Effect of β-cyclodextrin complexation on physicochemical properties of zaleplon

The physicochemical properties and dissolution profile of zaleplon (ZPN) β-cyclodextrin (βCD) inclusion complex were investigated. The phase solubility profile of ZPN with β-cyclodextrin was classified as A_L-type. Stability constant with 1:1 molar ratio was calculated from the phase solubility diagram and the aqueous solubility of ZPN was found to be enhanced by 714% (p < 0.001) for β-cyclodextrin. Binary systems of ZPN with βCD were prepared by kneading method. The solid-state properties of complex were characterized by differential scanning calorimetry, Fourier transformation-infrared spectroscopy and powder X-ray diffractometry. It could be concluded that ZPN could form inclusion complex with β-cyclodextrin. The dissolution profile of inclusion complex was determined and compared with those of ZPN alone and its physical mixture. The dissolution rate of ZPN was significantly increased by complexation with βCD, as compared with pure drug and physical mixture.     

Inclusion complexes of Schiff bases as phytogrowth inhibitors

This article details the preparation, characterization and phytotoxic evaluation of several Schiff base inclusion complexes obtained from β-cyclodextrin and p-sulfonic acid calix[6]arene. The inclusion complexes (1:1 molar ratio) were prepared by mixing a 5 mmol L^?1 aqueous solution (containing 1 % DMSO) of Schiff bases (guests) with aqueous solution (containing 1 % DMSO) of 5 mmol L^?1 of β-cyclodextrin or p-sulfonic acid calix[6]arene (hosts). The host–guest systems were characterized via a series of NMR experiments. The ability of the complexes to interfere with the radicle elongation of Sorghum bicolor (dicotyledonous species) and Cucumis sativus (monocotyledonous species) was evaluated. After 48 h, the inclusion complexes inhibited the radicle elongation of both species from 11 to 56 %. The formation of inclusion complexes was also investigated theoretically by molecular dynamics simulations in aqueous solution through implicit approach. Based on the experimental observation, the phytotoxic activity evaluated can be attributed to the formation of host–guest systems. This was supported by the theoretical findings based on stable interaction energy analyses for all the studied supramolecular systems.     

Competitive Binding of Tolmetin to β-Cyclodextrin and Human Serum Albumin: <Superscript>1</Superscript>H NMR and Fluorescence Spectroscopy Studies

The host–guest interaction of tolmetin (TOL) with β-cyclodextrin (β-CD) and the influence of human serum albumin (HSA) on the formation of the inclusion complex were studied by 1D and 2D NMR spectroscopy. The TOL/β-CD inclusion complex formed at a molar ratio of 1:1 with a binding constant value of 2164.5 L·mol^?1. Data analysis showed that the addition of 10 μmol·L^?1 of HSA weakened the strength of TOL binding to β-CD (K _a = 1493 L·mol^?1). The interaction of TOL with HSA in the absence and presence of β-CD was studied by analyzing the fluorescence quenching data. The Stern–Volmer quenching constants and the binding constants are found to be smaller in the presence of β-CD, suggesting that β-CD hinders the strong interaction of TOL with HSA by complex formation. Additionally, the presence of β-CD does not induce conformational and microenvironmental changes on HSA.     

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.     

Enhancement of Dissolution Behavior of Aceclofenac by Complexation with β-Cyclodextrin-Choline Dichloride Coprecipitate

The objective of the present investigation was to study the effect of presence of choline dichloride (CDC) in β-cyclodextrin (β-CD) on in vitro dissolution of aceclofenac (AF) from molecular inclusion complexes. The molecular inclusion complexes of AF with β-CD coprecipitated with CDC in 1:1 and 1:2 M ratio were prepared using kneading method. In vitro dissolution of pure drug, physical mixtures, and cyclodextrin inclusion complexes (AF-β-CD-CDC) were carried out. Molecular inclusion complexes of aceclofenac with coprecipitated β-CD showed considerable increase in the dissolution rate in comparison with physical mixture and pure drug in 0.1 N HCl, pH 1.2 and phosphate buffer, pH, 7.4. Inclusion complexes with 1:2 M ratio showed maximum dissolution rate in comparison to other ratios. FTIR spectroscopy and differential scanning calorimetry studies indicated no interaction between AF and β-CD-CDC in complexes in solid state. Dissolution enhancement was attributed to the formation of water soluble inclusion complexes with the precipitated form of β-CD. The in vitro release from all the formulations was best described by first order kinetics (R ² = 0.9354 and 0.9268 in 0.1 N HCl and phosphate buffer, respectively) followed by Higuchi release model (R ² = 0.9029 and 0.9578 in 0.1 N HCl and phosphate buffer, respectively). In conclusion, dissolution of aceclofenac can be enhanced by using the β-CD-CDC coprecipitate as a host molecule.     

