Statistical design analysis of isophorone electrocatalytic hydrogenation: the use of cyclodextrins as inverse phase transfer catalysts

Fundamentals and applications of a 2³ factorial design were performed for assessing the influence of the cyclodextrin (CyD) type, concentration and encapsulation time on the electrocatalytic hydrogenation (ECH) of isophorone. Electrolysis were carried out using nickel as electrocatalyst and sacrificial anode. A discussion of model validation is presented. The analysis of the results showed that the most significant factors to the conversion rate were the CyD type and concentration, with 3 mmol dm^?3 of βCyD giving the best results. The isophorone C=C hydrogenation yield, in the presence of βCyD, was 28 % higher than in its absence, and it is comparable to those obtained by other well-established ECH procedures in terms of hydrogenation yield, selectivity and current efficiency.     

New Aspects of Cyclodextrin Chemistry Induced by Outside Type Complex Formation; Asymmetric Reduction of Indol-3-Pyruvic Acid with NaBH4 in Aqueous Solution

Asymmetric reduction of indol-3-pyruvic acid (IPA) with NaBH₄ in aqueous solution in the presence of various cyclodextrins (α-, β-, γ-, mono-6-amino-6-deoxy-β- and di-6^ABamino-6^AB-deoxy-β-cyclodextrin) was investigated. From the NMR and circular dichroism spectral studies, the conformation of the CyD–substrate complexes is suggested; the part of carboxylic group stay in the cavity of α-CyD, whole of IPA in β-CyD, two molecules in a γ-CyD cavity, and IPA(s) is/are on the rim of the cavity of mono-6-amino-6-deoxy-β- and di-6^ABamino-6^AB-deoxy-β-CyD (AβCyD, DAβCyD) with electrostatic interaction between amino group and carboxylic group. This conformational difference provides in the difference in the optical selectivity of reduction.     

Structure and energy of formation of β- and γ-cyclodextrin complexes with amino acid enantiomers

The interaction between cyclodextrins (CyD), β-CyD, and γ-CyD, and the L- and D-optical isomers of several amino acids (Ala, Leu, His, Phe) are calculated using DFT. It is found that the L-forms of the investigated amino acids bond more strongly to CyD, due to the different numbers of hydrogen bonds that form. The structures of the resulting complexes are analyzed.     

Interactions of cyclodextrins with aromatic amino acids: a basis for protein interactions

Cyclodextrins (CyD) have proven effects on the stability of proteins and can be used in the formulation of aggregation prone therapeutic proteins. This effect stems from specific interactions between the CyD (preferably β-CyD) and solvent exposed amino acid residues. Here the interaction with hydrophobic aromatic amino acid residues stands out and the interaction between CyDs and these amino acid residues holds the key to understanding the observed effects, which CyDs exerts on proteins and peptides. Here we present a comparative study of the interactions between free and peptide bound aromatic amino acids and their derivatives with α, β and γ-CyDs using NMR spectroscopy. We propose a novel, quantitative means of assessing the penetration depth of guest molecules in CyD cavities, the penetration gauge Π, and apply it to the observed interaction patterns from ROESY NMR spectra. We demonstrate that the penetration depths of the aromatic rings within the CyDs rely highly on the nature of the remainder of the guest molecule. Thus the presence of charges, neighboring amino acids and the specific positioning on the surface of a protein highly influences the penetration depth and geometry of guest–CyD interactions.     

Study of aerodynamic and release properties of inhaled particles containing cyclodextrins

The aim of this study was to investigate the influence of different cyclodextrins (CyD) on physical characteristics of inhalation dry powders. The particle size was characterised by Aerosizer^® LD and aerodynamic behaviour of inhaled complexes assessed by twin-stage liquid impinger. The in vitro release profile of the powders was studied through Franz cell modified method. Produced particles showed a suitable size for pulmonary delivery, ranging between 1 and 5 μm. The nature of the CyD affected the powders performance on reaching the lower compartment (“Lungs”), mainly by the altering their aerodynamic properties, which is reflected on the different percentages of their emitted respirable fractions. HP-γ-CyD:fluticasone propionate complex showed a fast release of corticosteroid while γ-CyD had a constant release throughout time. The best characteristics for pulmonary delivery were obtained with acetyl-γ-CyD:fluticasone propionate complex.     

