Complexation of nevirapine with β-cyclodextrins in the presence and absence of Tween 80: characterization,thermodynamic parameters,and permeability flux

The work is undertaken to evaluate the effect of Tween 80 on the complexing ability of β-cyclodextrins to encapsulate the poorly soluble antiretroviral agent, nevirapine. The phase solubility diagram indicates 1:1 stoichiometry and is supported by electronspray ionization mass spectrometry. The complexes were characterized by DSC, FT-IR, and XRD in the solid state. The ternary systems were autoclaved before being lyophilized for the best results. Proton NMR suggests that the methyl pyridine ring of the drug is involved in inclusion and enters from the wider side of the cavity which was confirmed by COESY NMR. Solution calorimetry, a direct method to determine the thermodynamic parameters, was used to determine the complexation constant (K) and other thermodynamic properties. The process is associated with negative ∆H and positive ∆S indicating a stable inclusion complex. The value of K follows the order β-CD < HP-β-CD < M-β-CD. The molar enthalpy of solution in autoclaved solid formulation is less endothermic as compared to additive molar enthalpy of solution obtained by summation of enthalpy of solution of individual components suggesting synergistic interaction between the drug and its constituents. A threefold increase of the in vitro permeability flux was observed for binary systems which was elevated to fourfold for autoclaved ternary complexes.     

Preparation and evaluation of binary and ternary inclusion complexes of fenofibrate/hydroxypropyl-β-cyclodextrin

This study aimed to investigate the effect of hydroxypropyl methylcellulose on the complexation of fenofibrate and hydroxypropyl-β-cyclodextrin (HP-β-CD). Initially, phase solubility studies with an excess amount of drug in the HP-β-CD solutions with and without hydroxypropyl methylcellulose (HPMC) were investigated. Both of the binary and ternary complexes were prepared by ball-milling. The complexes were characterized by Fourier transform infrared spectroscopy (FI-IR), X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and nuclear magnetic resonance spectroscopy (¹H-NMR). The A_L type phase-solubility diagram revealed that the complexes of fenofibrate and HP-β-CD were formed with molecular ratio of 1:1. The results of FT-IR, XPRD, DSC and ¹H NMR analysis show the formulation of inclusion complexes. In conclusion, the interaction occurrs between fenofibrate and HP-β-CD in the complexes, and the existence of HPMC effectively improves the complexation efficiency and stability constant. The in vitro dissolution test suggests ternary complex is superior to binary complex in terms of the release of fenofibrate.     

Binary and ternary inclusion complexes of dapsone in cyclodextrins and polymers: preparation, characterization and evaluation

Dapsone (DAP) is a synthetic sulfone drug with bacteriostatic activity, mainly against Mycobacterium leprae. In this study we have investigated the interactions of DAP with cyclodextrins, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and β-cyclodextrin (βCD), in the presence and absence of water-soluble polymers, in order to improve its solubility and bioavailability. Solid systems DAP/HPβCD and DAP/βCD, in the presence or absence of polyvinylpyrrolidone (PVP K30) or hydroxypropyl methylcellulose (HPMC), were prepared. The binary and ternary systems were evaluated and characterized by SEM, DSC, XRD and NMR analysis as well as phase solubility assays, in order to investigate the interactions between DAP and the excipients in aqueous solution. This study revealed that inclusion complexes of DAP and cyclodextrins (HPβCD and βCD) can be produced in order to improve DAP solubility and bioavailability in the presence or absence of polymers (PVP K30 and HPMC). The more stable inclusion complex was obtained with HPβCD, and consequently HPβCD was more efficient in improving DAP solubility than βCD, and the addition of polymers had no influence on DAP solubility or on the stability of the DAP/CDs complexes.     

