A controlled-release anti-inflammatory drug

A procedure to obtain a controlled-release microencapsulated anti-inflammatory drug based on a solvent evaporation method is described. The present method makes use of ethylcellulose as the polymer and methylene chloride as solvent. The evaporation of solvent is controlled by means of an air stream. Variations in the preparative procedure and their effects on capsule dimensions and permeabilities were studied. The release behavior of the drug is determined, and two different diffusion constants are also determined: 7.0×10⁻¹⁰ cm²/s and 1.2×10⁻¹⁰ cm²/s, corresponding to low and high release time. Based on these results it is proposed that these microcapsules have a nonhomogeneous polymeric wall, and are more porous in the outer surface. This model might be applicable to the microcapsules obtained by means of the solvent evaporation method.     

Development and validation of a liquid chromatographic/tandem mass spectrometric assay for the quantitation of nucleoside HIV reverse transcriptase inhibitors in biological matrices

Besides liquid chromatographic (LC)/UV methods adapted to therapeutic drug monitoring, there is still a need for more powerful techniques that can be used for pharmacological research and clinical purposes. We developed an LC method coupled with tandem mass spectrometry (MS/MS) to separate, detect and quantify with high sensitivity the nucleoside analogues used in multitherapies (zidovudine, stavudine, zalcitabine, didanosine, lamivudine and abacavir) in plasma and in the intracellular medium. We worked on two essential issues: (i) the need to use two ionization modes in order to achieve the best sensitivity, which leads to the optimization of the chromatographic separation of drugs detected in the positive ionization mode and drugs detected in the negative ionization mode, and (ii) the need to optimize the extraction step in order to enhance sample recovery. The peripheral blood mononuclear cells were lysed in Tris buffer-MeOH. A clean-up procedure was performed by solid-phase extraction only for plasma samples. The LC separation was carried out on a Zorbax Stable Bond C(18) column followed by MS/MS analysis after electrospray ionization in either the negative or positive mode. The positive ionization mode was applied at the beginning of the run to detect zalcitabine and lamivudine, then the ionization mode was changed to negative for the detection of didanosine, stavudine, internal standard and zidovudine. The calibration range for all the analytes was 0.5-200 ng ml(-1). The recoveries were between 64 and 90%, with coefficients of variation (CVs) lower than 15%. The inaccuracy (bias) was +/-15% with CVs always lower than 12%. The analytes were stable at room temperature and in the extraction solvent for at least 24 h, after storage at -80 degrees C for 3 months, after three freeze-thaw cycles and in the injection solvent after 48 h at 4 degrees C. Together with the measurement of intracellular triphosphorylated metabolites thanks to the powerful plasma and intracellular assay method for intact drugs, it is possible to describe the behaviour of nucleoside analogues against HIV through plasma pharmacokinetics, cell membrane diffusion including drug transport involvement, and also the intracellular metabolism.     

Dynamic behaviour and X-ray analysis of chiral η-allylpalladium complexes. II

The DANTE technique and NOESY two-dimensional method have been employed to observe the isomerization of the chiral cationic complex [Pd(η³-CH₂CMeCH₂(P-P′)]⁺ (1a), where P-P′ = the chiral chelating ligand (S)(N-diphenylphosphino)(2-diphenylphosphinoxymethyl)pyrrolidine. The rate constant was found to be 0.5 s⁻¹ in CHCl₃ at 295 K and 1.50 s⁻¹ in the presence of added free ligand. In the latter case the epimerization proceeds by a π-σ-π mechanism via the intermediacy of a primary η¹-allylpalladium complex. Although the intermediate was not detected, the NMR findings reveal that it has the allylic terminus η¹-bonded to palladium. The structure of 1a in its PF₆⁻ salt has been determined. The compound crystallizes in the orthorhombic space group P2₁2₁2₁ with a 10.029(4) b 19.203(8) c 36.115(6) Å, Z = 8, R = 0.0572 and R_w = 0.0712 for 3716 observed reflections with I > 3σ(I).     

