Complex Formation of Hematoporphyrin with Cyclodextrins and 1,1′-Diheptyl-4,4′-bipyridinium Dibromide in Aqueous Solutions

At around 5×10^-6?mol?dm^-3 of hematoporphyrin (HP), an HP dimer exists as well as an HP monomer. The equilibrium constant for the dimerization of HP in pH 10.0 buffer has been evaluated to be 1.70×10⁵?mol^-1?dm³ from the HP concentration dependence of the absorption spectrum. In aqueous solution, HP forms 1:1 inclusion complexes with β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD). The fluorescence of HP is significantly enhanced by the addition of CDs. From simulations of the fluorescence intensity changes, the equilibrium constants for the formation of the CD–HP inclusion complexes have been estimated to be 200, 95.7, and 938?mol^-1?dm³ for β-CD, γ-CD, and TM-β-CD, respectively. HP forms a 1:1 complex with 1,1′-diheptyl-4,4′-bipyridinium dibromide (DHB) in aqueous solution. In contrast to the addition of CDs, the HP fluorescence is significantly quenched by the addition of DHB. The equilibrium constant for the formation of the HP–DHB complex has been evaluated to be 1.98×10⁵?mol^-1?dm³ from the fluorescence intensity change of HP. The addition of DHB to an HP solution containing β-CD induces a circular dichroism signal of negative sign, indicating the formation of a ternary inclusion complex involving β-CD, HP, and DHB. In contrast, there is no evidence for the formation of a ternary inclusion complex of HP with DHB and TM-β-CD.     

Inclusion complexes with cyclodextrin and usnic acid

Molecular inclusion complexes of usnic acid (UA) with β-cyclodextrin (β-CD) and 2-hydroxypropyl β-cyclodextrin (HP β-CD) were prepared by the co-precipitation method in the solid state in the molar ratio of 1:1. Structural complexes characterization was based on different methods, FTIR, ¹H NMR, XRD and DSC. Parallel to the complex by the above methods, corresponding physical mixtures of UA with cyclodextrins and complexing agents (β-CD, HP β-CD and UA) were analyzed. The results of DSC analysis showed that, at around 200 °C, the endothermal peak in the complexes with cyclodextrins originating from the UA melting has disappeared. Complex diffractogram patterns do not contain peaks characteristic for the pure UA. They are more appropriate to cyclodextrin diffractogram. This fact points to the molecular encapsulation of UA in the cyclodextrin cavity. Chemical shifts in ¹H NMR spectra after the inclusion of UA into the cyclodextrin cavity, especially H-3 protons (0.0012 and 0.0102 ppm in the β-CD and HP β-CD, respectively) and H-5 and H-6 (0.0134 ppm) and hydrogen from CH₃ (0.0073 ppm) HP β-CD also points to the formation of molecular inclusion complexes. The improved solubility of UA in water was achieved by molecular incapsulation. In the complex with β-CD the solubility is 0.3 mg/cm³, with HP β-CD 4.2 mg/cm³ while the uncomplexed UA solubility is 0.06 mg/cm³. The microbial activity of UA and both complexes was tested against eight bacteria and two fungi and during the test no reduced activity of UA in the complexes was observed.     

Evaluation the effect of cyclodextrin complexation on aqueous solubility of fluorometholone to achieve ophthalmic solution

In this study, the effect of different CDs including α-CD, β-CD, γ-CD, hydroxypropyl β-CD (HP β-CD), sulphobutylether β-CD (SBE β-CD) and HP γ-CD on aqueous solubility of fluorometholone (Flu) was investigated. Also the phase solubility studies were performed in the presence of eye drop excipients such as benzalkonium chloride, hydroxypropyl methylcellulose (HPMC) and buffers. The aqueous solubility of Flu was increased by 8, 15, 5, 100, 65 and 135 folds in the presence of 20% w/v α-CD, β-CD, γ-CD, HP β-CD, HP γ-CD and SBE β-CD, respectively. Aqueous solubility of Flu was 0.43 ± 0.08 and 1.16 ± 0.04 mg/mL in systems containing 5% w/v HP γ-CD and SBE β-CD, respectively. The aqueous solubility of Flu in the presence of HP γ-CD was not influenced by buffer type while the phosphate buffer caused a reduction in the aqueous solubility in the presence of SBE-β-CD. Also, investigations on the solubility of Flu in water in the presence of 5% HP γ-CD and SBE-β-CD and the additives such as benzalkonium chloride and HPMC indicated that these components had no remarkable effect on the aqueous solubility of Flu. In conclusion, CD complexation is able to improve the aqueous solubility of Flu and it would be possible to prepare ophthalmic solution of Flu by this method.     

