Phase transfer of CdS nanocrystals mediated by heptamine β-cyclodextrin

A fundamental and systematic study on the fabrication of a supramolecularly assembled nanostructure of an organic ligand-capped CdS nanocrystal (NC) and multiple heptamine β-cyclodextrin ((NH(2))(7)βCD) molecules in aqueous solution has been here reported. The functionalization process of presynthesized hydrophobic CdS NCs by means of (NH(2))(7)βCD has been extensively investigated by using different spectroscopic and structural techniques, as a function of different experimental parameters, such as the composition and the concentration of CD, the concentration of CdS NCs, the nature of the NC surface capping ligand (oleic acid and octylamine), and the organic solvent. The formation of a complex based on the direct coordination of the (NH(2))(7)βCD amine groups at the NC surface has been demonstrated and found responsible for the CdS NC phase transfer process. The amine functional group in (NH(2))(7)βCD and the appropriate combination of pristine capping agent coordinating the NC surface and a suitable solvent have been found decisive for the success of the CdS NC phase transfer process. Furthermore, a layer-by-layer assembly experiment has indicated that the obtained (NH(2))(7)βCD functionalized CdS NCs are still able to perform the host-guest chemistry. Thus, they offer a model of a nanoparticle-based material with molecular receptors, useful for bio applications.     

Complexation of tyrosol with cyclodextrins

Tyrosol (TY), 4-(2-hydroxyethyl)phenol, is an olive oil biophenol with antioxidant activity and positive effects on human health. This study has investigated the interactions of TY with cyclodextrins (CD) and a CD polymer. Complexation of TY with β-CD, hydroxypropyl-β-CD (HP-β-CD), and methyl-β-CD (Me-β-CD) has been evaluated both in aqueous solution and in the solid state. The techniques employed in solution to determine the apparent stability constants of the respective complexes were fluorescence and UV–visible spectroscopies. Complexation with β-CD and its derivatives involved an increase of both the UV absorbance and the intrinsic fluorescence of TY; a bathochromic shift of the UV spectrum was detected as well. The apparent stability constants obtained with native β-CD, Me-β-CD and HP-β-CD presented similar values. Complexes in the solid state were obtained by coevaporation and kneading. They were characterised by X-ray diffraction analysis and differential thermal analysis. The interaction of TY with β-CD led to a crystalline complex; the same diffraction pattern was obtained by coevaporation and kneading. The complexes obtained with methyl- and HP-β-CD were amorphous irrespective of the preparation method. In addition, the retention of TY in an insoluble polymer of CD crosslinked with epichlorohydrin has been quantified. In approximately 20 min, 1 mg of TY per gram of polymer was retained.     

Comparative Study on Co-Ground Products of Rofecoxib with β-Cyclodextrin and Its Sulfobutyl Ether-7 Derivative in Solution and in the Solid State

The inclusion behavior of sulfobutyl ether-7 derivative ofβ-cyclodextrin (SBE7βCD), in solution and solidstate was compared with that of natural β-cyclodextrin(βCD) toward a poorly water-soluble anti-inflammatoryagent, rofecoxib (ROFX), chemically 4[4-(methylsulfonyl)phenyl]-3-phenyl-2 (5H)-furazone. Drug-cyclodextrin solidsystems were prepared by cogrinding in a ball mill. A phasesolubility method was used to evaluate the stoichiometries andstability constants of ROFX-βCD (1 : 1 and 62 M^-1)and ROFX-SBE7βCD (1 : 1 and 132 M^-1) complexes.The formation of inclusion complexes with βCD andSBE7βCD in the solid state were confirmed by infraredspectroscopy, differential scanning calorimetry, X-ray diffractometry,scanning electron microscopy and in the liquid state by phasesolubility analysis, nuclear magnetic resonance spectroscopy andcircular dichroism studies. Dissolution studies using the USP paddlemethod were carried out in phosphate buffer pH 7.2 at 37 °Cfor both βCD and SBE7βCD complexes of rofecoxib.Solubility enhancement was much greater for the rofecoxib-SBE7βCDcomplex compared to drug-βCD complex. The stability constantobtained for the SBE7βCD inclusion complex of rofecoxib wasthe highest. Finally, dissolution profiles obtained suggest thatSBE7βCD is more effective than β-cyclodextrin inimproving the pharmaceutical properties of rofecoxib.     

