βCD Inclusion Complex Research Articles

Characterization, Antifungal Evaluation against Candida spp. Strains and Application of Nystatin: β-cyclodextrin Inclusion Complexes.

Nystatin (Nys) is a fungicidal drug commonly prescribed for candidiasis disease in several administration routes. However, Nys is a class IV drug, according to the Biopharmaceutical Classification System, that possesses limited bioavailability and is used for local activity. This study developed and characterized nystatin:β-cyclodextrin (Nys:βCD) inclusion complexes and evaluated their activity against Candida spp. Complexes were characterized by physicochemical techniques and drug dissolution profiles. The susceptibility of C. albicans, C. krusei, C. parapsilosis, C. glabrata, C. guilliermondii, C. tropicalis, and C. auris was assessed using the broth microdilution method. The applicability of Nys:βCD inclusion complex was evaluated by incorporating it into a temporary soft material for denture stomatitis treatment. Nys was better complexed in a 1:1 molar ratio by freeze-drying and spray-drying methods. The inclusion complexes show bi-exponential release, an initial burst release followed by a sustained manner, presenting higher dissolution efficiency than raw Nys. The 1:1 freeze-drying Nys:βCD complex presents antifungal activity against all evaluated Candida strains, showing the maintenance of the drug effectiveness. The inclusion complex incorporated into a tissue conditioner material for denture stomatitis treatment effectively inhibited more than 90% of C. albicans biofilm growth during 7 and 14 days, in a half dose compared to raw Nys. This work represents a significant contribution to treating a wide variety of diseases caused by the Candida species, optimizing the drug bioavailability and compliance to the treatment due to improved drug solubility, dissolution, and sustained delivery.

Silver Abietate and β-Cyclodextrin Inclusion Complex Doped Poly(vinyl alcohol) Nanowebs.

In this study, guesthost inclusion complexes of silver abietate with β-cyclodextrin were prepared by kneading and physical mixing techniques, and analyzed via fourier transformed infrared spectroscopy (FTIR) and thermogravimetric analyser (TGA). The 1:1 and 1:2 stoichiometry of the guesthost were prepared. Obtained FTIR and TGA results showed that formation of silver abietate:β-cyclodextrin (Ag-A:β-CD) inclusion complexes occurred at a mass ratio of both 1:1 and 1:2. Furthermore, prepared Ag-A:β-CD (1:2) inclusion complex was doped in Poly(vinyl alcohol) nanofibers during electrospinning process for obtaining nanowebs. The formation of nanowebs were investigated under scanning electron microscope (SEM), X-Ray diffraction (XRD), Fourier transformed infrared spectroscopy (FTIR) and thermogravimetric analyser (TGA). The results confirmed Ag-A:β-CD inclusion complex containing Poly(vinyl alcohol) (PVA) nanoweb production.

Ultrastructural and antimicrobial impacts of allyl isothiocyanate incorporated in cellulose, β‐cyclodextrin, and carbon nanotubes nanocomposites

AbstractAntimicrobial nanobio packaging with controlled‐release of active compounds is one of the most promising versions of active packaging. In this study, the antimicrobial effect of allyl isothiocyanate (AIT), complexed or not with β‐cyclodextrin (βCD), and carbon nanotubes (CNTs) in cellulose films against Salmonella choleraesuis and Listeria innocua was investigated. Structural changes caused by AIT in bacteria were evaluated by transmission electron microscopy (TEM), as well as changes in the surface of the films, which were analyzed by atomic force microscopy and scanning electron microscopy. The active films inhibited the growth of both bacteria and caused damage to the cell membrane. The presence of inclusion complex and CNTs resulted in structural changes in films, such as the formation of lumps and reduction of roughness, respectively. Complexation of AIT with βCD and the use of CNTs increased the retention of the antimicrobial agent, which is desired to promote its controlled diffusion and consequently increase the preservative action of the film. However, when considering the use of βCD inclusion complexes, caution is necessary to prevent detrimental changes in the films' surface.

