Cyclodextrins in the Pharmaceutical Field

Abstract

Cyclodextrins (CyDs) are cyclic oligosaccharides, containing a minimum of six D-(+)-glycopyranose units attached by α-1, 4-linkages produced by the action of the cyclodextrin-trans-glycosidase enzyme on a medium containing starch. CyDs are somewhat cone-shaped. The outside of CyDs is hydrophilic and the inside of the cavity is hydrophobic in character. If a molecule fits entirely or at least partially into the cavity, an inclusion complex may be formed. In general, hydrophobic molecules, rather than hydrophilic ones, have a higher affinity to the CyD cavity in aqueous solutions. The CyD complexes thus formed are stabilized by various intermolecular forces, such as hydrophobic interaction, van der Waals forces, hydrogen bonding, release of high energy water molecules in complex formation and release of strain energy in the macromolecular CyD ring. Orally administered CyDs have shown to be harmless, because insignificant amounts are absorbed.

Parenterally administered natural CyDs may cause severe nephrotoxicity, particularly β-CyD, due to the formation of low solubility of β-CyD-cholesterol complexes which precipitate in the kidney. Parenterally administered natural CyDs may also cause shape changes and hemolysis of human erythrocytes. Hydroxyalkylated-β-CyDs appear to lack these toxic potentials.

Molecular encapsulation may occur both in the solid state and in solution. Physicochemical properties of the guest molecule may be changed by CyD inclusion complexation. These alterations provide methods to characterize and detect inclusion. There are methods to detect inclusion in solid state and in solution. Some of the methods used to detect inclusion in solution may also be used to determine the complex stability constant. The alteration of physicochemical properties of the guest molecule may be useful to enhance drug properties such as solubility, dissolution rate, bioavailability, stability or to reduce side effects.     

Quantification of the Interaction between Charged Guest Molecules and Chemisorbed Monothiolated β-Cyclodextrins

The quantification of small molecules in aqueous solution by surface bound supramolecular host molecules is an important goal in the research field of chemo- and biosensor development. In this paper we present an attempt to quantify the interaction of different charged guest molecules with chemisorbed monothiolated β-cyclodextrin monolayers by means of impedance spectroscopy in the presence of the redox couple [Fe(CN)(6)](3)(-)/[Fe(CN)(6)](4)(-). Self-assembled monolayers of mercaptopropane-N-mono-6-deoxy-β-cyclodextrin amide (MPA-CD) on gold surfaces were formed with coverage of 99-100%. The inclusion of charged guest molecules was detected by monitoring the changes in the charge-transfer resistance, which is sensitive to the surface charge density in terms of repulsion or attraction of the redox active ions. Adsorption of positively charged 1-adamantanamino hydrochloride (1-ADHC) led to a considerable increase in the charge-transfer resistance, whereas the inclusion of both negatively charged 1-adamantanecarboxylic acid (1-ADC) and 2-(p-toluidinyl)naphthalene-6-sulfonate (2,6-TNS) caused a decrease. Applying the Frumkin correction to obtain the surface charge density and the Gouy-Chapman-Stern theory to account for the electrochemical double layer, we were able to quantify the binding of the charged guest molecules in terms of binding isotherms. The isotherms display a distinct two step adsorption process probably owing to the presence of two energetically different binding sites on the surface. Complete reversibility of the binding process of the guest molecules could be demonstrated by the addition of β-cyclodextrin in solution, which allowed the reuse of the functionalized surfaces.     

A new design strategy for efficient electro-optic single-component organic crystals

A new, theoretically-derived synthetic concept for designing geometrically optimized, single-component organic crystals for the electro-optic effect, is presented. The idea relies on the mechanism responsible for the spontaneous evolution of polarity in channel-type inclusion compounds consisting of non-polar hosts. Single, elongated, rod-like molecular structures which incorporate both a strongly hyperpolarizable core and peripheral, non-polariable R-groups, may mimic the two-component structures of the polar inclusion compounds. In both systems, the energy difference in the lateral directions between antiparallel and parallel alignment of the active molecules is assumed to be approximately zero, and terminal functional group interactions along the direction of alignment are responsible for polarity evolution. By choosing molecules in which the direction of the largest hyperpolarizability is common with the geometric long axis, then efficient crystals for the linear electro-optic effect are envisaged.     