Complexation studies of pioglitazone hydrochloride and β-cyclodextrin: NMR (1H, ROESY) spectroscopic study in solution

Pioglitazone hydrochloride (PIO) is an agonist of the peroxisome proliferator-activated receptor γ (PPARγ), used to treat diabetes. ¹H-NMR spectroscopic analysis of varying ratios of β-cyclodextrin (β-CyD) and PIO in D₂O confirmed the formation of β-CyD–PIO inclusion complex in aqueous solution. The 1:1 stoichiometry of β-CyD–PIO inclusion complex was determined by Scott’s plot method and binding constant (K _a ) was calculated to be 155 M^?1. 2D ROESY experiments confirmed that the phenyl ring of PIO act as a guest and deeply penetrate in β-CyD cavity from wider as well as narrower rim side and form two 1:1 stable inclusion complexes. Some of the PIO protons exhibited splitting, in the presence of β-CyD, indicating chiral differentiation of PIO by β-CyD.     

Glucose recognition by a supramolecular complex of boronic acid fluorophore with boronic acid-modified cyclodextrin in water

A boronic acid fluorophore (C1-APB)/boronic acid-modified γ-cyclodextrin (3-PB-γ-CyD) complex as a supramolecular sensor has been designed for selective glucose recognition in water. The fluorescent response behavior of the C1-APB/3-PB-γ-CyD complex under various pH conditions revealed that a C1-APB/3-PB-γ-CyD complex solution containing glucose showed a large increase in the fluorescence intensity under alkaline pH conditions. In contrast, only small increases in the fluorescence intensity were noted for fructose and without sugar solutions. The observed response selectivity for the C1-APB/3-PB-γ-CyD complex was on the order of glucose > galactose, mannose > fructose. The evidence on a large value of the inclusion constant (K(L·CyD) = 6.5 × 10(3) M(-1)), a marked broadening of the (1)H NMR spectra, and an enhancement of induced circular dichloism (ICD) intensity for the C1-APB/3-PB-γ-CyD complex by glucose binding supported the multi-point interaction of the C1-APB/3-PB-γ-CyD complex with glucose. These results demonstrated that the C1-APB/3-PB-γ-CyD complex functioned as an efficient supramolecular sensor for selective glucose recognition in water.     

Interaction of Natural and Modified β-Cyclodextrins with a Biological Membrane Model of Dipalmitoylphosphatidylcholine

Lipid vesicles made up of dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were used as a biological membrane model to investigate the interaction between natural and modified β-cyclodextrins and these membrane bilayers. Differential scanning calorimetry was used to study the thermotropic behavior of the DPPC vesicles and any change caused by the presence of cyclodextrins. The presence of dimethyl-β-cyclodextrin (DM-β-CyD) triggered a reduction in the enthalpy values related to the main transition peak from gel state to liquid crystal phase of DPPC aqueous dispersions, as a function of the DM-β-CyD molar fraction: the larger the amount of DM-β-CyD, the greater the reduction in ΔHvalues. This effect was probably due to the ability of DM-β-CyD to extract and to complex the DPPC molecules forming the phospholipid vesicles. The presence of β-cyclodextrin (β-CyD) or hydroxypropyl-β-cyclodextrin (HP-β-CyD) caused no particular alteration in the thermotropic parameters of DPPC vesicles, whereas trimethyl-β-cyclodextrin (TM-β-CyD) at molar fractions higher than 0.12 caused broadening of the transition peak due to a possible interaction with the hydrophobic part of the bilayers. Experiments on DPPC–cholesterol (10 mol%) vesicles showed the capability of β-CyD and TM-β-CyD to extract cholesterol from the ordered bilayer structures, triggering an alteration in the lipid constituents of the membranes. HP-β-CyD caused no variation in the thermotropic parameters of the DPPC–cholesterol (10 mol%) vesicles. The findings show that HP-β-CyD seems the most suitable molecular drug carrier forin vivoadministration.     

