Preparation and Characterization of Clopidogrel/DIMEB Complex

Surprisingly, it was found that Clopidogrel base (CLP) easily forms a solid complex with DIMEB in cold solution by precipitation. The complex can be isolated by filtration, the stoichiometry of the isolated complex corresponds to 1 : 1 molar ratio. Powder X-ray diffractometry proved the complex formation in solid state. The improved solubility of the complex offers the possibility of an adequate drug release over the whole pH-range of the GI-tract.     

Influence of (hydroxy)alkylamino substituents on enantioseparation ability of single-isomer amino-beta-cyclodextrin derivatives in chiral capillary electrophoresis

A family of single-isomer amino-beta-cyclodextrin (amino-beta-CD) derivatives containing an amino or (hydroxy)alkylamino group in one of the primary positions has been synthesized. The steric effect and hydrogen bond forming ability of the different substituents on enantioseparation of acidic enantiomers has been studied by capillary electrophoresis (CE). Three enantiomeric model compounds (mandelic acid, cis-permethrinic acid, and cis-deltamethrinic acid) having significantly different apparent complex stability constants with beta-CD were applied in the experiments. Dependence of separation selectivity, resolution as well as mobility difference on chiral selector concentration (0.1-20 mM, pH 6.0) was investigated. Each amino-beta-CD showed higher enantioselectivity than the native beta-CD. One hydroxyalkyl group attached to the primary amino N-atom significantly increased both the enantioselectivity and the resolution compared to the primary amino-beta-CD, while two hydroxyalkyl moieties decreased them due to the predominance of steric hindrance. The value of the apparent complex stability constants obtained suited well the mobility difference model (by Wren). On the other hand, the optimum selector concentrations calculated according to the model were slightly lower than the experienced concentrations giving the maximum enantioresolution of enantiomers.     

Limits of cyclodextrin application in oral drug preparations

Cyclodextrins are applied to facilitate formulation problems, to improve stability and bioavailability. Following factors are determining whether or not cyclodextrins can be applied in oral pharmaceutical preparations:

- properties of the selected CD: solubility, price, specific catalytic properties,

- the drug to be complexed: molecular weight, polarity, solubility,

- drug dose

- solubility properties of the complex and the “super solubility” /temporary over-saturation/

- complex stability and possibility to shift the dissociation equilibrium toward the appropriate direction

- legislative procedures

     

Pulsed EPR and DFT characterization of radicals produced by photo-oxidation of zeaxanthin and violaxanthin on silica-alumina

Pulsed electron nuclear double resonance (ENDOR) and two-dimensional (2D)-hyperfine sublevel correlation spectroscopy (HYSCORE) studies in combination with density functional theory (DFT) calculations revealed that photo-oxidation of natural zeaxanthin (ex Lycium halimifolium) and violaxanthin (ex Viola tricolor) on silica-alumina produces the carotenoid radical cations (Car*+) and also the neutral carotenoid radicals (#Car*) as a result of proton loss (indicated by #) from the C4(4') methylene position or one of the methyl groups at position C5(5'), C9(9'), or C13(13'), except for violaxanthin where the epoxide at positions C5(5')-C6(6') raises the energy barrier for proton loss, and the neutral radicals #Car*(4) and #Car*(5) are not observed. DFT calculations predict the largest isotropic beta-methyl proton hyperfine couplings to be 8 to 10 MHz for Car*+, in agreement with previously reported hyperfine couplings for carotenoid pi-conjugated radicals with unpaired spin density delocalized over the whole molecule. Anisotropic alpha-proton hyperfine coupling tensors determined from the HYSCORE analysis were assigned on the basis of DFT calculations with the B3LYP exchange-correlation functional and found to arise not only from the carotenoid radical cation but also from carotenoid neutral radicals, in agreement with the analysis of the pulsed ENDOR data. The formation of the neutral radical of zeaxanthin should provide another effective nonphotochemical quencher of the excited state of chlorophyll for photoprotection in the presence of excess light.     