Study on the complexation of isoquercitrin with β-cyclodextrin and its derivatives by spectroscopy

The inclusion complexes of isoquercitrin (IQ) with cyclodextrins (CDs) including β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD) and dimethyl-β-cyclodextrin (DM-β-CD) have been investigated using the methods of steady-state fluorescence, UV-vis absorption and induced circular dichroism. The stoichiometric ratio of the three complexes was found to be 1:1 and the stability constants (K) were estimated from spectrofluorometric titrations, as well as the thermodynamic parameters. Maximum inclusion ability was measured in the case of DM-β-CD due to the increased hydrophobicity of the host cavity, followed by HP-β-CD and β-CD. The effect of pH on the complexation process was also quantitatively assessed. IQ exists in different molecular forms depending on pH and β-CDs were most suitable for inclusion of the neutral form of IQ. The phase-solubility diagrams obtained with β-CD, HP-β-CD and DM-β-CD were all classical A_L type. And DM-β-CD provided the best solubility enhancement, 12.3-fold increase compared to 2.8- and 7.5-fold increase for β-CD and HP-β-CD. The apparent stability constants obtained from the solubility data at 25 °C were comparable with those obtained from the fluorescence assays. Moreover, ¹H NMR was carried out, which revealed that the IQ favorably inserted into the inner cavity from the chromone part instead of the phenyl part, which was in agreement with molecular modeling studies.     

十六烷基三甲基氯化铵在β-环糊精水溶液中的胶束化行为

通过测定十六烷基三甲基氯化铵（CTAC）+H_2O和CTAC+β-环糊精（β-CD） +H_2O体系在298.15K时的电导和密度，计算了一系列重要的热力学参数，如临界胶 束浓度、胶束离解主工、CTAC分子碳链从β-环糊精水溶液到胶束的转移自由能、 CTAC的标准偏摩尔体积以及CTAC和β-CD形成的包络物的计量比和包络常数等，结 果表明，β-CD对CTAC的胶束化有较显蓍的影响，由于CTAC的疏水碳链被β-CD空腔 包络，CTAC的热力学活度降低，削弱了其胶束的生成，但是，β-CD及其包络物基 本上不参与CTAC胶束的生成，而且一旦胶束形成，包络物对CTAC的胶束性质也没有 明显的影响，在简单模型的基础上不参与CTAC胶束的生成，而且一旦胶束形成，包 络对CTAC的胶束性质也没有明显的影响，在简单模型的基础上，计算了CTAC分子碳 链进入β-CD疏水空腔的CH_2基团的数目，从另一方面证明β-CD与CTAC分子形成了 包络物，当β-CD的浓度较高时，包络物的计量比为2∶1。     

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.     

Preparation and Spectroscopic Study of Different Stoichiometric Solid Supramolecular Inclusion Complexes of β-Cyclodextrin with Short Chain Aliphatic Amines

The solid Supramolecular complexes of β-cyclodextrin (β-CD) with ethylenediamine 1, diethylenetriamine 2 and triethylamine 3 were obtained and characterized using elemental analysis, powder X-ray diffraction, infrared spectroscopy, thermogravimetric analysis, and 1H nuclear magnetic resonance spectroscopy. Based on the results of elemental analysis and 1H NMR, the guest-host stoichiometries of the three solid complexes were determined to be 5:2 for 1-β-CD, 1:1 for 2-β-CD, and 1:3 for 3-β-CD. The yields were relative to the molar volume ratio of guest toβ-CD cavity, and increased in the order: 1-β-CD<2-β-CD<3-β-CD. X-ray diffraction patterns of the inclusion complexes gave very good exhibitions not only in location of diffraction peaks but also in shape and diffraction intensity of the peaks due to the intermolecular complexations betweenβ-CD and the guests. The formation of host-guest inclusion complexes exhibited obviously enhanced phase change temperatures of the complexed guests such as 1 and 3. The H-5 protons located at the narrower rim inside the CD cavity experienced a higher shift upon inclusion while all other protons experienced lower shifts.     