Model Analysis for Oral Absorption of a Drug/Cyclodextrin Complex Involving Competitive Inclusion Complexes

The bioavailability parameters of a drug after oral administration of a preparation containing drug/CyD complexes may be modified by formation of competitive inclusion complexes. In this study, we examined the effects of competitors on drug permeation from its CyD complex through in-vitro artificial membranes and in-situ recirculation conditions, for comparison with the results under in-vivo conditions in the bile duct of cannulated rats. Phenacetin, an antipyretic, was used as a model drug, natural CyDs and maltosyl--CyD as host molecules, and benzoic acid derivatives, sodium taurocholate and acetaminophen as competitors. The in-vitro cellophane membrane permeation rate and the in-situ absorption rate of phenacetin were quantitatively predicted by theoretical calculation using the stability constants of drug/CyD and competitor/CyD complexes when CyD weakly interacts with membrane components in lower CyD concentrations (generally below 10 mM). The in-vivo absorption behavior was only qualitatively reproducible by the theoretical calculation, probably because of various physicochemical and physiological factors affecting the absorption. The present results may be useful not only for prediction of intestinal absorption of drugs from CyD preparations, but also for formulation design of CyD preparations containing multi-components.     

Circular dichroic investigation of factors that affect inclusion complexes of cyclodextrins as a drug carrier

Drug/cyclodextrin (CyD) inclusion complexes have become one of the most widely used approaches to increase aqueous solubility of poorly soluble drugs, to increase their bioavailability and stability, to reduce undesirable side effects and prevent drug–drug and drug–excipient interactions. Although drug molecules as well as CyDs exhibit detectable changes in their physicochemical properties upon complexation, to date, the interaction of CyDs with drugs is not well understood. So far, only few methods can be applied to obtain structural information on drug/CyD complexes. Circular dichroism spectroscopy (CD) has often been used to study molecular binding, nevertheless, rarely do these studies exploit the full potential of optical techniques. The objective of this article is to highlight important factors that affect drug/CyD binding interaction in particular β-CyD. On the basis of chirality, (S)-(+)-ibuprofen, meta-chlorobenzoic acid and aspirin were used to study binding interaction with β-CyD using CD. Based on CD equations for a simple 1:1 binding complex, the Levenberg–Marquadt non-linear equation was used for binding analysis and the production of simulated graphical presentations to explain the effect of various factors that influence the binding reaction and the binding curve. The results show reliability indicated by the binding constant which is in agreement with literature values. In addition, the effect of guest/host concentrations and the extent of binding on the inclusion complexes are elucidated with accuracy. This work provides useful information that can prove valuable in drug binding studies.     

香豆素衍生物和β环糊精分子络合过程的稳态和时间分辨荧光研究

用稳态和时间分辨荧光光谱法研究某些香豆素衍生物(C_311, C_47, C_102, C_120和C_4)同βCyD在水溶液中的络合过程。观察到这些分子在βCyD水溶液中的荧光峰值兰向位移、强度增加和荧光寿命增大。结果表明CND分子在水溶液中同βCyD分子发生络合作用。测得的CND一βCyD体系的络合常数按下列次序递减; K_311>K_47>K_102>K_120>K_4, 这些事实揭示了客体分子的憎水性及同βCyD分子腔体尺寸医配是影响络合作用的重要因素。     

Release control of fragrances by complexation with β-cyclodextrin and its derivatives

The release control of fragrances, benzyl acetate (BA), citral (CR), linalool (LL), citronellol (CL) and linalyl acetate (LA), was conducted using β-cyclodextrin (β-CyD), 2-hydroxypropyl-β-CyD (HP-β-CyD) and 2,6-di-O-methyl β-CyD (DM-β-CyD). The release rate of the fragrances from 30% ethanol/water solution was significantly suppressed by the complexation with these CyDs, and the suppressing effect increased in the order of β-CyD?<?HP-β-CyD?<?DM-β-CyD. The concentration-dependent change of the release rate was quantitatively analyzed to obtain the stability constant (Kc) of the fragrance-CyD complexes. These Kc values were in good agreement with those determined by the solubility method. The results suggest that the release of fragrances can be prolonged by the complexation with β-CyDs and their effects can be controlled by choosing appropriate CyD derivatives with higher Kc values and by setting proper concentrations of the host molecules.     