Zaleplon co-ground complexes with natural and polymeric β-cyclodextrin

In this study, we compared the suitability of parent β-cyclodextrin (βCD) and its water soluble polymeric derivative (PβCD) as co-grinding additives aimed to enhance the solubility of zaleplon (ZAL), a hypnotic drug. Equimolar drug/carrier mixtures were co-ground in a high-energy micromill over different time intervals. Data obtained by differential scanning calorimetry, X-ray powder diffractometry and scanning electron microscopy showed a higher affinity of ZAL for the solid state interaction with PβCD, resulting in powders with lower relative drug crystallinity (RDC) compared to that obtained with natural βCD (RDC = 51.10 and 12.5 % for complexes with βCD and PβCD co-grounded for 90 min, respectively). On the other hand, grinding the drug alone did not result in a significant reduction of the drug crystallinity (RDC = 99.87 % for the sample ground for 90 min). Although ¹H-NMR spectroscopy confirmed that both co-ground products were readily converted into inclusion complexes upon dissolution in water, they presented different dissolution properties. The dissolution velocity of co-ground complex with PβCD was 25 % faster compared to that prepared with the parent βCD and almost double compared to that of the drug alone, irrespective of the pH value of the dissolution media. This clearly demonstrated the suitability of co-ground ZAL/PβCD complex in the development of an immediate release oral formulation of ZAL.     

Complexation of capsaicin with β-cyclodextrins to improve pesticide formulations: effect on aqueous solubility, dissolution rate, stability and soil adsorption

The binary systems of capsaicin (CP) and β-cyclodextrin (βCD) or hydroxypropyl-β-cyclodextrin (HPβCD) were investigated in an attempt to improve formulations of this pesticide. UV spectral shift methods indicated guest–host complex formation between CP and the two cyclodextrins (CDs). Phase solubility analysis showed B_s type diagrams with βCD, A_L type with HPβCD indicating the formation of an inclusion complex at 1:1 stoichiometric ratio in solution state. Solubility profiles indicated a 50-fold enhancement of CP solubility could be achieved in the presence of 60 mM HPβCD with respect to CP alone. Solid co-evaporated systems (CES) with 1:0.5–1:5 molar ratios of CP/CDs were physicochemically characterized, revealing that the true inclusion complexes could be formed in the solid CP/βCD systems with 1:5 molar ratio and in the solid CP/HPβCD systems with the molar ratios more than 1:3, respectively. In contrast, crystalline drug was detectable in all other systems. Compared with corresponding physical mixtures (PMs), the CES exhibited significant enhancement with regard to CP dissolution and the protection from CP degradation under the accelerated conditions. It was also revealed that complexation of CP with HPβCD had a pronounced improved effect on the pesticide formulations and greatly reduced the amount of CP adsorbed in the soil. These results demonstrate that HPβCD may be a preferred excipient, enabling more efficient and intelligent use of CP/CDs inclusion complexes in the development of pesticide formulations.     

Physical chemical characterization of binary systems of prilocaine hydrochloride with triacetyl-β-cyclodextrin

Interaction products of prilocaine hydrochloride (PRL), a local anesthetic agent highly soluble in water, with triacetyl-β-cyclodextrin (TAβCD), a hydrophobic CD derivative practically insoluble in water, were prepared to estimate their suitability for the development of a prolonged-release dosage form of the drug. Equimolar PRL-TAβCD solid systems were prepared by different methods (physical mixing, kneading, co-grinding, sealed-heating, coevaporation, spray-drying), in order to investigate their effectiveness and influence on the physical chemical properties of the end products. Differential scanning calorimetry, X-ray powder diffractometry, FTIR spectroscopy and environmental scanning electron microscopy (ESEM) were used for the solid-state characterization of the different PRL-TAβCD systems, whereas their in vitro dissolution properties were determined according to the dispersed amount method. On the basis of the overall solid-state studies results, the ability of the different methods to bring about effective drug-TAβCD interactions varied in the order: spray-drying > co-grinding ≈ coevaporation > sealed-heating > kneading > physical mixing. This rank order was not observed in dissolution studies, where coevaporated, kneaded and sealed-heated products exhibited very similar profiles, practically superimposable to that of pure drug and physical mixture, all reaching 100% dissolution in less than 10 min. Evidently, all these techniques gave rise only to weak surface interactions, rapidly destroyed in solution. Some decrease in dissolution rate was observed for co-ground system (100% dissolved drug after 40 min), probably due to electrostatic and aggregation phenomena associated with the high-energy mechanical treatment. A very different behaviour was shown by the spray-dried system, which give rise to an almost linear slow-dissolving profile, reaching 100% of dissolved drug after 420 min, suggesting in this case the formation of an actual inclusion compound. Thus, the drug-TAβCD product obtained by spray-drying was selected as the best candidate for the future development of a suitable prolonged-release oral dosage form of PRL.     

