Silylation of 2-hydroxypropyl-β-cyclodextrin

The effect of the reaction conditions or the nature of the silylating agents on the silylation of hydroxypropyl-β-cyclodextrin with tert-butyldimethylchloro- and diphenyl-methylchlorosilanes is investigated.     

Alkyl capped carbonates ofβ-cyclodextrin

The synthesis is described of alkyl capped carbonates of-cyclodextrin, obtained from diols activated with carbonyldiimidazole. The reaction preferentially gave monocapped derivatives which were characterized by HPLC, TLC, FT-IR and¹³C-NMR. These compounds are stable at pH <7, and methyl orange was found to form stronger inclusion compounds with capped-cyclodextrin than with the parent-cyclodextrin. Paramagnetic Gd(III) complexes were also studied, but they were found to be included into capped-cyclodextrin as well as into-cyclodextrin.Part of this work was presented at the 7th International Symposium on Cyclodextrins, 1994, Tokyo, April 25–28, Book of Abstract, page 54.     

Solubility characteristics ofβ-cyclodextrin inclusion complexes

Some inclusion complexes of-cyclodextrin (cyclomaltoheptaose) have been investigated, particularly with respect to their solubility. The mathematical characterization of the equilibrated host-guest system containing both solid and solution phases is discussed (first of all those, which contain 1:1 or 1:1 + 2:1 species) and demonstrated by different examples.     

Co-solvent modulation of the inclusion selectivity ofβ-cyclodextrin

The solubility of-CD, which is increased to 87 gL^–1 in 75% water - 25% isopropanol mixtures, does not behave in a linear fashion as a function of the water/isopropanol ratio. Application of this increased solubility to the formation of inclusion complexes between-cyclodextrin and cineole : eugenol, cineole : pinene and eugenol : pinene shows strong solvent modulation of the inclusion selectivity. The proportion of guests complexed is in inverse ratio to the compatibility of the guests in the solvent mixture.     

Inclusion complexes of sulfanilamide with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin

Sulfanilamide belongs to the group of drugs that have a bacteriostatic effect on different pathogenic microorganisms. This activity originates from the competitive antagonism with p-aminobenzoic acid, which is an integral part of folic acid. The safe use of sulfanilamide is limited due to poor solubility in the aqueous medium. Therefore, the aim of this paper is the synthesis of sulfanilamide, as well as preparing and structural characterization of its inclusion complexes with cyclodextrins. The crude sulfanilamide was obtained in the synthesis between acetanilide and chlorosulfonic acid according to the standard procedure. The synthesized sulfanilamide was recrystallized from water in order to obtain the satisfactory purity of the substance. Sufanilamide was complexed with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin by the co-precipitation method. A molecular encapsulation of sulfanilamide was confirmed by using FTIR, ¹H-NMR, XRD and DSC methods. Phase-solubility techniques were used to assess the formation of the inclusion complex between sulfanilamide and cyclodextrins. The photostability of sulfanilamide and its inclusion complexes was estimated by UVB irradiation in a photochemical reactor by applying the UV–Vis method. Based on the UV–Vis analysis, sulfanilamide:2-hydroxypropyl-β-cyclodextrin complex was presented as more photostable than sulfanilamide:β-cyclodextrin complex and sulfanilamide. The obtained results enable the potential use of these inclusion complexes for the preparation of oral formulations due to the enhanced solubility of sulfanilamide.     

Interaction of some antibiotics with hydroxypropyl-β-cyclodextrin

The interaction between 19 antibiotics and hydroxypropyl--cyclodextrin (HPCD) was studied by reversed-phase thin-layer chromatography. HPCD formed inclusion complexes with 16 compounds, the complex always being more hydrophilic than the uncomplexed drug. The intensity of interaction significantly increased with increasing specific hydrophobic surface area of the guest molecule proving the preponderant role of hydrophobic interactions in inclusion complex formation. The intensity of the HPCD-drug interaction significantly decreased with increasing concentration of methanol in the environment indicating that methanol can also enter the cyclodextrin cavity and inhibits competitively the inclusion complex formation or the free energy of transfer from water to the HPCD cavity should be less negative at higher concentration of methanol in the aqueous medium.Dedicated to Professor József Szejtli.     