Improvement of pharmaceutical potential of all-trans retinoic acid with hydroxypropyl-��-cyclodextrin

2-Hydroxypropyl-??-cyclodextrin (HP-??-CyD) includes all-trans retinoic acid (RA), covering the double-bond area of RA with substituted hydroxypropyl groups on CyD ring, as proved by the nuclear Overhauser effect (NOE) between methylene protons on the hydroxypropyl groups and the proton on RA. The formation of an inclusion complex results in hydrophilicity and stability. The effect of RA/HP-??-CyD and that of RA without HP-??-CyD on wrinkle scores and skin elasticity during skin treatment were identical, and the cutaneous stimulus was reduced comparing with RA. The results indicated that the RA/HP-??-CyD complex should help to realize new approaches in skin rejuvenation therapy.     

Potential use of polypseudorotaxanes of pegylated polyamidoamine dendrimer with cyclodextrins as novel sustained release systems for DNA

In this study, we demonstrated the potential use of polypseudorotaxanes (PPRXs) of polyethylene glycol (PEG, molecular weight: 2000)-grafted polyamidoamine dendrimer (PEG-dendrimer) with cyclodextrins (CyDs) as novel sustained release systems for plasmid DNA (pDNA). PEG-dendrimer/pDNA complex formed PPRXs with α-CyD and γ-CyD solutions, but not with β-CyD solution. In the PEG-dendrimer/CyDs PPRXs systems, 17.9 mol of α-CyD and 8.8 mol of γ-CyD were involved in the PPRXs formation with one PEG chain by α-CyD and γ-CyD, respectively. In addition, the CyDs PPRX formation provided the sustained release of pDNA from PEG-dendrimer complex with pDNA at least 72 h in vitro. In addition, the release of pDNA from CyDs PPRX retarded as the dissolution medium volume decreased. These results suggest that the PEG-dendrimer/CyD PPRX systems can work as a sustained DNA release system, and the PPRX formation with CyDs may be useful as a sustained drug delivery technique for other pegylated polymers.     

Guest-Binding and Catalytic Properties of Immobilized β-Cyclodextrins

Abstract

Cyclodextrins¹(CyDs), cyclic oligomers of 6–8 glucose units, form inclusion complexes with guest compounds and have been used as catalyst for the selective syntheses.² Previously, immobilization of CyD with epichlorohydrin as crosslinking agent have been described.^3-4 Here, we report the first successful immobilization of β-CyD using various crosslinking agents. The guest binding abilities and the catalytic abilities of these immobilized β-CyDs are shown.     

One-step synthesis of 2,6-naphthalenedicarboxylic acid from naphthalene using cyclodextrin as catalyst

The one-step synthesis of 2,6-naphthalenedicarboxylic acid from naphthalene with carbon tetrachloride, copper powder and aqueous alkali has been achieved under mild conditions by the use of β-cyclodextrin as catalyst, producing 2,6-naphthalenedicarboxylic acid in 65 mol-% yield with 79% selectivity.     

Thermodynamics of the distribution of some carboxylic acids between organic solvents and a perchlorate solution.