Study of benznidazole–cyclodextrin inclusion complexes, cytotoxicity and trypanocidal activity

The current chemotherapy for Chagas disease is still based on benznidazole, which has low solubility, but complexation with cyclodextrins provides a way of increasing the solubility. The objective of this work was to characterize the inclusion complexes formed between benznidazole (BNZ) and randomly 2-methyled-β-cyclodextrin (RM-β-CD) in aqueous solution and study cytotoxicity and trypanocidal. BNZ:RM-β-CD solution complex systems were prepared and characterized using the phase solubility diagram, nuclear magnetic resonance and a photostability assays, also to investigate the in vitro trypanocidal activity with epimastigote forms of Trypanossoma cruzi and the study of cytotoxicity against mammal cells. The phase-solubility diagram displayed an A _L-type feature, providing evidence of the formation of soluble inclusion complexes. The continuous variation method showed the existence of a complex with 1:1 stoichiometry. Toxicity assays demonstrated that inclusion complexes were able to reduce the toxic effects caused by benznidazole alone and that this did not interfere with the trypanocidal activity of the benznidazole. The use of inclusion complexes benznidazole:cyclodextrin is thus a promising alternative for the development of a safe and stable liquid formulation and a new option for the treatment of Chagas disease.     

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.     

相溶解度法研究不同环糊精对丹皮酚的增溶作用

采用相溶解度法,通过测定丹皮酚在不同温度不同浓度的β-环糊精(β-CD)、羟丙基-β-环糊精(HP-β-CD)、羟乙基-β-环糊精(HE-β-CD)、取代度为4的磺丁基醚-β-环糊精(SBE4-β-CD)以及取代度为7的磺丁基醚-β-环糊精(SBE7-β-CD)中的溶解度,绘制相溶解度曲线,丹皮酚的溶解度均随5种环糊精浓度的增加而成线性增加,相溶解度曲线为AL型,说明丹皮酚与环糊精以1∶1包合,实验结果表明,5种环糊精对丹皮酚均有增溶作用且SBE7-β-CD的增溶效果最佳.     

The effect of cyclodextrin mixtures on aqueous solubility of beclomethasone dipropionate

The aim of present study was to evaluate the effect of natural, synthetic cyclodextrins (CDs) and CD mixtures on aqueous solubility of beclomethasone dipropionate (BDP). The phase solubility studies were done in the presence of 6 CDs. Furthermore, aqueous solubility of BDP was tested in the presence of CD mixtures. The solubility of BDP in water was increased by 30, 77, 155 and 30 folds in the solution containing 20%?w/v α-CD, hydroxylpropyl β-CD (HP-β-CD), hydroxypropyl γ-CD (HP-γ-CD) and sulphobutylether β-CD (SBE-β-CD), respectively. CD mixtures had remarkable effect on the aqueous solubility of BDP so that solubility in water increased between 200 and 1,500 times in the presence of different CD mixtures. Further addition of sodium acetate to the solubilisation medium reduced the aqueous solubility. In conclusion, CD complexation was able to improve the aqueous solubility of BDP. The synergistic effect of cyclodextrin mixture was observed.     

Enrofloxacin inclusion complexes with cyclodextrins

Inclusion complexes using α-, β-, γ-, and hydroxypropyl-β-CD (HP-β-CD) were produced with the antibiotic enrofloxacin, with the aim of increasing its solubility by complexation. Phase solubility diagrams were obtained, to confirm the formation of inclusion complexes, and to determine the solubility enhancement and stability constant of each complex. Enrofloxacin inclusion in β-CD showed the highest value of the complex stability constant (35.56?mmol?L^?1), but the greatest increase in solubility was obtained using HP-β-CD reaching a 1258% increase over enrofloxacin solubility in the absence of CD. The order of highest enrofloxacin solubility achieved was: HP-β-CD?>?α-CD?>?γ-CD?>?β-CD. In addition, formation of complexes was confirmed by differential scanning calorimetry and thermogravimetry, applied to the complexes obtained by the kneading technique. The influence of citric acid, alone or as an adjunct of β-CD, on the solubility of enrofloxacin was also determined. A solution of 15?mmol?L^?1 citric acid dissolved 10?g?L^?1 of enrofloxacin, but a gradual increase in β-CD concentration in the presence of citric acid did not increase the degree of solubilization of enrofloxacin.     