Inclusion Complex of Paclitaxel in Hydroxypropyl-β-cyclodextrin

Introduction Paclitaxel (as Taxol) is a kind of diterpenoid natural product[1] extracted from Chinese yew. It has been reported to have high anti-tumor effects, such as the activity against oophorama, mammary cancer, encephaloma, cervical carcinoma, and non- small-cell lung carcinoma[2-5]. One of the major problems of paclitaxel applied to therapy is its extremely low solubility in water[6]. In addition, paclitaxel is administered as a slow infusion in a vehicle consisting of Cremophor EL (polyoxyethylated castor oil ). However, Cremophor has been observed to cause severe, occasionally fatal hypersensitivity reactions in animals and humans[7].Therefore, paclitaxel therapy includes a prophylactic regimen of antihistamines and corticosteroids[8] , along with a prolonged infusion time to reduce the severity and incidence of hypersensitivity reactions. Because of the reasons mentioned above, currently its preparation needs to be improved further[9].     

Binding of vitamin A byβ-cyclodextrin and heptakis(2,6-O-dimethyl)-β-cyclodextrin

Inclusion complexation of all-trans-retinol, retinal and retinoic acid with -cyclodextrin (-CD) and heptakis(2,6-O-dimethyl)--cyclodextrin (DM--CD) were investigated by means of UV-vis spectroscopy. The association constants (K _a) obtained for vitamin A with DM--CD is greater than with -CD. On the other hand, for the same host compoundK _a values of retinol, retinal and retinoic acid are very close to each other.     

Inclusion of acaricides by complexation withβ-cyclodextrin

Many synthetic pesticides (herbicides, insecticides, fungicides etc.) can be complexed with cyclodextrins. The inclusion complexes of acaricides such as Fenson, Chlorfenson and Genite were prepared. The formation of inclusion complexes was established by UV and X-ray diffraction techniques. The host-to-guest ratio was determined by UV spectral and GLC methods.This paper is dedicated to Professor A.B. Kulkarni on his 75th birthday.     

Investigation of monoterpenes complexation with hydroxypropyl-β-cyclodextrin

In this study, we investigated the inclusion complexation of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and eight monoterpenes (eucalyptol, geraniol, limonene, linalool, α-pinene, β-pinene, pulegone, and thymol) in aqueous solution and solid state. The formation constants (K _f) of inclusion complexes were determined using fluorescence spectroscopy and static headspace gas chromatography. The results indicated the formation of 1:1 inclusion complexes between HP-β-CD and all studied guests. A linear relationship was found between K _f values and the hydrophobic character of the monoterpenes expressed as logP. Solid complexes were prepared by the freeze-drying method in a 1:1 (HP-β-CD:monoterpene) molar ratio. Physicochemical characterization of solid inclusion complexes was carried out using Fourier transform infrared spectroscopy and differential scanning calorimetry. Finally, the encapsulation efficiency (EE%) of HP-β-CD was determined using HPLC analysis. Noticeable difference in the EE% was observed between monoterpene hydrocarbons and oxygenated monoterpenes. These results suggested that complexation with HP-β-CD could be a promising strategy to enlarge the application of monoterpenes in cosmetic, pharmaceutical and food industries.     

Inclusion Complex of Paclitaxel in Hydroxypropyl-β-cyclodextrin

Introduction Paclitaxel （as Taxol） is a kind of diterpenoid natural product extracted from Chinese yew. It has been reported to have high anti-tumor effects, such as the activity against oophorama, mammary cancer, encephaloma, cervical carcinoma, and non- small-cell lung carcinoma. One of the major problems of paclitaxel applied to therapy is its extremely low solubility in water. In addition, paclitaxel is administered as a slow infusion in a vehicle consisting of Cremophor EL （ polyoxyethylated castor oil ）. However, Cremophor has been observed to cause severe, occasionally fatal hypersensitivity reactions in animals and humans. Therefore, paclitaxel therapy includes a prophylactic regimen of antihistamines and corticosteroids , along with a prolonged infusion time to reduce the severity and incidence of hypersensitivity reactions. Because of the reasons mentioned above, currently its preparation needs to be improved further.     