Encapsulation of the Natural Product Tyrosol in Carbohydrate Nanosystems and Study of Their Binding with ctDNA

Tyrosol, a natural product present in olive oil and white wine, possesses a wide range of bioactivity. The aim of this study was to optimize the preparation of nanosystems encapsulating tyrosol in carbohydrate matrices and the investigation of their ability to bind with DNA. The first encapsulation matrix of choice was chitosan using the ionic gelation method. The second matrix was β-cyclodextrin (βCD) using the kneading method. Coating of the tyrosol-βCD ICs with chitosan resulted in a third nanosystem with very interesting properties. Optimal preparation parameters of each nanosystem were obtained through two three-factor, three-level Box-Behnken experimental designs and statistical analysis of the results. Thereafter, the nanoparticles were evaluated for their physical and thermal characteristics using several techniques (DLS, NMR, FT-IR, DSC, TGA). The study was completed with the investigation of the impact of the encapsulation on the ability of tyrosol to bind to calf thymus DNA. The results revealed that tyrosol and all the studied systems bind to the minor groove of ctDNA. Tyrosol interacts with ctDNA via hydrogen bond formation, as predicted via molecular modeling studies and corroborated by the experiments. The tyrosol-chitosan nanosystem does not show any binding to ctDNA whereas the βCD inclusion complex shows analogous interaction with that of free tyrosol.

An innovative active cardboard box for bulk packaging of fresh bell pepper

Active packaging including encapsulated essential oils (EOs) may highly increase the shelf life of horticultural products due to the higher antimicrobial activity of EOs in the vapour phase through a controlled release from the packaging. In that sense, the aim of the present study was to study the effects of an active packaging (a cardboard box including a βcyclodextrin (βCD) inclusion complex with an EOs mix) on the quality of bell peppers (green, red and yellow) during storage at 8 °C (90 % relative humidity) up to 18 d. The EO mix (carvacrol:oregano:cinnamon 70:10:20 v:v:v) was efficiently encapsulated within the βCD inclusion complex by 94 %. Green, red and yellow peppers packaged within the active box showed 1–2 lower log units of enterobacteria than the control (without the active coating) after 11–18 d. Furthermore, green/red and yellow peppers showed lower mould counts (approximately 1 log unit) than control samples at days 6 and 11, respectively. The decay incidence of samples was also highly controlled by the active packaging with percentages lower than 5 % after 18 d while control samples showed decay incidences of 10–15 %. The use of this active box did not negatively affect the physicochemical quality of peppers even showing red and green peppers of the active box better firmness than control samples after 18 d. The shelf life of peppers stored within the active box reached 18 d while samples stored with the control box were rejected. Carvacrol residues in peppers were very low (below 1 mg kg−1) avoiding off-flavours according to sensory results. Conclusively, this active packaging allowed to extend the shelf life of green, red and yellow peppers for at least 18 d at 8 °C.

β-Cyclodextrin as a Functional Excipient Used for Enhancing the Diminazene Aceturate Bioavailability.

In this study, we proposed formulations of diminazene aceturate (DA) designed to improve its bioavailability and to maximize the therapeutic index in animals by overcoming the rapid degradation under the acidic pH of the stomach. An important consequence is the fact that its amount in the bloodstream is close to the administered dose. This was made possible by incorporating DA into the β-cyclodextrin’s (βCD) cavity in a molar ratio of 1:1. The structure of the resulted inclusion complex was established by Raman, DSC, and Wide-Angle X ray Diffraction (WAXD) in solid state and by 1H-NMR and H-H ROESY in aqueous solutions. The stoichiometry of the DA:βCD inclusion complex was obtained by using the continuous variation method (Job’s plot), considering the chemical shifts variations of protons from both DA and βCD compounds in 1H-NMR spectra. The biological activity was estimated in vitro by antioxidant activity and in vivo by comparing the bioavailability of parent DA and its inclusion complexes after a single dose administration in Wistar rats by using the HPLC method on their blood plasma. In vitro tests showed an improved antioxidant activity. In vivo tests have shown that the DA concentration is always much higher in blood plasma of rats when DA:βCD inclusion complex of 1:1 molar ratio was administered (i.e., at 60 min, DA is around 11 and 3 times higher when DA:βCD inclusion complex of 1:1 molar ratio was administered than the parent DA one and DA:βCD lyophilized mixture of 1:2 molar ratio, respectively).