A combined structure and symmetry classification of the urea series channel inclusion compounds

The honeycomb inclusion compounds formed by the urea series hosts XC(NH₂)₂, X=O, S or Se, with hydrophobic guests, can be classified according to Hermann into 5 possible arrangements of the host molecules. However the space groups and unit cells found in practice vary greatly from those of the ideal host structures, as a result of distortions of the host lattice and/or ordering of the guest molecules in the channels. Nevertheless it is possible to make a correlation among structures of the same Hermann Type through a descent in symmetry, i.e. by constructing the corresponding Bärnighausen family tree, using the space group/maximal subgroup relations from International Tables. Three such trees have constructed to include 31 well-characterised inclusion compounds, with the following summary results: Type 1: 7 structures, 7 occupied and 3 unoccupied nodes, maximum subgroup index 12. Type 3: 17 structures, 7 occupied and 2 unoccupied nodes, maximum index 18. Type 4: 9 structures, 4 nodes, all occupied, maximum index 2. (Type 2 is the enantiomorph of Type 1, and no example of Type 5 is known.) Individual nodes on these trees correspond to a specific space group and unit cell, and may be associated with particular observed physical properties, such as guest disorder, chirality, second harmonic generation or ferroelasticity.     

超共轭有机苯甲脒类紫外线吸收剂

本文在总结了不同种类的紫外线吸收剂的基础上,重点介绍了苯甲脒类紫外线吸收剂。基于苯甲脒类紫外线吸收剂具有非常好的抗紫外线的效果,同时与高分子化合物有很好的相容性、并且沸点较高、热稳定性很好,所以能很好的适用于如塑料成型等高温实验中。特别是苯甲脒类紫外线吸收剂还可应用在聚氨酯PU上,使其抗紫外线效果明显优于使用其他的紫外线吸收剂。     

Crystalline inclusion complexes on the basis of the mixed “gossypol–pyrazine” host

Crystal engineering of gossypol using pyrazine as a complexing agent led to the discovery of new families of crystalline inclusion complexes on the basis of a mixed “gossypol–pyrazine” host. Depending on the H-bonding ability of the solvent guest molecules, different types of clathrates were formed. In these clathrates, pyrazine molecules incorporate gossypol molecules to relatively robust mixed host matrix through symmetrical H-bonds of the type O–H⋯N.     

Theoretical investigation on the inclusion of TCDD with β-cyclodextrin by performing QM calculations and MD simulations

The rapid enrichment and detection of trace polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are currently challenging issues in the field of environmental science. In this paper, by performing quantum chemistry (QM) calculations and molecular dynamics (MD) simulations, we studied the inclusion complexation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a representative PCDD molecule, with β-cyclodextrin (β-CD), one of the widely used compounds in supramolecular chemistry. The calculated results reveal that the stable inclusion complex can be formed in both the gas phase and solvent, which proposes that β-CD may serve as a potential substrate enriching TCDD. The calculated vibrational spectra indicate that the infrared (IR) and Raman spectroscopy may be suitable for the detection of β-CD-modified TCDD. The present theoretical results may be informative to environmental scientists who are devoting themselves to developing effective methods for detection and treatment of POPs.     

Pharmaceutical Uses of Cyclodextrins and Derivatives

Due to their particular conformation, cyclodextrins have the remarkable characteristic of being able to include various kinds of molecule inside their hydrophobic cavity, conferring on them an environmental hydrophily. These inclusion compounds have completely new pharmacotechnical properties, but the most important ones concern increases in water solubility and bioavailability. When administered orally, the inclusion compounds decompose, allowing the free active ingredient to be absorbed by the gastro-intestinal mucosa. However, a certain proportion of inclusion compound is absorbed without any dissociation.

Some cyclodextrin derivatives are very interesting because of their very high water solubility, and also because of their low parenteral toxicity compared with the original β-cyclodextrin. However, in parenteral administration, it is absolutely necessary to study the pharmacokinetic and pharmacological characteristics of the inclusion compound, which must be considered as the true active ingredient.     