Inclusion complexes of dihydroartemisinin with cyclodextrin and its derivatives: characterization,solubilization and inclusion mode

The characterization, inclusion complexation behavior and binding ability of the inclusion complexes of dihydroartemisinin with β-cyclodextrin and its derivatives, sulfobutyl ether β-cyclodextrin (SBE-β-CD), mono[6-(2-aminoethylamino)-6-deoxy]-β-cyclodextrin (en-β-CD) and mono{6-[2-(2-aminoethylamino)ethylamino]-6-deoxy}-β-cyclodextrin (dien-β-CD), were studied using phenolphthalein as a spectral probe. Spectral titration was performed in aqueous buffer solution (pH ca. 10.5) at 25 °C to determine the binding constants. The inclusion complexation behaviors were investigated in both solution and solid state by means of NMR, TG, XRD. The results showed that the water solubility and thermal stability of dihydroartemisinin were significantly increased in the inclusion complex with cyclodextrins (CDs). According to ¹H NMR and 2D NMR spectroscopy (ROESY), the A, B rings of dihydroartemisinin can be included into the cavity of CDs. The enhanced binding ability of CDs towards dihydroartemisinin was discussed from the viewpoint of the size/shape-fit concept and multiple recognition mechanism between host and guest.     

The role of maltosyl residue of maltosyl-β-cyclodextrin in the inclusion with dehydrocholic acid

Maltose substituted β-cyclodextrin (M-β-CD) is an important drug carrier due to its excellent water solubility and good compatibility. In this work, dehydrocholic acid (DHA) was taken as the model drug; the inclusion of M-β-CD/DHA was studied through molecular dynamics simulations. The effect of the maltosyl residue of M-β-CD on the interactions of M-β-CD with DHA, M-β-CD with water, and DHA with water were analyzed. Based on the results, the difference between the complex of M-β-CD/DHA and that of β-CD/DHA can be explained and understood.     

Thermodynamic study of inclusion complexes of zaleplon with natural and modified cyclodextrins

The thermodynamics and stoichiometry of zaleplon (ZAL) complexation with different cyclodextrin derivatives [β-CD, hydroxypropyl-β-cyclodextrin (HP-β-CD), randomly methylated-β-cyclodextrin (RAMEB), sulphobutylether-β-cyclodextrin (SBE-β-CD)] in aqueous solution was studied by spectrofluorimetry and ¹H NMR spectroscopy in order to obtain a more general understanding of the driving forces behind the inclusion phenomena. Job’s plot derived from the NMR spectral data and statistical analysis of spectrofluorimetric titration data confirmed the formation of equimolar complexes in all systems tested, excluding the possibility of higher order complex formation. Furthermore, thermodynamic parameters obtained by both techniques gave similar and negative values of ΔG° for all complexes, indicating spontaneous inclusion of drug into CDs. From a thermodynamic point of view, two types of inclusions were determined. One is enthalpy driven ZAL complexation with β-CD, HP-β-CD and RAMEB, while the other is entropy driven complexation observed in the case of SBE-β-CD. The mechanisms behind each type of inclusion were discussed in detail.     

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.     

