(-1). The adsorption isotherm was consistent with the proposed model at low surface coverage values, while discrepancies between the values experimentally measured and the predicted were found at higher adsorbate concentrations. The deviations from the predicted values were attributed to the fact that HEDP adsorption on calcite resulted in the formation of multiple layers. The model explained adequately the changes in the zeta-potential values of calcite in the presence of HEDP in the solution which resulted in charge reversal upon adsorption.     

Adsorption of atrazine on soils: model study

The adsorption of the widely used herbicide atrazine onto three model inorganic soil components (silica gel, gamma-alumina, and calcite (CaCO(3)) was investigated in a series of batch experiments in which the aqueous phase equilibrated with the solid, under different solution conditions. Atrazine did not show discernible adsorption on gamma-alumina (theta=25 degrees C, 3.8相似文献   

Collision-free photochemistry of methylazide: observation of unimolecular decomposition of singlet methylnitrene

Methylazide photolysis at 248 nm has been investigated by ionizing photofragments with synchrotron radiation in a photofragmentation translational spectroscopy study. CH3N and N2 were the only observed primary products. The translational energy release suggests a simple bond rupture mechanism forming singlet methylnitrene, 1CH3N, and N2. Thus, these experiments reveal the unimolecular decomposition of this highly unstable species. We explain our observations through a mechanism which is initiated by the isomerization of 1CH3N to a highly internally excited methanimine H2C=NH isomer, which decomposes by 1,1-H2 elimination forming HNC+H2 as well as sequential H-atom loss (N-H followed by C-H bond cleavage), to form HCN. No evidence for dynamics on the triplet manifold of surfaces is found.     

1 J/pulse Q-switched 2 microm solid-state laser

Q-switched output of 1.1 J/pulse at a 2.053 microm wavelength has been achieved in a diode-pumped Ho: Tm: LuLF laser with a side-pumped rod configuration in a master-oscillator-power-amplifier (MOPA) architecture. This is the first time to our knowledge that a 2 microm laser has broken the joule per pulse barrier for Q-switched operation. The total system efficiency reaches 5% and 6.2% for single- and double-pulse operation, respectively. The system produces an excellent 1.4 times transform-limited beam quality.     

GPU and APU computations of Finite Time Lyapunov Exponent fields

We present GPU and APU accelerated computations of Finite-Time Lyapunov Exponent (FTLE) fields. The calculation of FTLEs is a computationally intensive process, as in order to obtain the sharp ridges associated with the Lagrangian Coherent Structures an extensive resampling of the flow field is required. The computational performance of this resampling is limited by the memory bandwidth of the underlying computer architecture. The present technique harnesses data-parallel execution of many-core architectures and relies on fast and accurate evaluations of moment conserving functions for the mesh to particle interpolations. We demonstrate how the computation of FTLEs can be efficiently performed on a GPU and on an APU through OpenCL and we report over one order of magnitude improvements over multi-threaded executions in FTLE computations of bluff body flows.     

Complexation of Indole-3-acetic Acid with Iron(III): Influence of Coordination on the π-Electronic System of the Ligand

Summary.  The iron(III) complex of indole-3-acetic acid (1) was prepared, and its physicochemical properties, mode of iron(III) coordination, and electronic structure were studied using UV/Vis, diffuse reflectance infrared Fourier transform (DRIFT), and transmission ⁵⁷Fe M?ssbauer spectroscopic techniques. The data obtained provide evidence that iron(III) is not only coordinated by the carboxylic O-donor atom, but also via the conjugated π-electronic system of the pyrrole moiety involving both the non-shared electronic pair of the heteroatom and the C(2)*C(3) double bond. Considering the well-known increased sensitivity of the pyrrole residue in indole derivatives to oxidation as compared to the benzene ring, as well as the formation of a triple complex (peroxidase-1-O₂) proposed for the enzymatic 1 oxidative degradation mechanism involving as a key step the Fe³⁺ → Fe²⁺ transition in the enzyme form as discussed in literature, it is concluded that iron(III) coordination with 1 can influence the redox properties of the pyrrole ring by affecting its π-electronic system. Received September 17, 2000. Accepted (revised) October 31, 2000     

PHOTOSENSITIZATION BY ANTITUMOR AGENTS—1. PRODUCTION OF SINGLET OXYGEN DURING IRRADIATION OF ANTHRAPYRAZOLES WITH VISIBLE LIGHT

Abstract— Oxygen consumption, photoinduced by visible light, and sensitized by novel anthrapyrazole antitumor agents has been observed. Generation of singlet oxygen upon irradiation of ethanolic solutions of the drugs with visible light (480–520 nm) was demonstrated using a specific ¹O₂ acceptor, 2.5-dimethylfuran and a quencher, sodium azide. An electron paramagnetic resonance method was employed to measure the rate of oxygen consumption. Significant differences were found in the sensitizing properties among the anthrapyrazoles studied. Intramolecular hydrogen bonding within the chro-mophore is one of the structural factors that determine the efficacy of a given anthrapyrazole in ¹O₂ generation