Fritz Kastner

Hydrogel-based drug delivery systems: Comparison of drug diffusivity and release kinetics

Hydrogels are extensively studied as matrices for the controlled release of macromolecules. To evaluate the mobility of embedded molecules, these drug delivery systems are usually characterized by release studies. However, these experiments are time-consuming and their reliability is often poor. In this study, gels were prepared by step-growth polymerization of poly(ethylene glycol) (PEG) and loaded with fluoresceine isothiocyanate (FITC) labeled dextrans. Mechanical testing and swelling studies allowed prediction of the expected FITC-dextran diffusivity. The translational diffusion coefficients (D) of the incorporated FITC-dextrans were measured by fluorescence recovery after photobleaching (FRAP) and pulsed field gradient NMR spectroscopy. Because the determined values of D agreed well with those obtained from release studies, mechanical testing, FRAP, and pulsed field gradient NMR spectroscopy are proposed as alternatives to release experiments. The applied methods complemented each other and represented the relative differences between the tested samples correctly. Measuring D can therefore be used to rapidly evaluate the potential of newly developed drug delivery systems.

The enantiomers of N,N-dimethylthiobenzamides: Chromatographic behaviour and rotational barriers☆

N,N-Dimethylthiobenzamides bearing hydrogen atoms in both orthopositions were shown by 1H NMR in the presence of an optically active alcohol to have non-coplanar π-systems. The barrier to rotation about the C(sp2-C(sp2) bond amounts to 43 ± 2 kJ/mol. Liquid chromatography on triacetylcellulose served for the enrichment of enantiomers of 2-substituted thiobenzamides. In several cases considerable enantioselectivity (relative retention up to 8.7) was observed. The barriers to enantiomerization (Tables 3, 4 and 5), determined by thermal racemization, were discussed in terms of non-bonding interactions, electrostatic repulsions and buttressing effects in the transition state of rotation.

Chiroptical detection during liquid chromatography: III. Non-stop acquisition of circular dichroism spectra during liquid chromatography

A new type of spectrometer, built in-house, served as a circular dichroism detector for liquid chromatography. It acquired differential absorbances ΔA = f(λ) at all wavelengths, λ, between 208 and 268 nm simultaneously within a time interval of 9 s. Non-stop acquisition of circular dichroism spectra during liquid chromatography is described for the first time. The novel set-up gives automatic access to dichrograms without preparative enrichment of enantiomers, if some analytical separation on an optically active sorbent can be achieved. Like photodiode-array detection, the new technique collects ultraviolet spectra A = f(λ), but furnishes positive/negative information ΔA = f(λ) in addition. It was applied to (±)-2,2′-spirobi[2H-chromene] as a test sample and microcrystalline tribenzoylcellulose as a sorbent. Future applications of non-stop liquid chromatographic circular dichroic-ultraviolet data are discussed.

Chiroptical detection during liquid chromatography, part 5: On-line measurement of circular dichroism spectra Δε(λ) during stops of chromatographic flow

SummaryA procedure is described which serves to measure circular dichrograms Δε(λ) on line during stops of flow in liquid chromatography. Since the concentration of substrate in the spectrometer cell during the stop is not known, the differential absorption coefficients Δε are calculated from the experimental differential absorbances ΔA by means of UV absorption (i. e. photomultiplier voltage) data. Verifications of the procedure are obtained by its application to three substrates (Table 1), the Δε(λ) spectra of which were known. The present on-line technique is compared with a corresponding off-line method.The N,N-dimethylthiobenzamides1 and2 as well as the 9,10-phenanthrenequinone7 consist of interconvertible enantiomers because their planar states are destabilized by steric overcrowding of groups. The unknown dichrograms Δε(λ) of1, 2 and7 are obtained (Figs. 2 and 4) and discussed with reference to the helicities of these molecules.ZusammenfassungEin Verfahren zur on-line-Messung von Circulardichroismus-Spektren Δε(λ) während des Anhaltens des chromatographischen Flusses wird beschrieben. Die Konzentration des Substrats in der Spektrometer-Küvette während des Anhaltens ist nicht bekannt, weshalb die differentiellen Absorptionskoeffizienten Δε aus den experimentellen differentiellen Absorbanzen ΔA mit Hilfe von UV-Absorptions-Daten (d. h. Photomultiplier-Spannungen) berechnet werden. Die erfolgreiche Überprüfung des Verfahrens gelingt durch seine Anwendung auf drei Substrate (Tabelle 1), deren Δε(λ)-Spektren bekannt waren. Die vorgestellte on-line-Technik wird mit einer entsprechenden off-line-Methode verglichen.Die N,N-Dimethylthiobenzamide1 und2 sowie das 9,10-Phenanthrenchinon7 bestehen aus interkonvertierenden Enantiomeren, weil ihre ebenen Zustände durch räumliche Gruppenhäufung destabilisiert sind. Die unbekannten Dichrogramme Δε(λ) von1, 2 und7 werden ermittelt (Fig. 2 und 4) und im Hinblick auf die Helizitäten dieser Moleküle diskutiert.