Surface physical and chemical changes of pure iron after molybdenum ion implantation and their effects on the tribological behaviour II: Tribological behaviour

The components of tribological systems are all quite sensitive to the surface chemistry and microstructure of the tribological material which may be dramatically changed by ion implantation. This paper is aimed at studying the effect of surface physical and chemical changes caused by molybdenum ion implantation on the friction and wear behaviours of pure iron. For this purpose, the wear tests of unimplanted and implanted specimens were conducted on an SRV fretting wear machine in air, at room temperature and with or without lubrication. The surface morphology, composition and chemical state of the wear tracks were also examined using electron probe microanalysis, Auger electron spectroscopy and X-ray photoelectron spectroscopy. The experimental results indicate that the wear resistance of pure iron is largely improved by molybdenum ion implantation. Under dry friction conditions, the wear resistance of the specimen implanted with a dose of 3 × 10¹⁷ is increased to 2.8 times that of unimplanated pure iron since the anti-adhesion, anti-abrasion and anti-deformation abilities are improved as a result of the increase in microhardness. When liquid paraffin is used as a lubricant, the wear resistance of the implanted specimen is 4.8 times as high as that of the unimplanted one. This further increase in wear resistance compared with that for dry friction is mainly due to the boundary lubricating film provided by liquid paraffin, which reduces the adhesion between the wear counterpart and molybdenum atoms in the implanted specimen. When liquid paraffin plus sulphurized olefin is used as a lubricant, the wear resistance of the implanted specimen is 2.8 times as high as that of the unimplanted one. It can be seen that the increasing value of the wear resistance is lower than that of the sample lubricated with liquid paraffin. The reason is that the compounds FeS and FeSO₄ formed between the element of the wear specimen and the active elements of the lubricant in the wear process play an anti-wear role. However, the presence of a molybdenum element in the implanted specimen decreases the atomic ratio of iron, and thus decreases the amount of FeS and FeSO₄ and the wear resistance.     

Nickel-based wear-resistant coatings by vacuum melting

In various coating processes nickel-based hard alloy powders are applied in either an atomized or a mechanically pulverized form. The coatings show good corrosion resistance, a high abrasion resistance and a relatively low melting point. Since boron is sparingly soluble in nickel, the boride Ni₃B forms a low melting eutectic at about 1000 °C with the nickel solid solution. Boron and silicon act simultaneously as deoxidizers and improve both the properties of the coating and the bonding to the substrate. Diffusion into the substrate occurs during the coating procedures.In this paper we discuss the behaviour of heterogeneous powder compounds with nickel hard alloys. For many applications mixtures with various carbides are used. During coating, reactions take place between the Ni-Cr matrix and the added carbides. These heterogeneous or quasi-alloys, which are used because of their abrasion resistance, are metastable.The abrasion resistance depends primarily on the phases as well as on their grain size, the grain size distribution and alterations to the matrix. When carbidic quasi-alloys are exposed to abrasion and corrosion at high temperatures, reactions of the existing phases during use cannot be completely excluded. Heat treatment causes changes in the structure and abrasion resistance of carbide-containing quasi-alloys.It is difficult to follow reactions which take place during coating either in the fused mass of quasi-alloys or in heterogeneous compounds. Because of their relatively low melting points nickel-based hard alloys can be coated by furnace melting. Hence carbide compounds with Ni-Cr-B-Si powder alloys are most suitable for research also. In these mechanical alloys segregation, of relevance to practical applications, can be studied as well as the formation of various phases during the coating or heat treatment processes.The behaviour of mixtures of Ni-Cr-B-Si powder alloy with different amounts of a number of carbides is reported. The structures of the resulting phases were studied and we tried to correlate these with the results of our abrasion tests.For tungsten carbide-nickel hard alloy mixtures the formation of the ? phase is influenced by the coating parameters and the matrix as well as by the diffusion of iron from the substrate into the coating.We also investigated mixtures of an Ni-Cr-B-Si matrix with TiC (Ti, W)C and NbC. The wear resistance against steel and SiC was measured. Various wear mechanisms and the properties of the carbide-matrix interface the wear results.     

Pharmaceutical Uses of Cyclodextrins and Derivatives

Abstract

Due to their particular conformation, cyclodextrins have the remarkable characteristic of being able to include various kinds of molecule inside their hydrophobic cavity, conferring on them an environmental hydrophily. These inclusion compounds have completely new pharmacotechnical properties, but the most important ones concern increases in water solubility and bioavailability. When administered orally, the inclusion compounds decompose, allowing the free active ingredient to be absorbed by the gastro-intestinal mucosa. However, a certain proportion of inclusion compound is absorbed without any dissociation.

Some cyclodextrin derivatives are very interesting because of their very high water solubility, and also because of their low parenteral toxicity compared with the original β-cyclodextrin. However, in parenteral administration, it is absolutely necessary to study the pharmacokinetic and pharmacological characteristics of the inclusion compound, which must be considered as the true active ingredient.     