Preparation, characterization and pharmacodynamic activity of supramolecular and colloidal systems of rosuvastatin–cyclodextrin complexes

In the present study influence of nature of selected cyclodextrins (CDs) and of methods of preparation of drug–CD complexes on the oral bioavailability, in vitro dissolution studies and pharmacodynamic activity of a sparingly water soluble drug rosuvastatin (RVS) was investigated. Phase solubility studies were conducted to find the interaction of RVS with β-CD and its derivatives, which indicated the formation of 1:1 stoichiometric inclusion complex. The apparent stability constant (K_1:1) calculated from phase solubility diagram were in the rank order of β-CD < hydroxypropyl-β-cyclodextrin (HP-β-CD) < randomly methylated-β-cyclodextrin (RM-β-CD). Equimolar drug–CD solid complexes prepared by different methods were characterized by the Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). FTIR study demonstrated the presence of intermolecular hydrogen bonds and ordering of the molecule between RVS and CDs in inclusion complexes. DSC and XRD analysis confirmed formation of inclusion complex by freeze dried method with HP-β-CD and RM-β-CD. Aqueous solubility and dissolution studies indicated improved dissolution rates of prepared complexes in comparison with drug alone. Moreover, CD complexes demonstrated of significant improvement in reducing total cholesterol and triglycerides levels as compared to pure drug. However the in vivo results only partially agreed with those obtained from phase solubility studies.     

Thermodynamic and geometric study of diasteroisomeric complexes formed by racemic flavanones and three cyclodextrins through NMR

The main purpose of this work was to study the chiral recognition thermodynamics of inclusion complexes formed by flavanones and β-cyclodextrins, and its relation with the inclusion geometries, through NMR experiments. By using the racemic mixtures of (±)-flavanone (FL) and (±)-2′-hydroxyflavanone (2′OHFL), diasteroisomeric complexes were formed employing β-cyclodextrin (βCD), (2-hydroxypropil)-β-cyclodextrin (HPβCD) and heptakis-(2,6-O-dimethyl)-β-cyclodextrin (DMβCD). ¹H NMR experiments of the complexes showed enantiodifferentiation for FL/βCD, FL/HPβCD, FL/DMβCD, 2′OHFL/HPβCD and 2′OHFL/DMβCD complexes, so they were able to be studied by obtaining the stoichiometry (1:1 for each complex), association constants (Ka), Ka ratios, and thermodynamics (ΔH, ΔS and ΔG). The results show that Ka values decrease with increasing temperature and that Ka ratio values removed from 1 not always reflect better enantiodiscrimination by NMR. Thermodynamics (ΔH and ΔG) show an exothermic and spontaneous formation of the complexes. Since the results were established for each couple of diasteroisomeric complexes separately, comparison of thermodynamics between them was possible, concluding that one half of the couples of diasteroisomeric complexes present chiral recognition due to enthalpic phenomena and the other half due to entropic phenomena. Additionally, ROESY experiments were performed to estimate the inclusion geometry of the complexes, which are in good agreement with the thermodynamic and Ka results.     

Cyclodextrin complexation improves aqueous solubility of the antiepileptic drug,rufinamide: solution and solid state characterization of compound-cyclodextrin binary systems

Rufinamide (RUF) was characterized in terms of cyclodextrin (CD) complexation in order to improve its aqueous solubility. Binary systems of RUF with three CDs—β-cyclodextrin (β-CD), randomly methylated-β-cyclodextrin (RAMEB) and sulfobutylether-β-cyclodextrin (SBE-β-CD)—were characterized with a wide variety of analytical techniques. Liquid state characterization was carried out by complementary techniques such as nuclear magnetic resonance spectroscopy (NMR), capillary electrophoresis (CE), mass spectrometry (MS) and phase solubility studies. The latter revealed that the stability of the complexes decreased in the order of RAMEB?>?β-CD?>?SBE-β-CD. A_L-type diagrams were obtained in all cases, characteristic of 1:1 stoichiometry, with a maximum of over 15-fold increase in RUF solubility, when complexed with RAMEB. NMR Job plot and MS studies confirmed phase solubility results, regarding the binding stoichiometry. ¹H NMR and 2D ROESY investigations revealed the inclusion of the triazole moiety of RUF, confirmed by molecular modeling. Solid state complexation in 1:1 molar ratio was carried out by kneading method and investigated by differential scanning calorimetry (DSC) and infrared spectroscopy (IR). Comparative dissolution studies indicated an over two-fold improvement in dissolution efficacy of the kneaded products, when compared to the pure drug. Results of the present study might pave the way for a drug formulation with improved bioavailability.     