Effect of hydroxypropyl methylcellulose on beta cyclodextrin complexation of praziquantel in solution and in solid state

The effect of hydroxypropyl methylcellulose (HPMC) on complexation of praziquantel with beta cyclodextrin (PRZ–βCD) in solution and in the solid state was investigated. Phase solubility studies of βCD (0, 3, 6, 9 and 12 mmol L−1) were carried out by adding an excess amount of PRZ (8 mmol L−1) in the absence and presence of the polymer (with and without heating at 120 °C). Equimolar binary and ternary complexes were prepared by kneading and freeze-drying and characterized by DSC, DTA TGA, FTIR, XRPD and SEM patterns. A stoichiometry ratio of 1:1 was indicated by phase-solubility studies both in the presence and absence of 0.5 % HPMC. The molecular modeling confirms the 1:1 stoichiometry rate with Higuchi’s Al type. The presence of HPMC improved the complexation between PRZ and βCD by increases in both the intrinsic solubility of the drug as well as in values of the stability constant, complexation efficiency and Gibb’s free energy of the complex, principally in the presence of heating (up to ninefold relative to aqueous solubility of the drug). The synergic effect of HPMC was also observed in thermal analysis, with lower dehydration enthalpy for ternary complexes. The results of melting enthalpy were according to XRPD results, indicating that the preparation technique and presence of HPMC influenced thermal and crystallographic characteristics of inclusion complexes. The FTIR patterns suggest the complexation mechanism while SEM patterns showed the formation of inclusion complexes. The use of the HPMC and freeze-drying technique suggest more effective formation of PRZ:βCD inclusion complexes.

Electron transfer reactions associated with ethyl viologen-β-cyclodextrin complexation: equilibrium and kinetic aspects

Formation of the complex of ethyl viologen in its cationic (Ev+•) and neutral (Ev∘) forms with β-cyclodextrin (β-CD) was investigated by means of voltammetric technique in buffer solution of pH 7.00. The number of βCD (n or m) per viologen species (Ev+•) or (Ev∘), bonding equilibrium constants as well as bonding rate constants was calculated. The calculated values of $$K_{\text{eq}}^{(1)}$$ and $$K_{\text{eq}}^{ ( 2)}$$ (pertaining to the bonding of Ev+• and Ev∘ with βCD) are 13.6 M–n and 2.1 × 103 M−m , respectively, whereas the calculated values of n and m are 0.54 and 1.25, respectively. The bimolecular rate constant for the Ev∘−βCD inclusion complex formation is 3.03 × 103 M−1s−1. These results are supported by the simulation of the experimental cyclic voltammograms. This study also highlights the significance of the proposed electrochemical method as compared to earlier studies on viologen-Cyclodextrin systems.

In silico elucidation of the inclusion phenomenon and permeation behavior of a zidovudine–cyclodextrin complex via static lattice atomistic simulation

This study explored the molecular arrangement of the drug molecule zidovudine (AZT) within an inclusion complex of β-cyclodextrin (βCD). The intrinsic mechanistic profiling of the AZT–βCD inclusion complex was investigated using molecular modeling and structurally designed docking studies via molecular mechanics Force-Field simulations. The energetically and geometrically optimized molecular conformations revealed that the AZT molecule was preferentially oriented toward the primary rim of the βCD cavity with the azido group positioned within the cyclodextrin ring. In the second phase of this study, the mechanism of AZT permeability across the transmucosal membrane after inclusion into βCD was elucidated via interaction between βCD and the transmucosal lipid, glycosylceramide (GLC). Interestingly, βCD formed H-bonds with the lipid head groups of GLC via the secondary rim. A systematic merge of these findings elucidated a novel “tunnel model” designated to the trimolecular complex: AZT-1°ring–βCD-2°ring–GLC. The energetic parameters, grid surface area, molecular volume, surface-to-volume-ratio, Log-P, refractivity, and polarizability were computed for the molecular complexes. Computationally, the Molecular Mechanics Assisted Model Building and Energy Refinements (AMBER) algorithm was used to develop a molecular mechanics energy relationship (MMER). The MMER elucidated the role of destabilized bond stretching, angle modification and torsional strain in ionic stabilization of the geometrical complexes through hydrophobic H-bonding and electrostatic interactions. These results provided a novel bonding and non-bonding correlation for the formation and performance of βCD in terms of its role in the prospective permeation modification of the AZT molecule through the transmucosal membrane with an optimum hydrophilic–lipophilic-permeation balance.