利用极点顺序的多边形顶点凹凸性判别算法

提出一种根据多边形各个极点在顶点序列中的先后顺序确定多边形方向的算法.对于多边形顶点凹凸性的判别,提出通过确定某个顶点与其相邻两顶点构成三角形的方向,进而利用多边形方向与该三角形方向是否相同而确定该顶点凹凸性的方法.该算法包括了点包含的判别.试验表明,该算法不含乘法运算,使运算高效稳定.     

Synthesis of biodegradable films based on cassava starch containing free and nanoencapsulated β‐carotene

β‐Carotene may represent an excellent natural antioxidant, and nanoscale encapsulation may contribute to development of a new technique for addition of antioxidants in active packaging. The objective of this work was to develop active biodegradable films with addition of free β‐carotene or β‐carotene–loaded lipid‐core nanocapsules and to evaluate the interaction with the polymeric matrix. The addition of free β‐carotene led to a decrease in the mechanical properties of films, result of their hydrophobic character and less interaction with the matrix. β‐Carotene nanocapsules caused the increase of colour intensity of films, elongation at rupture, and less light transmission, with the gradual increase according to increase in concentration. Films with β‐carotene nanocapsules presented greater protection of sunflower oil, with lower formation of oxidation products. The lower stability of free antioxidant led to behavior similar to control film, with less oxidation protection. The addition of nanocapsules can provide better interaction with the structure, since the encapsulated carotenoid exhibits solubility in aqueous medium and present better distribution, without altering the rapid biodegradability and thermal stability of films. The results show that encapsulated bioactive compounds can be used as hydrophobic natural antioxidants and added in active biodegradable packages for maintaining food safety and extending the shelf life.     

Organic ferroelectrics

Ferroelectricity results from one of the most representative phase transitions in solids, and is widely used for technical applications. However, observations of ferroelectricity in organic solids have until recently been limited to well-known polymer ferroelectrics and only a few low-molecular-mass compounds. Whereas the traditional use of dipolar molecules has hardly succeeded in producing ferroelectricity in general, here we review advances in the synthesis of new organic materials with promising ferroelectric properties near room temperature, using design principles in analogy to inorganic compounds. These materials are based on non-covalent molecules formed by two or more components, in which ferroelectricity arises either from molecular displacements or from the collective transfer of electrons or protons. The principle of using multi-component molecular compounds leads to a much broader design flexibility and may therefore facilitate the development of future functional organics.     

Real-time detection of organic compounds in liquid environments using polymer-coated thickness shear mode quartz resonators

The selection of sensitive coatings is a critical task in the design and implementation of chemical sensors using coated thickness shear mode quartz crystal resonators (QCRs) for detection in liquid environments. This design or selection is performed through a study of the sorption process in terms of the partition coefficients of the analytes in the coatings. The partition coefficient, which is controlled by the chemical and physical properties of the coating materials, determines the inherent selectivity and sensitivity toward analyte molecules. The selection of the coatings is logically determined by the interactions between coating and target analyte molecules, but can also be made through a systematic variation of the coating's properties. The determination of the partition coefficients is only accurate if all contributions to the total measured frequency shifts, deltafs, of the coated QCR can be established. While mass loading is often assumed to be the dominant factor used in determining partition coefficients, viscoelastic effects may also contribute to deltafs. Both the effect of viscoelastic properties and the effect of mass loading on the sensor responses are investigated by using a network analyzer and oscillator circuit and by characterizing the total mechanical impedance of the loaded sensor. Different types of coatings including rubbery and glassy polymers are investigated, and the targeted analytes include classes of polar compounds (methanol), nonpolar compounds (toluene, xylenes), and chlorinated hydrocarbons (trichloroethylene, tetrachloroethylene, etc). It is seen that changes in viscoelastic properties due to analyte sorption may be significant enough to place the sensor in the nongravimetric regime. However, for most applications involving the detection of relatively low concentrations of organic compounds and the use of acoustically thin films, changes in the complex shear modulus of the coatings contribute less than 5% of the total shift in the series resonant frequency, depending on the coating. In that case, the measured deltafs and, hence, the calculated approximate classification and selection of the coatings for operation in a complex solution of water/analyte molecules.     