Inclusion complexes of rosmarinic acid and cyclodextrins: stoichiometry,association constants,and antioxidant potential

The interaction between β-cyclodextrin (β-CD) and the polyphenol rosmarinic acid (RA) is here reported by ¹H NMR titration experiments. The formation of an aqueous soluble inclusion complex is confirmed and valuable information regarding mode of penetration of guest into β-CD, stoichiometry, and stability of the complex is obtained. The analysis by the continuous variation method shows the undoubted formation of 1:1 β-CD/RA complex. Additionally, the estimated apparent association constants reveal the importance of the asymmetry of the RA in the complexation; the incorporation of the catechol moiety closer to the carboxylic group is more favorable (K?=?2,028 M^?1) than from the other end of the RA molecule (K?=?1,184 M^?1). Finally, we have also investigated the antioxidant activity and storage stability of the β-CD/RA complexed system; the presence of β-CD was found to produce a remarkable enhancement on the antioxidant activity.     

Chromatographic study of four sesquiterpenoids in volatile oil of Curcumae Rhizoma on reverse phase stationary phase with methyl-β-cyclodextrin as mobile additive

Abstract

The elution behavior of four sesquiterpenoids in volatile oil of Curcumae Rhizoma on reverse-phase high-performance liquid chromatography with methyl-β-cyclodextrin as mobile phase additive was studied, including germacrone, curzerene, furanodiene, and β-elemene. Stoichiometric ratio and apparent formation constants of inclusion complex formed by methyl-β-cyclodextrin and each analyte were calculated by varying the concentration of the additive in the mobile phase composed of methanol and water (90:10, v/v), in which the association constant for inclusion complex formed by the organic modifier methanol and methyl-β-cyclodextrin was also determined. Results showed that the stoichiometric ratio of all the inclusion complex was 1:1 when 0–9?mmol L^?1 of methyl-β-cyclodextrin was added in the mobile phase. Unusual retention behavior of the analyte germacrone was found, which was further investigated by the calculation of thermodynamic parameters. Meanwhile, enthalpy and entropy of the inclusion complexes and solute-stationary phase interactions were determined by linear van’t Hoff plots.     

Enhancing the dissolution of hydrophobic guests using solid state inclusion complexation: characterization and in vitro evaluation

The objectives of the present investigation were to prepare and characterize solid inclusion complexes of Etodolac (ETD) with β-cyclodextrin (β-CD) in order to study the effect of complexation on the dissolution rate of ETD, a hydrophobic guest molecule. Phase solubility curve was classified as a typical A_L-type for the cyclodextrins (CD’s), showing that soluble complex was formed. The inclusion complexes in the molar ratio of 1:1 and 1:2 (β-CD–ETD) were prepared by various methods such as kneading, co-evaporation and in molar ratio of 1:1 by spray dried technique respectively. The molecular behaviors of ETD in all samples were characterized by nuclear magnetic resonance (NMR) spectroscopy, fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies and Scanning Electron microscopy (SEM) analysis. The results of these studies indicated that complexes prepared by kneading, co-evaporation and spray drying techniques showed inclusion of the ETD molecule into the CD’s cavities. The highest improvement in in vitro dissolution profiles was observed in complexes prepared with spray dried technique. Mean in vitro dissolution time indicated significant difference between the release profiles of ETD from complexes and physical mixtures and from pure ETD.     

The effect of β-cyclodextrin on the solubility and dissolution rate of meloxicam and investigation of the driving force for complexation using molecular modeling

The aim of this study was to investigate the effect of β-cyclodextrin (β-CD) on the solubility and dissolution rate of meloxicam. The methods that were employed to prepare meloxicam–β-cyclodextrin complexes were physical mixture, kneaded dispersion, and spray drying. Spray drying method was found to be the best to form a true inclusion complex. Complexes were characterized by thermal analysis, X-ray diffractometry (XRD), and Fourier transform infrared (FT-IR) spectroscopy. The apparent stability constant of the complex, K _c, calculated from the slope and intercept of the A_L solubility diagram was found to be 429.73, 259.96, 183.31, and 36.50 L mol^?1 at pH 2, 3, 6.5, and 10.3, respectively. The dissolution rate of meloxicam from the complexes was higher than from meloxicam alone. Molecular modeling was also used to investigate the interaction between meloxicam and β-CD. The dominant driving force for the complexation was evidently Van der Waals force with very little electrostatic contribution.     