Four bromo‐substituted pyrazoline and isoxazolinone spiro derivatives

Conformational analyses and a structural comparison of the four spiro compounds 3‐bromo‐1,9‐di­phenyl‐4‐p‐tolyl‐7‐oxa‐1,2,8‐tri­aza­spiro­[4.4]­nona‐2,8‐dien‐6‐one, (I), C₂₄H₁₈BrN₃O₂, 3‐bromo‐4‐(4‐methoxy­phenyl)‐1,9‐di­phenyl‐7‐oxa‐1,2,8‐tri­aza­spiro­[4.4]­nona‐2,8‐dien‐6‐one, (II), C₂₄H₁₈BrN₃O₃, 3‐bromo‐4‐(4‐chloro­phenyl)‐1,7,9‐tri­phenyl‐1,2,7,8‐tetra­aza­spiro­[4.4]­nona‐2,8‐dien‐6‐one, (III), C₂₉H₂₀BrClN₄O, and 3‐bromo‐1,7,9‐tri­phenyl‐4‐p‐tolyl‐1,2,7,8‐tetra­aza­spiro­[4.4]­nona‐2,8‐di­en‐6‐one, (IV), C₃₀H_22.89Br_1.11N₄O, are presented. The mol­ecular structures are rather similar, which is as expected since the compounds are all products of concerted 1,3‐dipolar attack on (Z)‐4‐aryl­idene oxazolone and pyrazolone derivatives. The observed conformations tend to favour extended π conjugation of the benzene rings and other π systems, as shown by a comparison of selected geometric parameters of the four structures.     

5‐Benzoyl­amino‐3‐bromo‐4‐(4‐methoxy­phenyl)‐4,5‐di­hydro­isoxazole‐5‐carboxyl­ic acid

The title compound, C₁₈H₁₅BrN₂O₅, a promising N‐protected α‐amino acid, was synthesized directly from an unusual bromo dipole and a 4‐(aryl­methyl­ene)­oxazolone. The crystal packing of the title compound is a racemic mixture. Peculiar graph‐set motifs driven by the most important hydrogen bonds are described.     

Fast head-related transfer function measurement via reciprocity

An efficient method for head-related transfer function (HRTF) measurement is presented. By applying the acoustical principle of reciprocity, one can swap the speaker and the microphone positions in the traditional (direct) HRTF measurement setup, that is, insert a microspeaker into the subject's ear and position several microphones around the subject, enabling simultaneous HRTF acquisition at all microphone positions. The setup used for reciprocal HRTF measurement is described, and the obtained HRTFs are compared with the analytical solution for a sound-hard sphere and with KEMAR manikin HRTF obtained by the direct method. The reciprocally measured sphere HRTF agrees well with the analytical solution. The reciprocally measured and the directly measured KEMAR HRTFs are not exactly identical but agree well in spectrum shape and feature positions. To evaluate if the observed differences are significant, an auditory localization model based on work by J. C. Middlebrooks [J. Acoust. Soc. Am. 92, 2607-2624 (1992)] was used to predict where a virtual sound source synthesized with the reciprocally measured HRTF would be localized if the directly measured HRTF were used for the localization. It was found that the predicted localization direction generally lies close to the measurement direction, indicating that the HRTFs obtained via the two methods are in good agreement.     

Peculiar properties of water as solute

Water has been investigated for a long time as the most important solvent; the peculiar behavior of water as solute has been studied in binary mixtures with organic solvents, mainly exploring the whole phase diagram. In this Article, we studied the behavior of water in binary mixtures with propylene carbonate in the phase diagram region where water acts as a solute as a function of the water molar fraction X(water). Surface tension measurements, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) have been used to investigate the state of water molecules and hydrogen bonds when water is to be considered a solute instead of a solvent, and peculiar and interesting properties were discovered. The interaction of water molecules among themselves and between water and propylene carbonate has been shown to be dependent on the water concentration in the mixtures. All of the measured properties showed a break at X(water) approximately 0.15-0.20 similar to the break due to the critical micellar concentration in surfactant solutions. In particular, from the FTIR spectra, it was possible to deduce that at this concentration water has a transition from pure solute ("multimers" solvated by PC) to cosolvent ("intermediate" and "network" water).