Inclusion Complex of Carprofen with Hydroxypropyl-β-cyclodextrin

The aim of this study was to investigate the characteristics ofhydroxypropyl--cyclodextrin (HPCD) on the solubility,photostability and dissolution of carprofen (CP). It was found that the solubility of carprofen increased 52-fold when16% HPCD was added to H₂O (w/v). The phase-solubility diagram revealed the formation of a 1 : 1 inclusion complex of CP-HPCD with a stability constant (k_s) of 487 M^-1. Formation of the inclusion complex of CP-HPCD was analyzed using differential scanning calorimetry (DSC). Changes in chemical shifts of the ¹H-nuclear magnetic resonance spectra of CP-HPCD demonstrated that the inclusion site of CP by HPCD was carbazolyl aromatic ring skeleton rather thanthe side chain of propanoic acid. The photostability study revealed that theCP-HPCD complex could not significantly decrease the rate of photodegradation of CP, implying that the rate-determining step of CP mainly occurredat the side chain. The dissolution rates of CP were significantly enhanced as the proportions of HPCD increasedin the prepared discs. The dissolution of the physical mixture (in a 1 : 3 molarratio) increased by about 6-fold in comparison with the parent drug. The improvement of wettability and solubility of CP by complexing to HPCD was reflected in theenhanced dissolution rate.     

Selective hydroxymethylation of guaiacol in the presence ofβ-cyclodextrin

Studies on the effect of-cyclodextrin (BCD) and its derivatives on the selectivity in hydroxymethylation of guaiacol by formaldehyde was carried out. Fairly high selectivity with respect to isovanillyl alcohol formation was achieved. Significantly, the selectivity-enhancing effects of 2,6-di-O-methyl-BCD was much larger, giving rise to 22% more of isovanillyl alcohol formation than BCD and its polymer. UV, fluorescence,¹H-NMR spectroscopic and potentiometric studies were also carried out to determine the orientation of guaiacol inside the BCD cavity.     

Disposition of copper(II) inβ-cyclodextrin

Distances of glucose protons in-cyclodextrin (BCD) from copper(II) in copper(II)--cyclodextrin have been determined from¹H NMR spin-lattice relaxation time (T ₁) measurements for the first time. Very lowT _1p /T _2p values indicated the dipolar mechanism to be the most dominant one in determining the paramagnetic contribution to relaxation. The distances of copper(II) from BCD glucose protons indicated copper(II) to be present almost in the centre, inside the cavity in the same plane as H-1 and H-4. An average distance of about 5.0–5.9 Å was obtained for copper(II) from the H-2, H-3, H-1, H-4 and H-6 a and b protons in BCD.     

A structural study of the naringin-β-cyclodextrin complex

The structure of the inclusion complex formed between naringin (naringenin-7-O--neohesperidoside) and-cyclodextrin (BCD) was studied in detail by UV and NMR spectroscopic techniques and potentiometry. A binding constant value of 1016±150M^–1 was arrived at from UV studies. Potentiometric studies showed that pK values of 4-OH and 5-OH were affected by and-cyclodextrins. One-dimensional difference NOE and spin-lattice relaxation time (T ₁) measurements indicated that the aglycone protion was affected more than the neohesperidoside portion. TheT ₁ values analysed for local motions indicated that _c values of complexed naringin was higher than that of free naringin. The internal rotation calculated for different groups showed _i values for the phenolic and dihydrobenzopyran portion decrease by a factor of 2. Also a value of 0.12–0.17 observed for the aglycone portion indicated that the coupling between guest and host is weak. All the studies have shown that the disposition in which the phenol group at 2 is inside the BCD cavity with 4-keto and 5-OH hydrogen bonded to the secondary hydroxyl groups at the rim of the wider end of the BCD cavity is the most probable one.     