Complexation of ebastine with β-cyclodextrin derivatives

Complexation of ebastine (EB) with hydroxypropyl and methyl-β-cyclodextrin (HP-β-CD and Me-β-CD) was studied in aqueous solutions and in the solid state. The formation of inclusion complexes in aqueous solutions was analysed by the solubility method. The assays were designed using low CD concentrations compared with the solubility of these derivatives in order to avoid non-inclusion phenomena and to obtain a linear increase in EB solubility as a function of CD concentration. The values of complexation efficiency for HP-β-CD and Me-β-CD were 1.9 × 10^?2 and 2.1 × 10^?2, respectively. It seems that the non polar character of the methyl moiety slightly favoured complexation. In relation to solid state complexation, 1:1 EB:CD systems were prepared by kneading, and by heating a drug-CD mixture at 90 ºC. They were analysed using X ray diffraction analysis by comparison with their respective physical mixtures. A complex with a characteristic diffraction pattern similar to that of the channel structure of β-CD was formed with Me-β-CD in 1:1 melted and 1:2 EB:CD kneaded systems. Complexation with HP-β-CD was not clearly evidenced because only a slight reduction of drug crystallinity was detected. Finally, the loading of EB in two β-CD polymers cross-linked with epichlorohydrin yielded 7.3 and 7.7 mg of EB/g polymer respectively.     

Infrared Study of Solid Dispersions of β-Cyclodextrin with Naphthalene Derivitaves

The inclusion complexes of β-cyclodextrin (β-CD) with naphthalene and some of its derivatives in the solid state have been studied by infrared spectroscopy. Digital subtraction, deconvolution and curve fitting have been used to investigate the interactions between the naphthalene derivatives andβ-CD. Several preparation methods for the solid dispersions have been tested, using FTIR as an effective tool to evaluate the interactions at the molecular level. The effects of temperature and humidity on the spectra have been also analyzed. A carbonyl moiety in the guest molecule can increase the stability of the complex by establishing specific interactions with the hydroxyl groups of the CD cavity rims. The stability of the complexes is higher for 2-naphthylacetate than that for 1-naphthyl acetate, andso is the degree of association of its carbonyl groups. On the other hand, 2-acetylnaphthaleneforms very stable inclusioncomplexes although its carbonyl groups appear to be significantly less associated.     

Influence de la tension de vapeur sur une transition de phases et un equilibre peritectoide

The compound As₄Se₃ exhibits two polymorphs, α andβ. The latter undergoes a peritectoid decomposition. The two phenomena require a vapour pressure action. They are both explained on the basis of aT- V- x diagram. Two cases are described. In the first hypothesis, no solid solution exists. The second hypothesis implies two solid solutions for the two forms α andβ. A comparative study of these two cases has been made. The existence of two invariant planes has been shown in the second case, which makes it rather different from the first one.     

Cyclodextrin solubilization of celecoxib: solid and solution state characterization

The low aqueous solubility of celecoxib (CCB) hampers its oral bioavailability and permeation from aqueous environment through biological membranes. The aim of this study was to enhance the aqueous solubility of CCB by complexation with cyclodextrin (CD) in the presence of water-soluble polymer. The effects of different CDs (αCD, βCD, γCD, 2-hydroxypropyl-β-cyclodextrin and randomly methylated β-cyclodextrin (RMβCD)) and mucoadhesive, water-soluble polymers (hydroxypropyl methylcellulose (HPMC), chitosan and hyaluronic acid) were investigated. The phase solubility profiles and CCB/CD complex characteristics were determined. RMβCD exhibited the greatest solubilizing effect of the two CDs tested. However, γCD was also selected for further investigations due to its safety profile. Addition of polymer to the aqueous CD solutions enhanced the CD solubilization. Formation of CCB/RMβCD/HPMC and CCB/γCD/HPMC ternary complexes resulted in 11 and 19-fold enhancement in the apparent complexation efficiency in comparison to their CCB/CD binary complex, respectively. The size of ternary complex aggregates in solution were determined to be from about 250 to about 350 nm. The data obtained from Fourier transform infra-red, differential scanning calorimetry and powder X-ray diffraction indicated presence of CCB/CD inclusion complexes in the solid state. Proton nuclear magnetic resonance data demonstrated that CCB was partially and totally inserted into the hydrophobic central cavities of RMβCD and γCD.     