Native and β-cyclodextrin-enclosed curcumin: entrapment within liposomes and their in vitro cytotoxicity in lung and colon cancer

With a view to improving the solubility and delivery characteristics of poorly water-soluble drugs, we prepared β-cyclodextrin-curcumin (βCD-C) inclusion complexes (hydrophilic curcumin) and entrapped both native curcumin (hydrophobic) and the complexes separately into liposomes; these were then assessed for in vitro cytotoxicity in lung and colon cancer cell lines. Optimization of curcumin entrapment within βCD was achieved, with the resultant βCD-C complexes prepared by methanol reflux. Inclusion complexes were confirmed using UV spectroscopy, Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction. The water solubility of βCD-C complexes improved markedly (c.f. native curcumin) and successful entrapment of complexes into liposomes, prepared using a thin-film hydration approach, was also achieved. All the liposomal formulations were characterized for curcumin and βCD-C complex entrapment efficiency, particle size, polydispersity and stability at 2–8°C. Curcumin, βCD-C complex and their optimized liposomal formulations were evaluated for anticancer activity in lung (A-459) and colon (SW-620) cancer cell lines. All curcumin-containing formulations tested were effective in inhibiting cell proliferation, as determined via an MTT assay. The median effective dose (EC50) for all curcumin formulations was found to be in the low µM range for both lung and colon cancer cell lines tested. Our results confirm that βCD inclusion complexes of poorly water soluble drugs, such as curcumin can be entrapped within biocompatible vesicles such as liposomes, and this does not preclude their anticancer activity.

Spectroscopic (fluorescence, 1D-ROESY) and theoretical studies of the thiabendazole and β-cyclodextrin inclusion complex

The inclusion complex between the anti-helminthic drug thiabendazole (TBZ) and the β-cyclodextrin (βCD) was characterized in solution using fluorescence and 1H-Nuclear Magnetic Resonance spectroscopy and studied theoretically by semi empirical PM3 and density functional theory (DFT) quantum mechanical calculations. Thermodynamic stability associated with the formation of the TBZ:βCD inclusion complex in aqueous solution was determined treating the drug’s fluorescence enhancement in the presence of cyclodextrin by a non-linear model, which indicated a moderate host–guest affinity at equilibrium (K 150 ± 31 at 25 °C). Its supramolecular structure in solution was studied through the 1D-ROESY NMR experiment, which produced evidence that the guest molecular encapsulation occurs preferably via the drug’s benzimidazole group. Theoretical study employing molecular optimization with the semi empirical PM3 method provided two energetic-equivalent complex structures that are in accordance with the NMR experimental evidences. Single point energy calculations with DFT at the B3LYP/6-31G (d,p) level suggest the most stable structure of the inclusion complex and further comprehension on the interactions and conformational strains involved in its formation.

Enantiodifferentiation of chiral baclofen by β-cyclodextrin using capillary electrophoresis: A molecular modeling approach

Using capillary electrophoresis baclofen (BF) enantiomers were separated only in the presence of β-cyclodextrin (βCD) as a chiral selector when added to the background electrolyte. Proton nuclear magnetic resonance and electrospray ionization mass spectrometry (ESI–MS) techniques were used to determine the structure of the BF–βCD inclusion complexes. From the MS data BF was found to form a 1:1 complex with α- and βCD, while the NMR data suggest location of the aromatic ring of BF into the cyclodextrin cavity. A molecular modeling study, using the semiempirical PM6 calculations was used to investigate the mechanism of enantiodifferentiation of BF with cyclodextrins. Optimization of the structures of the complexes by PM6 method indicated that separation is obtained in the presence of β-CD due to a large binding energy difference (ΔΔE) of 46.8kJmol−1 between S-BF–βCD and R-BF–βCD complexes. In the case of αCD complexes ΔΔE was 1.3kJmol−1 indicating poor resolution between the two enantiomers. Furthermore, molecular dynamic simulations show that the formation of more stable S-BF–βCD complex compared to R-BF–β-CD complex is primarily due to differences in intermolecular hydrogen bonding.