Increasing selectivity for TNT-based explosive detection by synchronous luminescence and derivative spectroscopy with quantum yields of selected aromatic amines

The detection of explosive material is at the forefront of current analytical problems. A detection method is desired that is not restricted to detecting only explosive materials, but is also capable of identifying the origin and type of explosive. It is essential that a detection method have the selectivity to distinguish among compounds in a mixture of explosives. The nitro compounds found in explosives have low fluorescent yields or are considered to be non-fluorescent; however, after reduction, the amino compounds exhibit relatively high fluorescence. We discuss how to increase selectivity of explosive detection using fluorescence; this includes synchronous luminescence and derivative spectroscopy with appropriate smoothing. By implementing synchronous luminescence and derivative spectroscopy, we were able to resolve the reduction products of one major TNT-based explosive compound, 2,4-diaminotoluene, and the reduction products of other minor TNT-based explosives in a mixture. We also report for the first time the quantum yields of these important compounds. Relative quantum yields are useful in establishing relative fluorescence intensities and are an important spectroscopic measurement of molecules. Our approach allows for rapid, sensitive, and selective detection with the discrimination necessary to distinguish among various explosives.     

The Effect of Cyclodextrin Inclusion Complexation on the in Vitro Protein Binding and in Vivo Prothrombin Time of Warfarin

Abstract

That the inclusion complexation occurred in an aqueous solution was proved by solubility determination and a membrane permeation study. The effects of inclusion complexation on the protein binding and prothrombin time of warfarin were studied by the technique of ultrafiltration and prothrombin time measurements respectively. The apparent stability constant of 1:l complex was obtained from the initial portion of the straight line of phase solubility diagrams. The apparent stability constant of α or β - cyclodextrin complex is 10.29 M ^-1 or 148.88 M^-1. The greater the stability constant of the inclusion complex the less the permeability of the warfarin. The magnitude of the stability constant of the inclusion complex also determined the protein binding and the prothrombin time of warfarin. The greater the stability constant of the inclusion complex, the lesser the protein binding and the more prolonged the prothrombin time of warfarin. β-cyclodextrin showed a significantly different behavior from α-cyclodextrin in vitro protein binding and in vivo prothrombin time. The present results indicate a greater stability constant of the inclusion complex formed might determine the binding of warfarin to ablbumin and lead to an increased anticoagulant activity of warfarin.     

Supersonic jet/multiphoton ionization/mass spectrometry of dioxins formed by the thermal reaction of phenols in the absence and presence of an FeCl3 catalyst

Dioxins, which are thermally produced from several precursor molecules, were investigated by supersonic jet/multiphoton ionization/time-of-flight mass spectrometry (SSJ/MPI/TOF-MS). Dibenzofuran and dibenzo-p-dioxin were efficiently generated from o-chlorophenol and also from phenol after a chlorination reaction with FeCl3. The present technique was employed for the continuous monitoring of a specified isomer, e.g., m-chlorophenol, which is formed at relatively low temperatures by chlorination of phenol with FeCl3. A dimerization reaction that forms a dibenzo-p-dioxin, e.g., dichlorodibenzo-p-dioxin from 2,4-dichlorophenol, at relatively high temperatures was also investigated. The number of chlorine atoms in the dioxin molecule was largely correlated with the number of chlorine atoms in the precursor molecule. However, some unexpected compounds, which probably occur by dechlorination and rearrangement reactions, were also found. Thus, the SSJ/MPI/TOF-MS technique represents a sensitive, as well as selective, analytical method for monitoring thermally generated dioxins.     

Molecular recognition in monolayers and species detection by surface-enhanced resonance Raman spectroscopy

The current emphasis in efforts to produce systems capable of highly specific molecular recognition has produced a wide variety of compounds such as crown ethers, cryptands, cyclodextrins and other inclusion systems. A more desirable approach, and one obviating laborious organic synthesis, would be based upon a mechanism more like that seen in the in vivo antigen-antibody reaction. Sites having the capability for specific molecular recognition based on a predetermined template molecule would allow realization of systems of the desired specificity. The technique of cosorption of a silane and a surface-active molecule onto a glass surface has been comprehensively described by Sagiv and by Maoz and Sagiv and has indicated the feasibility of this approach, e.g. with surface-active dyes. In the present study, adsorbed monolayers were produced with sites based on chosen template molecules, using the Sagiv method, and the systems then reconstituted with the original template molecule as well with molecules of closely similar structure (i.e. porphyrins or chlorophylls). A high degree of recognition was evidenced, as shown by the use of surface-enhanced resonance Raman spectroscopy as the detection tool. It was also shown that chemically dissimilar species can be reconstituted into sites formed by other species, provided that the molecular shapes are compatible. The ease of resorption into performed sites is strongly dependent on the presence of amphiphilic character in the molecule re-entering a site.