Inclusion complexation of 4,4′-dihydroxybenzophenone and 4-hydroxybenzophenone with α- and β-cyclodextrins

The inclusion complexation behaviours of 4,4′-dihydroxybenzophenone (DHBP) and 4-hydroxybenzophenone (HBP) with α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD) were investigated using UV–visible fluorescence, time-resolved fluorescence, molecular modelling, scanning electron microscopy (SEM), FTIR, differential scanning calorimeter, X-ray diffraction, ¹H NMR and molecular modelling techniques. In both molecules, biexponential decay was observed in water, whereas triexponential decay was observed in the CD medium. The DSC thermogram of the DHBP/α-CD and DHBP/β-CD inclusion complex nanomaterials shows the endothermic peak at 60.8, 101.9, 119.6 and 112.8°C. The upfield chemical shift observed for HBP protons reveal that the phenyl ring (without hydroxyl substitution) entered the CD cavity and the hydroxyl group of HBP is exposed outside the CD cavity. The SEM image of DHBP appears as needle-shaped crystals on the micrometre scale, whereas the irregular bar shape was observed for HBP. Transmission electron microscopy images show that both guest molecules formed nano vesicles with α-CD and formed nano rods with β-CD.     

Inclusion Complex of β-cyclodextrin with CTAB in Aqueous Solution

Cetyltrimethylammonium bromide (CTAB)/potassium bromide (KBr) micellar system has been used as a viscosity probe to study the inclusion complexation between β-cyclodextrin (β-CD) and CTAB. Viscosity measurements show that the inclusion complexation between β-CD and CTAB may cause the breakdown of CTAB/KBr wormlike micelles, resulting in the decrease of the solution viscosity. The viscosity minimum at C_β-CD/C_CTAB=2 indicate the molecular ratio of host molecule to guest molecule is 2:1 in the β-CD/CTAB inclusion complex.     

Inclusion complexation of chloropropham with β-cyclodextrin: preparation, characterization and molecular modeling

An inclusion complex between the agrochemical chloropropham (CIPC) and β-cyclodextrin (β-CD) was prepared. A 2:1 host-guest stoichiometry was conformed by elemental analysis. From the phase solubility studies, the calculated stepwise stability constants were K(1)=224.6L/mol and K(2)=939.2L/mol, respectively. FT-IR, thermoanalysis and (1)H NMR spectra were applied to characterize the complex. It was speculated that the inclusion mode was two β-CD cavities included the chlorophenyl and the isopropyl moiety of one CIPC molecule, which was in agreement with the most predominant configuration optimized by molecular modeling. By complexation with β-CD, the water solubility and the thermal stability of CIPC were prominently improved.     

Inclusions of methylene blue and phenothiazine by β-cyclodextrin in sodium dodecyl sulfate micelles

The inclusions of methylene blue and phenothiazine by β-cyclodextrin (β-CD) in sodium dodecyl sulfate (SDS) micelles and SDS/n-C₅H₁₁OH mixed micelles are studied by fluorescence spectroscopy. β-CD molecules can include monomers of methylene blue only after they have included SDS at a ratio of 1:1. However, phenothiazine can be included in the β-CD cavities even with β-CD concentrations lower than the total SDS concentration in SDS micelles, but not for solutions with SDS/n-C₅H₁₁OH mixed micelles.     

Theoretical and experimental study of the inclusion complexes of ferulic acid with cyclodextrins

The inclusion complexation behaviour of ferulic acid (FA) with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated by UV–vis, fluorescence and ¹H NMR spectroscopy. Since the guest may exist in either anionic or neutral form, the experiments were performed at different pH values. The stoichiometry and association constants of the complexes were determined by nonlinear regression analysis. The phase-solubility studies indicated that the water solubility of FA was improved through complexation with β-CD and HP-β-CD. An increase in the antioxidant reactivity was observed when inclusion complexes that FA formed with CDs were studied. Based on the NMR data, the spatial configurations of FA/β-CD and FA/HP-β-CD complexes were proposed, which suggested that FA entered into the cavity of β-CD from the narrow side, with the lipophilic aromatic ring and ethylenic moieties inside the CD cavity, and the –COOH group was close to the wider rim and exposed outside the cavity. A theoretical study of the complexes using molecular modelling gives the results in good agreement with the NMR data.     