Physicochemical characterization of terbinafine-cyclodextrin complexes in solution and in the solid state

Terbinafine (TB) is an allylamine derivative used as oral and topical antifungal agent. The physicochemical properties of the complexes between TB and different cyclodextrins (CDs): α-CD, β-CD, hydroxypropylβ-CD, methylβ-CD and γ-CD, have been studied in pH 12 aqueous solutions at 25 °C and in the solid state. Different phase solubility profiles of TB in the presence of CDs have been obtained: A_L type for TB with hydroxypropylβ-CD and γ-CD, A_P type for the complexes with methylβ-CD and α-CD, while a B_S profile was found for TB-β-CD. The apparent stability constants of the complexes were calculated at 25 °C from the phase solubility diagrams. The higher increase of TB solubility, up to 200-fold, together with the higher value of the stability constant were found for the complex with methylβ-CD. Solid systems of 1:1 drug:CD molar ratio were prepared and characterised using X-ray diffraction patterns, thermal analysis and FTIR spectroscopy. The coevaporation method can be considered the best method in preparing these solid complexes. The complexes of TB with natural CDs, except with α-CD, were crystalline, whereas the methyl and hydroxypropyl derivatives gave rise to amorphous phases. Dissolution rate studies have been performed with TB-β-CD and TB-HPβ-CD complexes, showing a positive influence of complexation on the drug dissolution.     

An efficient and versatile solid-phase synthesis of 5'- and 3'-conjugated oligonucleotides

[reaction: see text] An easy and efficient solid-phase strategy to obtain 5'- and 3'-oligonucleotide conjugates in highly pure form has been developed. Ad hoc derivatized solid supports, to which the first nucleoside unit can be attached through a phosphate linkage, have been exploited both in a pre- and post-DNA assembly conjugation approach. A number of 5'- or 3'- oligonucleotide conjugates, incorporating a variety of labels covalently linked through a phosphodiester or a phosphoramidate bond, have been synthesized and characterized.     

Sorption of phenols by single and mixed cyclodextrin polymers

Cyclodextrin (CD) hydrogels were synthesized by a crosslinking reaction with the same cyclodextrin/epichlorohydrin mole ratio (1/11) using αCD, βCD, γCD, and 50:50 mixtures of α/βCD and β/γCD. In order to investigate the sorption capacity of these hydrogels to different solutes, five model molecules have been selected: phenol, 3-nitrophenol, 4-nitrophenol, 1-naphthol, and the antiinflamatory drug diflunisal. The amounts sorbed have been related to the different affinities of the solutes. 1-naphthol shows the highest affinity for these polymers, especially in the case of sorbents containing βCD. The sorption is considerably poorer for phenol than for its nitro derivatives. The two structural isomers 3- and 4-nitrophenol show significant differences in their affinities towards αCD, βCD and α/βCD. Finally, in the case of diflunisal, a bulkier model molecule, remarkable differences were found on the sorption behaviour by polymers whose cyclodextrins have a similar affinity for this solute (βCD, γCD, and β/γCD).     

Layered assemblies composed of sulfonated cyclodextrin and poly(allylamine)

Layered assemblies containing cyclodextrin (CD) have been prepared by layer-by-layer deposition of poly(allylamine) and sulfonated α-CD or β-CD on a solid surface. A quartz crystal microbalance study revealed that α-CD and β-CD form multilayers in the films upon each deposition. The sulfonated-α-CD-containing film bound methyl orange (MO) by forming an inclusion complex, resulting in the isolation of MO as a monomer in the film, whereas MO formed aggregates in the sulfonated-β-CD and CD-free films.     

Preparation of pilot library with tetrahydro-β-carboline alkaloid core skeleton using tandem intramolecular Pictet-Spengler cyclization

A solid phase strategy has been developed for the synthesis of tetrahydro-β-carboline alkaloid library. The key transformation is an acid-catalyzed tandem intramolecular Pictet-Spengler cyclization from l-tryptophan which forms acyl iminiums with synchronous cleavage of products from the acid-labile SASRIN™ solid support. A pilot library with two diversity points has been successfully synthesized in high purity to demonstrate this strategy.     

Synthesis and characterization of poly(ethylene glycol) based β-cyclodextrin polymers

A series of novel water soluble β-cyclodextrin (βCD) polymers has been synthesized from functionalized poly(ethylene glycol) (PEG). The chemical composition of the polymers has been characterized by ¹H NMR and the βCD content is found to be between 48 and 33% (w/w). The molecular weight has been determined by Size Exclusion Chromatography (SEC) and depends on the ratio between βCD and PEG, varying from 2.1 × 10⁴ to 8.6 × 10⁴ g mol^?1. The physico chemical properties have been characterized by differential scanning calorimetry (DSC), viscometry and isothermal titration calorimetry (ITC). ITC shows that the polymers have association constants comparable to βCD with different guest molecules, indicating a good accessibility of the CDs.     