Water-insoluble β-cyclodextrin polymer crosslinked by citric acid: synthesis and adsorption properties toward phenol and methylene blue

Water-insoluble β-cyclodextrin polymer (β-CDP) crosslinked by citric acid was obtained with a yield of 65% through an environment friendly synthesis procedure. FT-IR spectra disclosed that the hydroxyl groups of β-CD had reacted and condensated with the carboxyl groups of citric acid, and at the same time the structural characteristics of β-CD were essentially maintained in β-CDP. The β-CDP exhibited notable adsorption capability toward phenol (q _max = 13.8 mg g^?1) and especially large adsorption capability toward methylene blue (q _max = 105 mg g^?1). The concentration of methylene blue in water could be reduced to 0.11 mg L^?1 by the β-CDP, indicating the excellent adsorption sensitivity of β-CDP toward methylene blue. The adsorption results disclosed that the interior cavity and inclusion property of β-CD were maintained in the synthesized β-CDP.     

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.     

Inclusion of parabens in β-cyclodextrin: A solution NMR and X-ray structural investigation

A parallel study was conducted of the inclusion of alkyl parabens (guests) in the host β-cyclodextrin (β-CD). ¹H NMR data indicated an insertion of the guest phenyl ring into the β-CD cavity. The stoichiometry of each complex was 1:1, as determined by a continuous variation method that utilises the chemical shifts of the host protons. These chemical shifts were additionally used to determine the association constant yielding K values of 1631, 938, 460 and 2022 M^? 1 at 298 K for the methyl-, ethyl-, propyl- and butyl paraben solution state complexes, respectively. NOE experiments conducted on the methyl paraben solution complex indicated that the phenolic group of the guest was located at the secondary rim of the cyclodextrin cavity. Solid state structure analyses of the methyl and propyl paraben β-CD complexes were performed. Both complexes crystallised at ambient temperature in the space group C2, Z = 4 with a host to guest ratio of 1:1. Additionally, a second crystal structure between methyl paraben and β-CD is reported. This complex crystallised at 7^oC in the space group P1, Z = 2 with a 1:1 host–guest stoichiometry.

¹H NMR and solid state structure analyses were conducted on the inclusion of alkyl parabens in the host β-cyclodextrin. Both indicated an insertion of the guest phenyl ring into the β-CD cavity.     

Solid state characterization of the inclusion complex of valsartan with methyl β-cyclodextrin

In this work, we illustrate the usefulness of cyclodextrins, namely, methyl-β-cyclodextrin (MβCD), an amorphous, methylated derivative of the natural β-cyclodextrin, as a tool to form an inclusion complex with Valsartan (VAL), a poorly water soluble drug. The phase solubility study showed A_L type of curve with slope less than one indicating the formation of complexes in 1:1 molar ratio of drug and CD. The stability constant was found to be 538.14 ± 5.4 Mole^?1. Solid binary systems between VAL and MβCD were prepared experimentally in a stoichiometry 1:1 by different techniques (physical mixing, kneading, co-evaporation). Afterward these products were characterized by Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Scanning electron microscopy (SEM) and ¹H Nuclear magnetic resonance study (¹H NMR). The results obtained suggested that co-evaporation methods yield a higher degree of amorphous entities suggesting the formation of inclusion complex between VAL and MβCD. The dissolution of VAL from the binary systems was studied to select the most appropriate system for the formulation development. It was concluded that the preparation technique played an important role in the dissolution behavior of the drug and the inclusion complex between VAL and MβCD obtained by co-evaporation method allowed better performance.     