Spectroscopic study and antioxidant properties of the inclusion complexes of rosmarinic acid with natural and derivative cyclodextrins

Measurement of total antioxidant activity/capacity of polyphenols in various solvent media necessitates the use of cyclodextrins to solubilize lipophilic antioxidants of poor aqueous solubility. The inclusion complexes of the slightly water soluble antioxidant, rosmarinic acid (RA), with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), 2-hydroxyethyl-β-cyclodextrin (HE-β-CD), and methyl-β-cyclodextrin (M-β-CD) were investigated for the first time. The effect of cyclodextrins (CDs) on the spectral features of RA was measured in aqueous medium using UV-vis and steady-state fluorescence techniques by varying the concentrations of CDs. The molar stoichiometry of RA-CD inclusion complexes was verified as 1:1, and the formation constants of the complexes were determined from Benesi-Hildebrand equation using fluorescence spectroscopic data. Among the CDs, maximum inclusion ability was measured in the case of M-β-CD followed by HP-β-CD, HE-β-CD, β-CD and α-CD. Solid inclusion complexes were prepared by freeze drying, and their functional groups were analyzed by IR spectroscopy. Antioxidant capacity of CD-complexed rosmarinic acid was measured to be higher than that of the lone hydroxycinnamic acid by the CUPric Reducing Antioxidant Capacity (CUPRAC) method. The mechanism of the TAC increase was interpreted as the stabilization of the 1-e oxidized o-catechol moiety of RA by enhanced intramolecular H-bonding in a hydrophobic environment provided by CDs, mostly by M-β-CD.     

虫草素与羟丙基-β-环糊精的包合行为及性能研究

通过饱和溶液方法制备了虫草素(COR)与羟丙基-β-环糊精(HPβCD)形成的包合物.采用紫外-可见光谱法对水溶液中HPβCD与虫草素(COR)的包合行为进行研究,利用Job曲线法确定COR/HPβCD包合物的包合比,通过1 H NMR和2D NMR、DSC、TG、XRD、FTIR和SEM对COR/HPβCD包合物进行表征和性能测定.结果表明,COR/HPβCD包合物的包合比为1:1,虫草素与HPβCD形成包合物后,其水溶性、热稳定性及生物环境稳定性都得到明显提高.COR/HPβCD包合物在医药领域具有潜在的应用前景.     

Macroscopic observations of molecular recognition: discrimination of the substituted position on the naphthyl group by polyacrylamide gel modified with β-cyclodextrin

Macroscopic molecular recognition observations were realized using polyacrylamide-based gels modified with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), 1-naphthylmethyl (1Np), and 2-naphthylmethyl (2Np) moieties, which are denoted as αCD(x)-gel, βCD(x)-gel, 1Np(y)-gel, and 2Np(y)-gel, where x and y indicate the mol % of CD and Np moieties, respectively. The αCD(5)-gel did not adhere to either the 1Np(5)-gel or 2Np(5)-gel, whereas the βCD(5)-gel interacted with both to form alternating or checkered assemblies. Although the difference in the association constants of β-CD for the model polymers was small, the βCD(x)-gel successfully discriminated between 1Np(y)-gel and 2Np(y)-gel at the appropriate x and y.     

Pharmacology and structures of the free base of the anaesthetic kazcaine and its complex with β-cyclodextrin

The base form of the local anaesthetic kazcaine (BFK, [1-(2-ethoxyethyl)-4-ethynyl-4-benzoyloxypiperidine, C₁₈H₂₃NO₃]) and β-cyclodextrin (β-CD) co-crystallized as BFK:β-CD inclusion complex in 1:2 M ratio from a mixture of water and ethanol while the filtered mother liquor yielded crystals of free BFK. X-ray diffraction showed that the crystals of BFK and its inclusion complex with β-CD belong to monoclinic (P2₁/c) and triclinic (P1) space groups, respectively. The crystals of free BFK are stabilized by pairs of C–H?O, C–H?π and ≡C–H?O type interactions and van der Waals contacts. In the 1:2 BFK:β-CD complex the two β-CD molecules are in hydrogen-bonding contact with their primary hydroxyl groups, the 1-(2-ethoxyethyl)-4-ethynyl-piperidine moiety being located in one and the benzoyloxy group of BFK in the other β-CD. This crystal structure is of the channel-type, the β-CD molecules of the 1:2 BFK:β-CD complex interacting with their secondary hydroxyl groups. The pharmacological activities of the 1:2 BFK/β-CD inclusion complex have been determined in mice, rats, porpoises and rabbits and compare favourably with those of kazcaine, procaine, dicaine, lidocaine and trimecaine. The methods used include terminal (superficial), infiltration, conduction anaesthesia, and acute toxicity.