Sensitive assay for triazolam in plasma following low oral doses.

At low doses of triazolam currently recommended increased assay sensitivity is required for measurement of low plasma concentrations. A highly sensitive capillary gas chromatographic analytical method with a limit of detection of 0.02 ng/ml was developed and used to describe the pharmacokinetics of triazolam following the oral intake of 0.125, 0.250 and 0.375 mg. Six male subjects were studied with blood sampling at the following times: 0, 15, 30 and 45 min and 1, 1.5, 2.0, 2.5, 3, 4, 5, 6 and 8 h. The mean pharmacokinetic parameters for the three doses, respectively, were as follows: half-life, 2.7 +/- 0.4, 3.2 +/- 0.5 and 3.2 +/- 0.6 h; apparent oral clearance, 302.3 +/- 59.0, 260.2 +/- 67.9 and 328.6 +/- 77.8 ml/min; apparent volume of distribution, 64.3 +/- 9.6, 62.0 +/- 12.6 and 73.3 +/- 7.7 l; time to maximum concentration, 0.7 +/- 0.2, 0.6 +/- 0.1 and 0.8 +/- 0.3 h; maximum concentration, 2.2 +/- 0.3, 4.3 +/- 0.6 and 5.0 +/- 0.5 ng/ml; and the area under the concentration-time curve (AUC) up to 8 h, 6.8 +/- 1.2, 16.8 +/- 2.9 and 19.6 +/- 3.5 ng/ml h; and AUC extrapolated to infinity, 8.5 +/- 1.7, 21.4 +/- 4.4 and 26.3 +/- 7.2 ng/ml h. There were no significant differences in the half-life, clearance, volume of distribution and time to maximum concentration among the three doses. The AUC was significantly different on the three occasions and was linearly correlated with dose: r = 0.64 (p less than 0.005).     

Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study

Lesinurad (systematic name: 2‐{[5‐bromo‐4‐(4‐cyclopropylnaphthalen‐1‐yl)‐4H‐1,2,4‐triazol‐3‐yl]sulfanyl}acetic acid, C₁₇H₁₄BrN₃O₂S) is a selective uric acid reabsorption inhibitor related to gout, which exhibits poor aqueous solubility. High‐throughput solid‐form screening was performed to screen for new solid forms with improved pharmaceutically relevant properties. During polymorph screening, we obtained two solvates with methanol (CH₃OH) and ethanol (C₂H₅OH). Binary systems with caffeine (systematic name: 3,7‐dihydro‐1,3,7‐trimethyl‐1H‐purine‐2,6‐dione, C₈H₁₀N₄O₂) and nicotinamide (C₆H₆N₂O), polymorphs with urea (CH₄N₂O) and eutectics with similar drugs, like allopurinol and febuxostat, were prepared using the crystal engineering approach. All these novel solid forms were confirmed by XRD, DSC and FT–IR. The crystal structures were solved by single‐crystal and powder X‐ray diffraction. The crystal structures indicate that the lesinurad molecule is highly flexible and the triazole moiety, along with the rotatable thioacetic acid (side chain) and cyclopropane ring, is almost perpendicular to the planar naphthalene moiety. The carboxylic acid–triazole heterosynthon in the drug is interrupted by the presence of methanol and ethanol molecules in their crystal structures and forms intermolecular macrocyclic rings. The caffeine cocrystal maintains the consistency of the acid–triazole heterosynthons as in the drug and, in addition, they are bound by several auxiliary interactions. In the binary system of nicotinamide and urea, the acid–triazole heterosynthon is replaced by an acid–amide synthon. Among the urea cocrystal polymorphs, Form I (P, 1:1) consists of an acid–amide (urea) heterodimer, whereas in Form II (P2₁/c, 2:2), both acid–amide heterosynthons and urea–urea dimers co‐exist. Density functional theory (DFT) calculations further support the experimentally observed synthon hierarchies in the cocrystals. Aqueous solubility experiments of lesinurad and its binary solids in pH 5 acetate buffer medium indicate the apparent solubility order lesinurad–urea Form I (43‐fold) > lesinurad–caffeine (20‐fold) > lesinurad–allopurinol (12‐fold) ? lesinurad–nicotinamide (11‐fold) > lesinurad, and this order is correlated with the crystal structures.     