Comparison of inter- and intramolecular cyclodextrin complexes

Abstract

We present the first comparative steady-state and time-resolved fluorescence studies of inter- and intramolecular cyclodextrin complexes. Specifically, we report equilibrium and kinetic results for dansyl-glycine complexed with β-cyclodextrin (intermolecular) and the dansyl-glycine-β-cyclodextrin adduct (intramolecular). The fluorescence intensity decay profile for the intermolecular system is best described by a discrete triple exponential decay law. This is consistent with stepwise 1:1 and 2:1 (β-cyclodextrin:guest) inclusion complexation. Equilibrium constants are in line with previous results on similar species. In contrast, we found that the intramolecular case was described by a doubly exponential decay law—consistent with a single intramolecular inclusion complex. Displacement experiments, with borneol, confirm the simplicity of the intramolecular complex. In all cases, continuous distribution models failed to fit the experimental data.     

Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation

Fluconazole (FZ) is a triazole antifungal drug administered orally or intravenously. It is employed for the treatment of mycotic infections. However, the efficacy of FZ is limited with its poor aqueous solubility and low dissolution rate. One of the important pharmaceutical advantages of cyclodextrins is to improve pharmacological efficacy of drugs due to increasing their aqueous solubility. The aim of present study was to prepare an inclusion complex of FZ and β-cyclodextrin (β-CD) to improve the physicochemical and biopharmaceutical properties of FZ. The effects of β-CD on the solubility of FZ were investigated according to the phase solubility technique. Complexes were prepared with 1:1 M ratio by different methods namely, freeze-drying, spray-drying, co-evaporation and kneading. For the characterization of FZ/β-CD complex, FZ amount, practical yield %, thermal, aqueous solubility, XRD, FT-IR and NMR (¹H and ¹³C) analysis were performed. In vitro dissolution from hard cellulose capsules containing FZ/β-CD complexes was compared to pure FZ and its commercial capsules and evaluated by f₁ (difference) and f₂ (similarity) factors. Paddle method defined in USP 31 together with high pressure liquid chromatographic method were used in in vitro dissolution experiments. It was found that solubility enhancement by FZ/β-CD complexes depends on the type of the preparation method. High release of active agent from hard cellulose capsules prepared with β-CD complexes compared to commercial capsules was attributed to the interactions between β-CD and active agent, high energetic amorphous state and inclusion complex formation.     

Spectroscopic study and antioxidant activity of the inclusion complexes of cyclodextrins and amlodipine besylate drug

The aim of the study was to synthesize and characterization the inclusion complexes of amlodipine besylate (AML) drug with β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) which has antioxidating activity property. The guest/host interaction of AML with β-CD and γ-CD in order to complexation drug in β-CD and γ-CD were investigated. The interaction inclusion complexes was characterized by fourier transform infrared and ultraviolet–visible spectroscopies. The formation constant was calculated by using a modified Benesi–Hildebrand equation at 25 °C. The stoichiometry of inclusion complexes was found to be 1:1 for β-CD and γ-CD with AML drug. The antioxidant activity of AML drug and its inclusion complexes were determined by the scavenging of stable radical 2,2′-diphenyl-1-picrylhydrazyl (DPPH^·). Kinetic studies of DPPH^· with AML and CDs complexes were done. The experimental results confirmed the forming of AML complexes with CDs also these indicated that the AML/β-CD and AML/γ-CD inclusion complexes was the most reactive than its free form into antioxidant activity.     

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.     

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.     

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.     

Solubility and Kinetic Release Studies of Naproxen and Ibuprofen in Soluble Epichlorohydrin-β-cyclodextrin Polymer

Naproxen (NAP) and ibuprofen (IBU) are poor water soluble anti-inflammatory drugs. A water-soluble epichlorohydrin-β-cyclodextrin polymer (β-CDEPI) was synthesized in a highly basic aqueous solution and at a molar ratio β-CD/EPI of 1:12. Drug solubility and kinetic release of NAP and IBU from the inclusion complexes they form with β-CDEPI as host was studied. Water solubility for both drugs in the presence of this polymer increased (NAP 0.28 mmol and IBU 0.40 mmol per gram of β-CDEPI). The apparent inclusion constants for both drugs in β-CDEPI were calculated from the solubility-phase diagrams with K_incl values of 4300 ± 100 L.mol^? 1 for NAP and 5100 ± 300 L.mol^? 1 for IBU. Kinetic release of Ibuprofen gave a pure Fick trend (t^1/2) behavior. However, for Naproxen a zero order was obtained (t). These results indicate that the nature and bulkiness of the drugs are ruling these kinetic behaviors in the environment of a highly branched polymer.