Zn2+‐Complexation by a β‐Peptidic Helix and Hairpin Containing β3hCys and β3hHis Building Blocks: Evidence from CD Measurements. Preliminary Communication

Two new β³‐homohistidine‐ and β³‐homocysteine‐containing β‐peptides have been prepared by solid‐phase synthesis. A β‐octapeptide ( 2 ) contains seven β³‐amino acids and one β²‐amino acid. The β²/β³ segment has been placed in the middle of this peptide, which contains β³‐amino acids of alternating configuration, to induce the formation of a hairpin secondary structure. A β‐decapeptide ( 3 ) has been designed to fold to a 3₁₄‐helical secondary structure with neighboring His side chains in 6‐ and 9‐positions. Circular‐dichroism (CD) measurements show the capability of both peptides to bind Zn²⁺ ions in aqueous solution. In the case of the β‐octapeptide, binding of Zn²⁺ causes a dramatic change of the CD spectrum, indicating a change or a stabilization of its secondary structure. Zn²⁺ Ions clearly stabilize the 3₁₄‐helix of the β‐decapeptide, in neutral and basic solution. For the construction of the two new β‐peptides, we needed to have a supply of the β‐amino acid derivatives Fmoc‐β³hCys(Trt)‐OH and Fmoc‐β³hHis(Trt)‐OH, the preparation of which is described herein.     

Aβ40和hIAPP在溶液和表面的成核与交叉成核聚集行为

阿尔茨海默氏病(AD)和2型糖尿病(T2DM)是常见的由蛋白质错误折叠引起的疾病，作为与此二者相关的致病蛋白，淀粉样β蛋白(Aβ)和人胰岛淀粉样多肽(hIAPP)的交叉聚集行为暗示了AD和T2DM的相关性。然而，Aβ和hIAPP在体内的交叉聚集过程尚不明确。为了更好地模拟体内环境特征，即同时存在不同形式的淀粉样蛋白聚集体，且少量的聚集体附着在血管壁上会成为聚集过程的种子，本文以硫代黄素T荧光测定，原子力显微镜，圆二色光谱，石英晶体微天平以及MTT法作为研究手段，探究了Aβ和hIAPP在溶液和固体表面的成核与交叉成核聚集行为。结果表明，少量的Aβ40和hIAPP种子(单体浓度的1/50)即可显著改变异源聚集的聚集路径，形成具有不同形态且含有更多β-折叠结构的异源聚集体，导致更高的细胞毒性。溶液和固体表面上的结果均证明异源成核聚集效率低于同源聚集，且异源聚集的特征很大程度上取决于种子类型。此外，不同于溶液中所得结果，hIAPP种子在固体表面的交叉成核聚集效率显著高于Aβ40种子，证明了界面性质对交叉聚集过程的影响。这些结论对于理解淀粉样蛋白交叉聚集过程具有重要意义。     

Solid‐Phase Synthesis and Characterization of N‐Terminally Elongated Aβ−3–x‐Peptides

In addition to the prototypic amyloid‐β (Aβ) peptides Aβ_1–40 and Aβ_1–42, several Aβ variants differing in their amino and carboxy termini have been described. Synthetic availability of an Aβ variant is often the key to study its role under physiological or pathological conditions. Herein, we report a protocol for the efficient solid‐phase peptide synthesis of the N‐terminally elongated Aβ‐peptides Aβ_?3–38, Aβ_?3–40, and Aβ_?3–42. Biophysical characterization by NMR spectroscopy, CD spectroscopy, an aggregation assay, and electron microscopy revealed that all three peptides were prone to aggregation into amyloid fibrils. Immunoprecipitation, followed by mass spectrometry, indicated that Aβ_?3–38 and Aβ_?3–40 are generated by transfected cells even in the presence of a tripartite β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. The elongated Aβ peptides starting at Val(?3) can be separated from N‐terminally‐truncated Aβ forms by high‐resolution isoelectric‐focusing techniques, despite virtually identical isoelectric points. The synthetic Aβ variants and the methods presented here are providing tools to advance our understanding of the potential roles of N‐terminally elongated Aβ variants in Alzheimer's disease.     

Unusual inversion phenomenon of β-cyclodextrin dimers in water

A conformational analysis of three triazole-containing bridged bis-β- cyclodextrins (CD) has been carried out to evaluate their recognition ability. NMR spectroscopy and ITC measurements clearly demonstrate that one of the CD glucopyranose units undergoes a 360° rotation in water so that the spacer linking the two CDs is deeply included into one of the CD cavities. The amplitude of this inversion phenomenon depends on the nature of the spacer and results in a limited accessibility to the CD cavities in line with previous catalytic results.