Molecular inclusion complexation of tolbutamide with permethyl-β-cyclodextrin

The formation of a stable inclusion complex between tolbutamide and permethyl- cyclodextrin was systematically studied. It shows that permethyl--CD forms a 1 : 1 complex with tolbutamide. Its molecular structure was elucidated by physicochemical methods including IR and high field NMR analysis. The influence of pennethyl--cyclodextrin on the hypoglycemic effect of tolbutamide was evaluated by measuring the blood glucose level. The reduction in plasma glucose was significantly greater when the rabbits were treated with the complex than with tolbutamide alone. The enhancement of the bioavailability of tolbutamide by permethyl--cyclodextrin is likely attributed to the molecular inclusion effect.     

Enhanced water-solubility of albendazole by hydroxypropyl-β-cyclodextrin complexation

The inclusion complexation of methyl (5-(propylthio)-1H-benzimidazol-2-yl) carbamate, albendazole (ABZ) with 2-hydroxypropyl--cyclodextrin (HPCD) in water was investigated with a view to improving the low aqueous solubility of the drug. The combination of albendazole and HPCD in a molar ratio of 1/10 resulted in a significant increase in the aqeous solublity of the drug, up to 3500 times. Albendazole/HPCD complexes could be recommended as a parenterally administered formulation because of its good solubility properties and the safety of the cyclodextrin used.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on Release Rate of Metoprolol from Ternary Metoprolol/2-hydroxypropyl-β-cyclodextrin/Ethylcellulose Tablets

The effect of 2-hydroxypropyl--cyclodextrin (HP--CyD) on the release of a water-soluble ₁-selective adrenoreceptor antagonist, metoprolol (Met), from ternary Met/HP--CyD/ethylcellulose (EC) tablets was investigated. The release rate of Met from the ternary tablets was dependent on amounts of HP--CyD in the tablets, i.e., the rate decreased when small amounts of HP--CyD were added, while large amounts of HP--CyD accelerated the rate. The slowest rate was observed for the tablet consisted of a 30/10/60 weight ratio of Met/HP--CyD/EC. The analyses of the release rates by the Korsmeyer equation and their temperature dependence suggested that Met is released from the EC matrix containing HP--CyD according to the diffusion-controlled mechanism. The water penetration studies and the micro- and macroscopic observations suggested that the retarding effect of HP--CyD is attributable to a viscous gel formation in small pores on the surface of the tablets, where HP--CyD gels may work as a barrier for the water penetration into the tablets and the release of the drug from the tablets. The in-vitro release property of the ternary tablets was reflected in the in-vivo absorption profile in dogs. The results indicated that a combination of HP--CyD and EC is useful for the release control of water-soluble drugs such as Met.     

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

-,- and -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 of-cyclodextrin is greatly enhanced, leads to a proposal that the abnormally low solubility of-CD may be explained by the presence of aggregates and the unfavourable interaction of these aggregates with the hydrogen bonded structure of water.     

Complex formation of cinnamaldehyde-methyl-β-cyclodextrin and muscone-methyl-β-cyclodextrin by supercritical carbon dioxide processing and sealed heating method

Firstly, the interaction between cinnamaldehyde (CIN) and methyl-β- cyclodextrin (MBCD) was studied in aqueous solution. 1:1 inclusion complex was formed and the association constant was 187 ± 9 M^?1. Then the complex of CIN–MBCD and muscone–MBCD was prepared both by sealed heating method and by supercritical carbon dioxide (sc CO₂) approach. Complete complex was obtained by both methods for CIN–MBCD. Some CIN molecules was weakly associated with MBCD molecules in products by sealed heating method, all CIN molecules was strongly associated with MBCD molecules in products by sc CO₂ processing. Complete complex between muscone and MBCD was not obtained. The choice for the size of guest molecule still existed for MBCD cavity in sealed heating method and sc CO₂ processing.