Interaction between hydrophilic drug and α-cyclodextrins: physico-chemical aspects

The aim of the study was to evaluate if the complexation of a hydrophilic molecule by cyclodextrins is possible. Cyclodextrins (CDs) are hydrophilic cone shaped molecules, which are used as vehicles able to include organic molecules. Because of the presence of hydroxy groups (OH) outside of the molecule, cyclodextrins are not predisposed to include hydrophilic drugs. They are therefore used to improve the solubility of poor water-soluble molecules. In order to evaluate if the complexation of a hydrophilic molecule by cyclodextrins is possible, lyophilized complexes of cysteamine hydrochloride with α-cyclodextrins (α-CD) have been realized. Six analytical techniques (High performance Liquid Chromatography coupled to UV detection, Thin-Layer Chromatography, Fourier Transform Infrared spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Mass Spectrometry (SM) and Proton Nuclear Magnetic Resonance (NMR-NOESY spectra)) were used in order to characterize the interaction between the drug and the α-CD. The realization of complex between a cyclodextrin and a water-soluble drug seems feasible. In the case of a hydrophilic molecule, the complexation is not obtained by inclusion of the drug in the cyclodextrin, but by binding to the outside of the cone. This “external complexation” is however sufficient to improve some features of the molecule, such as organoleptic features, and to modifiy measurable parameters (FT-IR, DSC, SM and NMR-NOESY spectra).     

Naproxen: Hydroxypropyl-β-Cyclodextrin:Polyvinylpyrrolidone Ternary Complex Formation

The aim of the present study was to investigate the effect of the presence of thewater-soluble polymer polyvinylpyrrolidone (PVP) MW = 24000 g/mol, on thecomplexation of the phototoxic anti-inflammatory drug naproxen, in its sodiumsalt form, with hydroxypropil-β-cyclodextrin (HP-β-CD). The datashown that the polymer interacts with the free naproxen and with thenaproxen:HP-β-CD inclusion complex. The presence of different proportions of PVP, in the 0–1%(w/w) rangesystematically increased the K_app of the naproxen:HP-β-CD inclusioncomplex formation. The cause of this increase is that the polymer interactswith the HP-β-CD with a binding constant of K₂ = 29000 ± 53 M^-1; and with the naproxen:HP-β-CD inclusion complex, to givea ternary complex naproxen:HP-β-CD:PVP. The binding constant of thisprocess was K₃ = 5350 ± 1 M^-1. NMR data revealed that in the ternary system, PVP is outside of the cyclodextrin, and therefore must be wholly or partially recovering the naproxen:HP-β-CD inclusion complex.     

Preparation and characterization of hydroxypropyl-β-cyclodextrin inclusion complex of eugenol: differential pulse voltammetry and (1)H-NMR

The objective of present investigation was to improve the solubility of Eugenol by preparing the inclusion complex of Eugenol with hydroxypropyl-β-cyclodextrin (Hp-β-CD) and characterize the prepared complex by using NMR and differential pulse voltammetry (DPV). Phase solubility curve was plotted using Hp-β-CD in ranging from 0-40 mM of Hp-β-CD and found to be linear. Therefore, inclusion complex was prepared in equimolar ratio of Eugenol and Hp-β-CD by lyophilization method. Fourier transform infrared spectroscopy (FT-IR), (1)H-NMR and DPV were performed for Eugenol, Hp-β-CD and prepared inclusion complex of Eugenol. 2D (two dimensional) NMR was also performed for prepared inclusion complex. The proton of phenol moiety of Eugenol experienced a pronounced chemical shift variation in (1)H-NMR. The positive sign of the variation for proton in (1)H-NMR indicated that the proton was located near to an oxygen atom in the Hp-β-CD cavity and its magnitude showed a strong interaction between -OH proton of Eugenol and Hp-β-CD. 2D NMR confirms the interaction between phenolic group and hydrogen atoms of Hp-β-CD. A well defined anodic peak current corresponding to oxidation of Eugenol in non-encapsulated and Hp-β-CD-Eugenol inclusion complex in phosphate buffer (pH 6.8) was obtained at about 0.35 V and 0.40 V, respectively. The positive shift in oxidation potential indicated the formation of complex via hydrophobic interactions. The oxidant power of Eugenol was retained in complex form as indicated by DPV results. Thus, its oxidation dependent pharmacological property such as antimicrobial activity is not affected after complexation with Hp-β-CD. Thus, (1)H-NMR, 2D-NMR and DPV techniques can be used as valuable tools to determine the mechanism of complexation and state of electrochemical active drug in inclusion complex.     