The distribution of formic, benzoic and 4-methylbenzoic acids between a 0.1 mol dm(-3) (Na+, H+)ClO4- solution and octanol and carbon tetrachloride was studied at five different temperatures of 10 - 30 degrees C. The thermodynamic parameters for the transfer process of monomeric acid between two phases and for the dimerization of monomeric acid in carbon tetrachloride (deltaH and deltaS) were evaluated from the van't Hoff isochore. The free-energy change for the transfer of a methylene group from water to organic solvents was entropically controlled, irrespective of the organic solvents. The distribution constants of formic and benzoic acids were larger than those expected from the distribution constants of acetic and phenylacetic acids, respectively. The free-energy change for all solutes, except for benzoic and 4-methylbenzoic acids, was also entirely entropically controlled in the case of octanol as a solvent. The enthaly-entropy compensation for the dimerization constant of acids in carbon tetrachloride was observed.     

Combined use of cyclodextrins and hydroxypropylmethylcellulose stearoxy ether (Sangelose®) for the preparation of orally disintegrating tablets of type-2 antidiabetes agent glimepiride

Despite recent advances in the formulation of orally disintegrating tablets (ODTs), the efforts to enhance the swallowing of the drug after disintegration have been limited. In this study, the feasibility of the combined use of cyclodextrins (CyDs) and a functional drug carrier, hydroxypropylmethylcellulose stearoxy ether (Sangelose^®) was investigated to improve usability of ODTs. Glimepiride, a potent third generation hypoglycemic agent for type 2 diabetes was used as a model drug, because it is poorly water-soluble and elimination half life is fairly short. The direct compression method was employed for the preparation of glimepiride tablets, containing CyDs and Sangelose^®, and various characteristics of the tablets were examined. In the cases of α-CyD and β-CyD, a short disintegration time with an appropriate hardness was obtained, complying with ODT criteria. On the other hand, γ-CyD, HP-β-CyD and HB-β-CyD increased in the hardness and disintegration time of the tablets. The rheological evaluation revealed that CyDs, except γ-CyD, significantly reduced the viscosity of the fluids after disintegration of the tablets, suggesting an ease of swallowing. This was ascribable to the complexation of the hydrophobic stearoyl moiety of Sangelose^® with CyDs after dissolution, leading to the inhibition of the polymer–polymer interaction of Sangelose^® and to the decrease in viscosity of the solution. The interaction of glimepiride with α- and β-CyDs was studied by the solubility method, demonstrating that glimepiride formed water-soluble complexes with these CyDs. Results obtained here suggested that α-CyD and β-CyD can be particularly useful for the Sangelose^®-based ODT formulation, compared to γ-CyD, HP-β-CyD and HB-β-CyD, because of the short disintegration time of the tablets containing α-CyD and β-CyD, their shear-thinning effect on Sangelose^® solutions and their solubility enhancing effect on the drug.     

煤酸异构化制对苯二甲酸

进行了煤氧化产物煤酸（水溶酸WSA）钾在催化剂碳酸镉的存在下，异构化制对苯二甲酸(TPA)的研究。主要考察了催化剂用量、二氧化碳初压、反应温度和反应时间对TPA产率的影响。结果表明，在催化剂存在下煤酸可以转化成TPA。单独煤酸钾异构化时，较佳反应条件：温度430 ℃～450 ℃，压力4.0 MPa，催化剂CdCO3用量4%，反应时间2 h。煤酸钾与苯甲酸（BA）钾混合异构化时，较佳反应条件与单独煤酸钾时基本相同。单独煤酸钾在较佳条件下异构化时，粗TPA产率达34%左右，相当于根据其中有效成分苯多羧酸（BPCA）计算的理论产率的75%左右，选择性较好。煤酸钾加苯甲酸钾在较佳条件下异构化时,粗TPA产率可达68%，扣除假定BA自身岐化生成TPA理论产量之后，则煤酸的TPA产率高达70%，比煤酸单独异构化TPA产率(34%)高1倍。粗TPA经精制可得纯度99%以上的精TPA。     

Selective synthesis of 4,4′-biphenyldicarboxylic acid using cyclodextrin as catalyst

The selective carboxylation of 4-biphenylcarboxylic acid with carbon tetrachloride in aqueous alkali to obtain 4,4′-biphenyldicarboxylic acid was achieved by the use of ß-cyclodextrin and copper powder II under mild conditions.