Tetraoxa [24] porphyrinogen(4.0.4.0)/tetraoxa[22]porphyrin(4.0.4.0) dication a further isomer of the aromatic 22π-tetraoxaporphyrins

Abstract While the antiaromatic tetraoxa[24]porphyrinogen(2.2.2.2) 1 ( trans , cis , trans , cis ) and the corresponding aromatic dication 1 2+ have been published recently, the synthesis of the title compounds is described for the first time. Beside the cis , trans , cis , trans -tetraoxa[24]porphyrinogen(4.0.4.0) 2b the isomeric porphyrinogens 2a ( trans , cis , cis , trans ) and 2c ( all - trans in the cisoid conformation) could be isolated. The tetraoxa[22]porphyrin(4.0.4.0) dication is an aromatic 22π-system, it exists only in the cis , trans , cis , trans -configuration. The dication 2b 2+ can be reduced with tetrakis-N,N-dimethylaminoethene to give pure porphyrinogen 2b . The electrochemistry of the system 2/ 2b 2+ and AM1 calculations are described.

Synthese von diepoxy[16]annulen(6.2) durch intramolekulare McMurry-Kupplung

Abstract The synthesis of diepoxy[16]annulene(6.2) 3 is described. The dialdehyde ( E , E )-3,3′-([2,2′-bifuran]-5,5′-diyl)bis[2-propenal] 4 undergoes an intramolecular as well as an intermolecular as well as an intermolecular McMurry coupling to give the diepoxy[16]annulene 3 beside the tetraepoxy[32]annulene(6.2.6.2) ( 5 ). According to the spectroscopic data 3 has the Z , Z , E , Z -configuration and it turns out to be a strongly paratropic, highly dynamic system, where the E -ethenediyl-1,2-bond rotates around the adjacent single bonds. According to VT- 1 H-NMR spectroscopy, this rotation is even not yet entirely frozen at −130°C. The calculated free activation energy of the rotation is about 24 kJ/mol (5,74 kcal/mol), the smallest value observed ever for the rotation of E -ethenediyl-1,2-bonds in annulenes.

Synthese von Carbazolderivaten, 1. Mitt.: Über die Reaktion von 3‐(2‐Nitroethenyl)indol‐2‐malonestern mit Michael‐Akzeptoren

Michael‐analoge Reaktionen der Verbindungen vom Typ 9 wurden untersucht: Additionreaktionen mit Acrolein und Methylvinylketon führen in Abhängigkeit von den Reaktionsbedingungen zu den Pyridoindolin 16 oder 14 und/oder zu Tetrahydrocarbazolen vom Typ 17 oder 15. Unter Triton B‐Katalyse zeigen die Verbindungen 15 retro‐Michael‐Eliminierung der Nitromethyl‐Gruppe, gefolgt von Hydrolyse/Decarboxylierung und Dehydrierung zu den zweifach substituierten Carbazolen 20. Im Fall von 17a konnte das primäre Eliminierungsprodukt 18 isoliert werden. Das Synthesepotential dieser Reaktionen wird diskutiert. Einige der beschriebenen Verbindungen und ihrer Derivate sind antimykobakteriell aktiv.

Regiospecific synthesis and structural study of some trifluoromethyl substituted dibenzosemibullvalenes

SummaryPreparation of the regiospecifically trifluoromethyl substituted dibenzosemibullvalenes3 and5 is described. An unequivocal proof of chirality of3 and5 was obtained by enrichment of their enantiomers using liquid chromatography on triacetyl- or tribenzoylcellulose. The stereostructure of compounds3 to5 was proved by their1H-NMR spectra and confirmed by X-ray crystallographic analysis. The geometrical data from X-ray structural analyses showed that five-membered rings involved in the skeleton of3 and5 adopt flattened envelope conformations. These results indicate also a significant substituent-induced bond length asymmetry in the cyclopropane rings of3 and5.ZusammenfassungEs wird die Herstellung der Trifluormethyl-substituierten Dibenzosemibullvalene3 und5 beschrieben. Der eindeutige Beweis ihrer Chiralität wurde durch Anreicherung der Enantiomeren mittels Flüssigchromatographie an Triacetyl- bzw. Tribenzoylzellulose erbracht. Die Stereochemie der Verbindungen3 und5 wurde mittels1H-NMR und Röntgenstrukturanalyse geklärt. Die Röntgenstrukturdaten zeigten, daß der Fünfring in3 und5 eine abgeflachte Briefumschlagkonformation einnimmt. Es zeigt sich auch eine signifikante substituentenbedingte Asymmetrie in den Bindungslängen der Cyclopropanringe von3 und5.