Effect of hydroxypropyl-β-cyclodextrin complexation on the aqueous solubility, structure, thermal stability, antioxidant activity, and tyrosinase inhibition of paeonol

The objective of this paper is to study the effect of hydroxypropyl-β-cyclodextrin (HP-β-CD) complexation on the aqueous solubility, structure, thermal stability, antioxidant activity, and tyrosinase inhibition of paeonol (PAE). The inclusion complex (PAE-HP-β-CD complex) of HP-β-CD and PAE was prepared by a freeze-drying method. Phase solubility tests showed that the stability constant of the inclusion complex was about 33.8?M^?1 at 25?°C. The experimental results of proton nuclear magnetic resonance (H-NMR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) suggested that PAE was included by HP-β-CD to form the PAE-HP-β-CD complex. Furthermore, the thermogravimetric analysis (TGA) results showed that the thermal stability of PAE was improved when it was complexed with HP-β-CD. Comparing the antioxidant activity of PAE with that of the PAE-HP-β-CD complex at the same concentration revealed that the complex of PAE with HP-β-CD was better able to eliminate radical. Furthermore, the experimental results revealed that the formation of a complex with HP-β-CD increased the water solubility of PAE, improving its apparent inhibitive activity of tyrosinase.     

Effects of inclusion of cetirizine hydrochloride in β-cyclodextrin

Following the preparation of inclusion complex of cetirizine (CTZ) and β-cyclodextrin (β-CD), the compound was investigated to assess the possibility of modifying the physicochemical properties (solubility, release, stability, permeability) of CTZ after complexation that are vital for subsequent formulation studies involving the said complex. Changes in FT-IR/Raman spectra, DSC thermograms and XRD diffractograms confirmed the formation of a CTZ–β-CD system. Hydrophilic interaction chromatography with a DAD detector was employed to determine alterations of the CTZ concentration during studies following complexation. An analysis of a phase-solubility diagram of c_CTZ?=?fc_β-CD indicated a linear rise in the solubility of CTZ as the concentration of β-CD increased. The inclusion of CTZ in a system with β-CD significantly reduced the instability of CTZ in the presence of oxidizing factors. It was also found that regardless of the pH of the acceptor fluids used in the release studies an increase was observed in the concentration of CTZ in CD system compared to its free form. The ability to permeate artificial biological membranes manifested by CTZ after complexation was enhanced as well. In summary, CD has significant potential to mask the bitter taste of CTZ and to counter the instability induced by oxidizing factors.     

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 interaction of chloramphenicol and heptakis (2,6-di-O-methyl)-β-cyclodextrin: phase solubility and spectroscopic methods

The inclusion interaction between chloramphenicol and heptakis (2,6-di-O-methyl)-β-cyclodextrin (DMBCD) had been investigated by phase solubility and spectroscopic methods such as UV-vis spectroscopy, circular dichroism, Fourier transform infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance spectroscopy ((1)H NMR) as well as 2D-ROESY spectra. Phase solubility analysis showed A(L)-type diagram with DMBCD, which suggested the formation of 1:1 inclusion complex of DMBCD with chloramphenicol. The estimated stability constant (K(s)) of the inclusion complex of chloramphenicol with DMBCD is 493 M(-1) at 293 K. The solubility enhancement of chloramphenicol in the presence of DMBCD is stronger than that in the presence of β-CD, HP-β-CD and M-β-CD. The results obtained by spectroscopic methods showed that the nitrophenyl moiety of chloramphenicol is deeply inserted into inner cavity of DMBCD from the narrow rim of DMBCD, which the inclusion model of chloramphenicol with DMBCD differs from that with β-CD.