The influence of ultrasonic waves on the viscosity and stability of vanadium pentoxide sol

Summary The vanadium pentoxide sol when exposed to ultrasonic waves shows an increased value of hydrogen ion concentration and conductivity. It is postulated that this change is due to either supersaturation of metavanadic acid in presence of the high frequency waves or to the production of peroxyvanadic acid under the influence of hydrogen peroxide which is known to be formed in traces under these conditions. The change in viscosity of vanadium pentoxide sol in presence of electrolytes under the influence of ultrasonic waves has also been recorded.

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Zusammenfassung Das Vanadium-Pentoxyd-Sol zeigt, wenn Ultraschall ausgesetzt, einen steigenden Wert an Wasserstoffionen-Konzentration und Leitf?higkeit. Es wird festgestellt, da\ diese Ver?nderung entweder einer übers?ttigung an Meta-Vanadins?ure in Gegenwart der Ultraschallwellen oder der Erzeugung von Peroxyd-Vanadins?ure unter Einflu\ von Wasserstoffsuperoxyd zuzuschreiben ist. Wasserstoffsuperoxyd wird bekanntlich unter diesen Bedingungen in Spuren gebildet. über die ?nderung der Viskosit?t des fraglichen Sols in Gegenwart von Elektrolyten unter gleichzeitigem Einflu\ von Ultraschall wird ebenfalls berichtet.

     

GC-MS-SIM quantitation of amantadine in biological samples

Summary A simple, selective and sensitive method for the quantitation of amantadine in biological samples is described. After extraction from biological samples using a two-step procedure, amantadine is quantitatively converted into its isothiocyanate (NCS) derivative by treatment with carbon disulfide and then determined quantitatively using isobaric compounds, p-methoxyphenyl-ethylamine-NCS or N-acetylamantadine as external standards. The applicability of this method is illustrated by determining plasma levels of amantadine for pharmacokinetic studies and levels in dialysate samples of amantadine treated patients who were on dialysis machines.     

N-acetyl-N'-salicyl hydrazine as a reagent for industrial analysis of titanium in ores and minerals

Summary N-Acetyl-N'-Salicyl Hydrazine (ASH) has been found to be a better reagent for the gravimetric determination of microquantities of titanium in ores and minerals. The precipitation is quantitative in the pH range 3.5-5. The composition of the precipitate corresponds to formula TiO(C₉H₈O₃N₂).

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N-Acetyl-N'-Salicylhydrazin als Reagens für die industrielle Analyse titanhältiger Erze und Minerale

Zusammenfassung N-Acetyl-N'-Salicylhydrazin hat sich als Reagens für die gravimetrische Bestimmung von Mikromengen Titan in Erzen und Mineralen bewährt. Im pH-Bereich 3,5-5 ist die Fällung quantitativ. Die Zusammensetzung des Niederschlages entspricht der Formel TiO(C₉H₈O₃N₂).

     

Synthesis of fused polycyclic nitrogen-containing heterocycles via cascade cyclization

A novel strategy for the synthesis of fused polycyclic-nitrogen containing heterocycles via cascade cyclization is described. The methodology involves condensation of 1-(2-aminophenyl)-9H-β-carboline-3-carboxylic acid amide with isothiocyanates followed by in situ treatment of the resulting thioureas with HgCl₂ for 1 h at rt. The one-pot cascade cyclization leads to interesting changes in molecular structure and an increase in molecular complexity. A mechanistic rationale for the cascade cyclization is discussed.     

Natural polyene α-pyrones. Total synthesis of citreomontanin from penicillium pedomontanum.

A total synthesis of all-$\text{E}$-citreomontanin (7), a novel polyene α-pyrone produced by $\text{Penicillium pedomontanum}$, is described.     

A novel and facile iodine(III)-mediated approach for C(5)-acetoxylation of 6-hydroxyflavone and 6-hydroxyflavanones

Oxidation of 6-hydroxyflavone 1 and 6-hydroxyflavanones 2a-c with iodobenzene diacetate (IBD) in acetic acid leads to regioselective acetoxylation, thereby providing a novel and convenient route for the synthesis of 5-acetoxylated products.     

Intramolecular hydrogen bond strength and pK(a) determination of N,N'-disubstituted imidazole-4,5-dicarboxamides

N,N'-Disubstituted imidazole-4,5-dicarboxamides (I45DCs) form an intramolecular hydrogen bond worth an estimated 14 +/- 1 kcal/mol, as measured with a model structure in DMSO-d6 at 3 mM, thereby predisposing the molecular conformation to a folded rather than extended form. The I45DCs also show evidence of aggregation in both CDCl3 (>1 mM) and DMSO-d6 (>10 mM) solutions. These compounds are uncharacteristically weak bases in comparison with imidazoles bearing similar electron-withdrawing groups.