Synthesis of biocompatible nanocomposite hydrogels as a local drug delivery system

Nanocomposite biocompatible hydrogels (NCHG) were synthesised as model systems for in situ cured potentially local drug delivery devices for curing periodontal infections. The composite consists of the following components: nanoparticles (NPs), matrix gel, and chlorhexidine (CHX) as antibacterial drug. The NPs were obtained by free radical initiated copolymerization of the monomers, 2-hydroxyethyl methacrylate (HEMA) and polyethyleneglycol dimethacrylate (PEGDMA), in aqueous solution. The same monomers were used to prepare crosslinked matrices by photopolymerization. NCHGs were obtained by mixing NPs, monomers, and drug in an aqueous solution then crosslinked by photopolymerization. Mechanical properties, swelling behavior, and the kinetics of drug release have been investigated. It was found that compression strength values increased with increasing ratio of the crosslinker PEGDMA. Incorporation of NPs into the matrix resulted similar compression strength as the matrix hydrogel. The hydrated NCHGs swelled more slowly but admitted more water. The drug was incorporated in NPs by swelling in CHX aqueous solution or added to the solution of monomer mixture followed by photopolymerization. Studies of release kinetics revealed that on average 60% of the loaded drug was released. The most rapid release was observed over a 24 h period for matrix gels with low crosslinking density. For NCHGs, the release period exceeded 48 h. An unexpected result was observed for NCHGs without drug in the NPs. In this case, increasing release was observed for the first 24 h. Thereafter, however, the apparent quantity of detectable drug decreased dramatically.     

The physical process of melting and freezing

It is suggested that at the melting temperature the wavelength of the average thermal phonon vibration is equal to or is a harmonic of the distance separating the atomic layers in the crystal. This resonance between the phonon and lattice vibrations equals out the energy of the vibrating atoms in the surface layer. If this “uniform” energy is higher than the energy corresponding to the metastable transition state then all the surface atoms lose its position stability. In order to make the jump to the next potential well energy is required to overcome on the viscous resistance of the liquid. If this energy, latent heat of fusion, is supplied then the atomic/molecular sheet or platelets from the surface are detached and melting occurs. The proposed model is consistent with all of the characteristic features of melting and freezing. Equations calculating the average phonon wavelength and the corresponding lattice distance at the melting temperature are derived from fundamental thermodynamic relationships. The required thermodynamic parameters are determined from experiments of the nine selected highly symmetrical solids. The calculated wavelengths of the phonon vibration are equal to or is a harmonic of the $d$-spacing of the atomic/molecular layers in agreement with theory.     

On a Question of Erdős and Ulam

Ulam asked in 1945 if there is an everywhere dense rational set, i.e., 1 a point set in the plane with all its pairwise distances rational. Erdős conjectured that if a set S has a dense rational subset, then S should be very special. The only known types of examples of sets with dense (or even just infinite) rational subsets are lines and circles. In this paper we prove Erdős’ conjecture for algebraic curves by showing that no irreducible algebraic curve other than a line or a circle contains an infinite rational set.     

1,3-Dipolare Cycloadditionen von 3,4-Dihydro-6,7-dimethoxyisochinolinium-N-methoxycarbonylmethylid mit N-substituierten Maleinimiden

Summary 1,3-Dipolar cycloadditions of 3,4-dihydro-6,7-dimethoxyisoquinolinium-N-methoxycarbonylmethylide2 with N-phenyl- and N-methylmaleimide (3 and4) have been investigated. Cycloadducts of theendo- andexo-type were formed, the structure elucidation and conformational analysis of which has been performed by NMR methods.

     

Fendiline-β-Cyclodextrin inclusion complex

Fendiline (N-[1-phenylethyl]-3,3-diphenylpropylamine hydrochloride, trade name: Sensit) is a -receptor blocker and a Ca antagonist. It is a viscous oil and even its crystalline hydrochloride is a very hydrophobic and sparingly soluble compound in water.-Cyclodextrin complexes fendiline base in a molar ratio of 21. In aqueous-cyclodextrin solution, the significantly increased solubility and the intensive induced circular dichroism prove the formation of true inclusion complexes with both the base and the hydrochloride. In artificial gastric juice, the solubility of the complexed forms of the fendiline base and its hydrochloride is 40 and 22 times higher, respectively, than that of free drugs. The complexation withCD resulted in a two-threefold increase in the rate constants of diffusion and absorption determined in a Sartorius apparatus.