A liquid chromatography-mass spectrometry method for the quantification of both etoricoxib and valdecoxib in human plasma

A practicable and selective liquid chromatography-mass spectrometry assay for the determination of two cyclooxygenase-2 inhibitors, etoricoxib and valdecoxib, in human plasma is presented. The analytical technique is based on reversed-phase high-performance liquid chromatography (HPLC) coupled to atmospheric pressure chemical ionisation (APCI) mass spectrometry (Finnigan Mat LCQ ion trap). Mass analysis was performed in the positive ion mode. The ion trap was operated in the tandem MS mode (MS2) and the transitions of etoricoxib (m/z 359.2 --> 280.3) and valdecoxib (m/z 315.1 --> 235.1) were followed by selected reaction monitoring. Retention times of etoricoxib and valdecoxib were 1.05 and 1.08 min, respectively. The method was validated over a linear range 10-2500 and 5-1000 microg/L using the other substrate as internal standard. After validation, the method was used to study the pharmacokinetic pro fi le of etoricoxib or valdecoxib in a healthy volunteer after administration of a single oral dose (valdecoxib, 20 mg; etoricoxib, 90 mg). The presented method was suf fi cient to cover more than 90% of the area under the plasma concentration time curve.     

Luminescent crown ether amino acids: selective binding to N-terminal lysine in peptides

Crown ether amino acids (CEAAs) with a luminescent phthalic ester or phthalimide moiety have been prepared. Simple peptide chemistry covalently tethers the macrocycles to give ditopic ammonium-ion binders. The binding events of both crown ether groups are monitored independently by changes of their specific emission properties. The affinity of the bis-CEAA to bis-ammonium ions is distance dependent, which allows distinguishing between isomeric small peptides containing a lysine residue in different positions.     

In Situ Characterization of Polymorphic Forms: The Potential of Raman Techniques

The use of hot-stage Raman microscopy — the direct coupling of Raman spectroscopy and thermomicroscopy — is demonstrated for the drug substances paracetamol and lufenuron.Paracetamol is a well-known analgesic and antipyretic drug, for which three polymorphic forms are currently known. Lufenuron is a benzoylphenyl urea derivative that has been classified as a chitin synthesis inhibitor. It is indicated for the use in pets for the prevention and control of flea population and used in crop protection for the control of Lepidoptera, Western Flower thrips and rust mites. It is the first time that the polymorphism of lufenuron is addressed. All known modifications of paracetamol and lufenuron were produced and identified by hot-stage Raman microscopy. A close correlation of thermal and spectroscopic information was achieved by this combination of techniques.For lufenuron a series of new polymorphic forms were found and characterized. Raman spectroscopy allowed to identify the thermodynamic stable form A as the one which is marketed in tablets.This revised version was published online in November 2005 with corrections to the Cover Date.     

Tumor selectivity at short times following systemic administration of a liposomal temoporfin formulation in a murine tumor model

Meso-tetra(hydroxyphenyl)chlorin (mTHPC) (INN: Temoporfin) is one of the most potent photodynamically active substances in clinical use. Treatment protocols for Temoporfin-mediated photodynamic therapy often rely on drug-light intervals of several days in order for the photosensitizer to accumulate within the target tissue, though tumor selectivity is limited. Here, the mTHPC localization was studied at 2-8 h following systemic administration of a liposomal Temoporfin formulation (0.15 mg kg(-1) b.w.) in HT29 human colon adenocarcinoma in NMRI nu/nu mice. Photosensitizer distribution within tumor and internal organs was investigated by means of high performance liquid chromatography following chemical extraction, as well as in situ fluorescence imaging and point-monitoring fluorescence spectroscopy. For tumor tissue, the Temoporfin concentrations at 4 h (0.16+/-0.024 ng mg(-1)) and 8 h (0.18+/-0.064 ng mg(-1)) were significantly higher than at 2 h (0.08+/-0.026 ng mg(-1)). The average tumor-to-muscle and the tumor-to-skin selectivity were 6.6 and 2, respectively, and did not vary significantly with time after photosensitizer injection. In plasma, the Temoporfin concentration was low (0.07+/-0.07 ng mg(-1)) and showed no significant variation with time. Our results indicate a rapid biodistribution and clearance from the bloodstream. Within the same type of organ, data from both fluorescence methods generally exhibited a significant correlation with the extraction results.     

Heterocyclic polyamides containing hexafluoroisopropylidene groups

New heterocyclic polyamides have been synthesized by solution polycondensation of aromatic diamines containing phenylquinoxaline units with diacid chlorides having both imide and hexafluoroisopropylidene (6F) groups. These polymers are soluble in polar aprotic solvents, such as N-methylpyrrolidone (NMP) or N, N-dimethylformamide (DMF), and can be cast into flexible thin films from solutions. They show high thermooxidative stability with decomposition temperatures above 400°C and glass transition temperatures in the range of 225-300°C. The polymer films exhibit good chemical resistance towards diluted acids and good electrical insulating properties with dielectric constants in the range of 3.2–3.7.     

Assignment of E/Z isomers in Schiff bases of 3-acyltetramic acids with ethylenediamine by 1H and 13C NMR spectroscopy

The reaction of ethylenediamine with an equivalent mixture of diversely substituted 3-acyltetramic acids leads to Z/Z, Z/E, E/Z and E/E isomers. The E/Z isomerisation is slow in the NMR time scale of the ¹H and ¹³C chemical shifts; therefore at room temperature and in deuterochloroform all isomers of the new synthesized asymmetric compounds N,N′-ethylene-(1-ethyl-5,5-dimethyl-1′,5′,5′-trimethyl-3,3′-acetyltetramic acid) a, N,N′-ethylene-(5,5-dimethyl-1′,5′,5′-trimethyl-3,3′-acetyltetramic acid) b and, N,N′-ethylene-(1,5,5-trimethyl-1′,5′,5′-trimethyl-3-acetyl-3′-formyl-tetramic acid) c could be found in the corresponding spectra. To assign the ¹³C NMR signals we used two-dimensional ¹³C-¹H one-bond (HMQC) and ¹³C-¹H multibond (HMBC) correlated spectroscopy and the empirical rule that CO signals involved in hydrogen bonds are shifted to a lower field. The relative stability of isomers depending on substitution pattern could be estimated from the composition of the equilibria. b crystallizes as Z/Z isomer from ethanolic solution. The X-ray structural analysis of b has shown two CH-O hydrogen bonds. Received: 31 May 1996 / Revised: 26 June 1996 / Accepted: 1 July 1996     

Nitraza-/Oxa-Propylene- and Hydrazonemethylene-Bridged 1,2,4-Nitraminotriazoles and Selected Salts

Two new bridged nitraminotriazoles with bridging oxapropylene and nitrazapropylene moieties were synthesized, and converted into several salts, as well as from the hydrazonemethylene bridged nitraminotriazole. All compounds were fully characterized by NMR and IR spectroscopy, elemental analysis as well as differential thermal analysis. The sensitivity towards friction and impact were determined according to BAM standard technics and the energetic properties were calculated by using the EXPLO5 computer code. The neutral compounds as well as the various salts were examined in terms of their physicochemical properties and detonation performance to each other and compared to the commonly used secondary explosive RDX.     

Modelling day‐ahead electricity prices

A production‐based approach is introduced to take into account different attitudes and liabilities of market participants to discuss the equilibrium day‐ahead prices on electricity. Conditions ensuring the existence of the equilibrium are given and price distribution is considered. A discussion of reasons for high price volatility is given.