Ioannis Nicolis

Aggregation of cyclodextrins: An explanation of the abnormal solubility ofβ-cyclodextrin

Abstractα-,β- and γ-Cyclodextrins have been shown to exist as aggregates in solution bound together by a network of hydrogen bonds. Removal of this network by ionisation of the hydroxyl groups leads to a greatly increased solubility and removal of aggregation. The presence of aggregates in solution of structure breaking solutes in which the solubility ofβ-cyclodextrin is greatly enhanced, leads to a proposal that the abnormally low solubility ofβ-CD may be explained by the presence of aggregates and the unfavourable interaction of these aggregates with the hydrogen bonded structure of water.

Copper(II)–l-glutamine complexation study in solid state and in aqueous solution

Abstract Among copper transport alterations in humans, Menkes disease is due to a lethal genetic disorder. The current treatment is the administration of physiological Cu(II)– l -histidine complex. However, this therapy is only effective in some cases and when started early in life. In order to distribute copper in all the biological compartments for Menkes disease patients, the administration of other Cu(II) amino acids complexes has been considered. Several ternary Cu(II)–amino acids complexes were detected in human serum playing an important role in the copper pathway, in particular l -histidine–Cu(II)– l -glutamine. Before the biopharmaceutical studies of l -histidine–Cu(II)– l -glutamine complex, a physicochemical characterisation of binary Cu(II)– l -glutamine complex must be conducted. Indeed, the identification of Cu(II)– l -glutamine species has not been clearly determined at physiological pH in the past. In the present work, the stoichiometry, formation constants and distribution of the various Cu(II)– l -glutamine species have been determined by polarography and UV–Vis spectroscopy in a large pH range. [Cu(II)(Gln) 2 ] complex is the major component at physiological pH and its formation constant is equal to 10 12.5 l 2 mol −2 . For the first time, the structure of [Cu(II)(Gln) 2 ] has been determined in the solid state and in solution. Given the small size of the obtained crystals, it has been necessary to use an X-ray synchrotron source to collect the diffraction data. X-ray crystal structure showed a 4-2 distorted octahedral geometry. In the basal plane Cu–O and Cu–N distances ranged from 1.93 to 1.98 A. Two additional oxygen atoms at 2.70 and 2.86 A complete a severely distorted octahedron. EXAFS and EPR results have shown that the structure of [Cu(II)(Gln) 2 ] is preserved at physiological pH in aqueous solution.

EXAFS characterization of oxaliplatin anticancer drug and its degradation in chloride media.

Oxaliplatin is a second-generation platinum-based anticancer drug. Its degradation is studied in solution, in the presence of chloride ions (in neutral or acidic media) in excess. In both cases the degradation product precipitates immediately. The EXAFS spectra of these products show that they are identical. EXAFS modeling and refinement of the first coordination sphere shows that two light atoms are replaced by two chloride ions. The complete refinement of the local structure is possible by studying the multiple-scattering signal. The results show that the main multiple-scattering contribution is due to the binding oxalato group and that the degradation product is [Cl(2)-(diaminocyclohexane)-Pt(II)].

X-ray absorption spectroscopy of low-molar-mass metallic complexes in pharmacy

X-ray absorption spectroscopy provides valuable information on metallic speciation and so has a wide range of applications in bioinorganic systems. In this paper, low-molar-mass metallic complexes as used in pharmaceutical science are focused on. The results of structural studies on metal-based drugs applied as disease treatments, nutritional supplements or tools for diagnostic methods are presented. Then metal speciation (spatial and chemical distribution) in biological samples through micro-XANES imaging experiments are dealt with. Problems arising from the analysis of noisy data collected from these diluted samples are discussed.

Molecular composites based on first-sphere coordination of calcium ions by a cyclodextrin

Two organic-inorganic composites based on first-sphere coordination of calcium ions by α-cyclodextrin, highlight the possible creation of different architectures, even when involving identical molecular building blocks and inorganic clusters. In both forms, the mineral and organic matrices form separate motifs, with 40% of the crystal structure occupied by the mineral components. Copyright

Characterization of the Absorption of Theophylline From Immediate- and Controlled-Release Dosage Forms With a Numerical Approach Using the In Vitro Dissolution-Permeation Process Using Caco-2 Cells

After oral administration, drug absorption rate is recognized to be dependent on two major factors: dissolution and intestinal cells permeability. Caco-2 monolayer cells have been largely used as a permeation study model. In this study, a numerical approach funded on an exponential first-order time relationship was tested to compare immediate- and controlled-release tablets of theophylline using a dissolution-permeation system. The dissolution performance using USP II paddle apparatus was coupled to the permeability studies investigated in Caco-2 cell monolayers. The dissolved samples were taken at different times; their pH and osmolarity were adjusted to render them suitable to Caco-2 permeability studies (osmolarity = 300 mosm, pH = 7.4). The experimental data show that the dissolution fits the exponential first-order relationship rate. The permeability values were in a range of 4.45 10− 6–5.28 10− 6 cm/s, and percentages of absorbed drug dose were dependent on the fraction initially present in the donor compartment, indicating that absorption of theophylline was dissolution rate limited. Plotting experimental absorbed fractions (Fa) against experimental dissolved fractions (Fd) show that permeation is the rate-limiting step in drug absorption process in the extended release form of theophylline. Our results demonstrate a general agreement between observed Fa/Fd relationships and theoretical Fa/Fd relationships obtained with our approach funded on dissolution and permeation behavior. We concluded that the couple dissolution-caco-2 system could be a useful tool to characterize intestinal permeation for a new formulation of a drug compared with the conventional one.

A Novel Consideration of Species Distribution of Copper(II)/Histidine System at Physiological pH

Abstract The copper(II)–L‐histidine system plays a pivotal role in copper transport across cell membranes. The coordination mode of copper(II)–L‐histidine species at physiological pH has been elusive in aqueous solution for the last four decades, despite exhaustive characterization studies. Recently, the isolation and the X‐ray crystal structure of the physiological [Cu(His)2] complex have been reported. The X‐ray structure is different from all the structures suspected for this complex in solution. We carried out a polarographic analysis to identify copper(II)–L‐histidine species at physiological pH. In our experimental conditions, three copper(II)–L‐histidine species coexist around the physiological pH. These novel considerations can explain the controversy encountered in the investigation of the coordination mode in aqueous solution.

A NEW BIOINORGANIC COMPLEX: EXAFS ANALYSIS AND MOLECULAR MODELLING OF A BIS-CuBr2 COMPLEX OF 6A,6B,6D,6E-TETRA-o-NICOTINOYL-α-CYCLODEXTRIN

Abstract Chemically modified 6A,6B,6D,6E-tetra-o-nicotinoyl-α-cyclodextrin forms a 1:2 complex with CuBr2. EXAFS analysis has been performed on this complex showing direct Cu-macrocycle coordination via the nicotinate groups. Two nitrogen and two bromide atoms are at an average distance of 1.99 and 2.46 A from the copper, respectively. A structural model has been built using molecular dynamics simulation, consistent with the EXAFS results.