Tomohiro Endo

Physicochemical properties and inclusion complex formation of δ-cyclodextrin

δ-Cyclodextrin (CD) is a cyclic oligosaccharide composed of nine α-1,4-linked d-glucose units. Its physicochemical properties have been characterized only in terms of its X-ray crystal structure (Fujiwara et al., 1990). A method for the purification of δ-CD was examined, and its physicochemical properties and complexation abilities were elucidated and compared with those of α-, β-, and γ-CD (Kobayashi et al., 1986; Miyazawa et al., 1993). Purification of δ-CD from the commercially available CD powder was mainly carried out with the combined treatment of HPLC and column chromatographies. The molecular weight of δ-CD was determined by FAB-MS, and the cyclic structure of δ-CD was identified by 1H-NMR and 13C-NMR. The aqueous solubility of δ-CD was greater than that of β-CD but less than that of α-CD or γ-CD. No surface activity of δ-CD was observed. δ-CD did not exhibit any hemolytic activity at 4.0 × 10−2 M δ-CD, which was close to its saturated solution. The acid-catalyzed hydrolysis increased in the following order: α-CD < β-CD < γ-CD < δ-CD. δ-CD did not show any significant solubilization effect on most of the slightly soluble or insoluble drugs in water. However, in the case of a large guest molecule such as spironolactone (SP) and digitoxin, which have a steroidal framework, the enhancement of solubility of the guest molecule by δ-CD was greater than that by α-CD. The solubility of SP increased about 30-fold in the presence of δ-CD (4.5 × 10−2 M), showing the features of an Al type phase diagram.

An anhydrous polymorphic form of trehalose.

An anhydrous polymorphic form of alpha,alpha-trehalose was prepared from trehalose dihydrate by two different drying methods: (1) heating under vacuum; and (2) heating in hot air. Preparation of this anhydrous form by vacuum heating showed good reproducibility. This form was characterized by X-ray powder diffraction analysis and differential scanning calorimetry. This anhydrous form was converted to an amorphous phase at 127 degrees C and was found to be hygroscopic. At 43% relative humidity at 25 degrees C, this form rapidly reverted to dihydrate, while the amorphous phase remained unchanged. When an amorphous phase coexisted with this form, the rate of water adsorption to the amorphous phase was slower than that to the amorphous phase alone. These properties of this anhydrous form of alpha,alpha-trehalose may explain the effects of trehalose in dehydration tolerance of plants and insects in the desert.

Inclusion complex formation constants of α-, β-, γ-, δ-, ε-, ζ-, η- and θ-cyclodextrins determined with capillary zone electrophoresis

Abstract In contrast to the well known small cyclodextrins (CD), cyclomaltohexaose ( α -CD), cyclomaltoheptaose ( β -CD) and cyclomaltooctaose ( γ -CD), very limited information is available on larger CD and their inclusion complex forming properties. Using capillary electrophoresis, the binding constants of inclusion complexes formed with cyclomaltononaose ( δ -CD), cyclomaltodecaose ( e -CD), cyclomaltoundecaose ( ζ -CD), cyclomaltododecaose ( η -CD) and cyclomaltotridecaose ( θ -CD) and various anions were determined and compared to the corresponding binding constants of α -, β - and γ -CD. All of the large CD were capable to form inclusion complexes. Dependent on the type of guest molecules, δ - and e -CD were the weakest complex formers. The complex forming ability of e , ζ -, η -, and θ -CD increased with increasing size of the ring structure and θ -CD displayed inclusion complex formation constants comparable to γ -CD.

Evaluation of a Sulfobutyl Ether β-Cyclodextrin as a Solubilizing/Stabilizing Agent for Several Drugs

To evaluate the potential use of beta-cyclodextrin sulfobutyl ether, 7 sodium salt (SBE7-beta-CD) as a drug solubilizing and stabilizing agent, the solubilizing effects of SBE7-beta-CD on 22 different poorly water-soluble drugs were compared with those of intact beta-CD and heptakis-(2,6-di-O-methyl)-beta-CD (DMCD). SBE7-beta-CD was generally a more effective solubilizer for poorly water-soluble drugs than was intact beta-CD, but SBE7-beta-CD was not as effective as DMCD. The effects of SBE7-beta-CD on the acid hydrolysis rate of prostaglandin I2, the alkaline hydrolysis rate of indomethacin, the dehydration of prostaglandin E1, and the isomerization of prostaglandin A1 were also investigated and compared to those for intact beta-CD, DMCD, and 2,3,6 partially methylated-beta-CD (PMCD). The stabilizing effects of SBE7-beta-CD on chemically unstable drugs were generally higher than those of other CDs.

Interaction of Antimalarial Agent Artemisinin with Cyclodextrins

To obtain an effective solution of the poorly water soluble antimalarial agent artemisinin, the use of several kinds of cyclodextrins (CDs) as solubilizers was examined. The following CDs were used in this study: α-CD, β-CD, γ-CD as parent CDs, 2-hydroxypropyl-β-CD (HP-β-CD), sulfobutyl ether β-CD (SBE7-β-CD), heptakis (2,6-di-O-methyl)-β-CD (DM-β-CD), 2,3,6-partially methylated-β-CD (PM-β-CD) as modified CDs, and glucosyl-β-CD (G1-β-CD), and maltosyl-β-CD (G2-β-CD) as branched CDs. The solubility curves of artemisinin with CDs can all be classified as type AL. The apparent stability constants for artemisinin-parent CD complexes increased in the order of α- < γ- ≤ β-CD. The constants for artemisinin-β-CD derivative (and β-CD) complexes increased in the order of G2-β-CD ≅ G1-β-CD cong; PM-β-CD ≅ β-CD < HP-β-CD < SBE7-β-CD < DM-β-CD. These results suggest that the addition of CDs enables the solubilization of artemisinin.

Effects of Cogrinding with β-Cyclodextrin on the Solid State Fentanyl

Fentanyl base and β-cyclodextrin (β-CD) were coground at 1:1 and 1:2 molar ratios (fentanyl: β-CD) and the physicochemical characteristics of the mixtures were studied using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), solid state (13)C nuclear magnetic resonance (NMR) spectroscopy and powder X-ray diffraction (PXRD) measurement. Additionally, portions of the coground samples were exposed to high relative humidity to investigate fentanyl and β-CD interactions. The results of DSC and PXRD analyses indicate that the ground mixtures are in an amorphous state, and the FTIR measurements show hydrogen bonding interactions between fentanyl and β-CD. Solid state (13)C NMR indicates that a fentanyl/β-CD inclusion compound is formed in the humidified mixture. Furthermore, PXRD data from the humidified mixtures are similar to the PXRD patterns from the inclusion complex.

Isolation, purification, and characterization of cyclomaltodecaose (ε-CD)

e-Cyclodextrin (e-CD) is a cyclic oligosaccharide, composed of ten α-1,4-linked D-glucoses reported by French et al. in 19651), but has not been studied because of the difficulty in the preparation and purification of large-ring CDs composed of more than nine α-1,4-linked D-glucose units. This report describes the purification and characterization of e-CD. Furthermore, the crystal and molecular structure of e-CD hydrate (e-CD 19H2O) was elucidated by X-ray analysis.

Evaluation of the interaction between β-cyclodextrin and psychotropic drugs by surface plasmon resonance assay with a Biacore ® system.

Phase-solubility studies have been used to evaluate the solubilizing effects of cyclodextrins (CDs) on lipophilic, water-insoluble drugs. However, large amounts of CDs and drugs are required to measure solubility by phase-solubility studies. Thus, more efficient approaches to evaluate the interaction of CDs with drugs are needed. Herein we introduce a method that evaluates the interaction between immobilized β-cyclodextrin and psychotropic drugs by surface plasmon resonance assay with a Biacore(®) system. Association constants and stoichiometries observed were generally consistent with values calculated by traditional methods, such as phase-solubility and continuous variation methods. Results showed that the analytical method using Biacore(®) was suitable to evaluate CD-drug interactions.

Interaction of Cyclomaltononaose (δ-CD) with Several Drugs

The effects of δ-cyclodextrin (δ-CD; cyclomaltononaose) on solubility of 14 drugs that are slightly soluble or insoluble in water were studied and compared with those of conventional cyclodextrins (CDs) such as α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD). In general, δ-CD had a weak complex-forming ability with the drugs examined in comparison with β-CD and γ-CD. However, in the case of digitoxin, δ-CD enhanced solubility of the guest molecules. To determine the mechanism of inclusion complex formation of δ-CD with digitoxin, the interaction of both drugs was investigated by the solubility method and spectroscopic methods such as ultraviolet (UV) and 1H-NMR (nuclear magnetic resonance). The changes in chemical shift (1H) and hypsochromic shift of UV suggested that digitoxin was partially included in the cavity of δ-CD.

X-Ray Structure of i-Cyclodextrin

Abstract Crystal structure of i-cyclodextrin consisting of 14 glucose units were determined by the X-ray method. The crystal of 9 hydrate belongs to a monoclinic space group C2 with Z=2 and cell dimensions are a = 36.536(9), b = 10.085(4), c = 20.944(2) A, and β = 114.97(2)°. The molecule with crystallographic twofold symmetry is in a saddle-like shape where the elliptical macrocyclic ring is bent by 75.2°. The seven glucose units in the asymmetric unit are arranged in a left-handed helical fashion to form a U-shape. Distances from the center of the molecule to each O4 atom are in the range from 7.6 to 9.7 A indicating the presence of a large cavity in the molecule. Adjacent two glucose units in the asymmetric portion is in cis arrangement where the O2H hydroxyl group forms a hydrogen bond with O3H of next glucose unit. In contrast, symmetry-related glucose units are connected with trans arrangement and the O3H hydroxyl group is hydrogen-bonded to O6H of the adjacent glucose unit. The latter conformation ...