Solid-state characterization and dissolution profiles of the inclusion complexes of omeprazole with native and chemically modified β-cyclodextrin

The aim of this work was to investigate the formation of the inclusion complex between omeprazole (OME), a benzimidazolic derivative and a methylated cyclodextrin, methyl-β-cyclodextrin (MβCD), with an average degree of substitution of 0.5. Inclusion complex between OME and β-cyclodextrin (βCD), a natural cyclodextrin, was used as reference. In aqueous media, apparent stability constants ( K s), which describe the extent of formation of the complexes, have been determined by UV spectroscopy and 1H NMR experiments. The stoichiometry of the complexes was found to be 1:1 mol:mol OME:cyclodextrin (CD) and the value of K s was higher for OME:MβCD than for OME:βCD inclusion complexes. Solid binary systems of OME and CDs were prepared by different techniques, namely kneading, spray-drying and freeze-drying. The formation and physicochemical characterization of solid inclusion complexes were investigated by differential scanning calorimetry (DSC), Fourier transform-infrared (FTIR), X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The results show that freeze-drying method produces true inclusion complexes between OME and both CDs. In contrast, crystalline drug was detectable in kneaded and spray-drying products. The dissolution of OME from the binary systems was studied to select the most appropriate system for the development of a buccal drug delivery formulation. It was concluded that the preparation technique played an important role in the dissolution behaviour of the drug and the inclusion complex between OME and MβCD obtained by spray-drying and freeze-drying allowed better performances.

Inclusion complexes of 2-phenoxyethanol and alkoxyethanols in cyclodextrins: an 1H NMR study

The association in aqueous solutions of small amphiphilic molecules [2-phenoxyethanol, PhE1, and some α-n-alkyl-ω-hydroxyoligo(oxiethylenes], C4E1, C4E2 and C6E2) with β-cyclodextrin (βCD), heptakis(2,6-di-O-methyl)-β-cyclodextrin (DIMEB) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB) was investigated by 1H NMR spectroscopy. The upfield shifts observed for the H3 and H5 NMR signals due to anisotropic shielding confirm that the host–guest associations are of inclusion type. The stoichiometries and the apparent inclusion constants, K app, were determined by 1H NMR spectroscopy using the H5 and H3 signals. The relative differences in the K app values for βCD inclusion complexes seem to reflect the hydrophobic/hydrophilic balance of the guests. The K app values for the PhE1 inclusion complexes can be related to the degree of methylation and hydrophobicity variation within the considered hosts. In addition, a comparative study between βCD and TRIMEB inclusion complexes using 2D ROESY (Rotating-frame Overhauser Enhancement SpectroscopY) NMR spectra provides structural features for these complexes which are inaccessible by other experimental methods.

Physicochemical characteristics and bioavailability of a novel intestinal metabolite of ginseng saponin (IH901) complexed with β-cyclodextrin

In an effort to improve the bioavailability (BA) of the insoluble compound 20- O-(β- d-glucopyranosyl)-20( S)-protopanaxadiol (IH901), we prepared β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes containing IH901. IH901 is a major metabolite formed by intestinal bacteria from protopanaxadiol ginseng saponins. We developed and validated an HPLC-based method to measure IH901 levels from samples prepared in vitro. The phase solubility profiles with both cyclodextrins (CDs) were classified as A L-type, indicating the formation of a 1:1 stoichiometric inclusion complex. Stability constants ( K s) calculated from the phase solubility diagrams showed that the βCD complex was more stable than the HPβCD complex. Consequently, complexes of IH901 and βCD were prepared by a freeze-drying method and were analyzed by fourier transformation-infrared spectroscopy (FT-IR), X-ray diffraction, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). From these physicochemical characterizations, we confirmed the presence of a new solid phase in the freeze-dried samples. The IH901 released from the complex in a pH 1.2 solution, the pH range of gastric fluids, was considerably lower than the amount released in the other solutions. The IH901 released from the complex in pH 6.8 solution, the range of intestinal fluids, was 9.0-fold greater than pure IH901 powder. However, the amount of IH901 released from the complex in pH 4.0–8.0 was less than 20%. After oral administration of the IH901–βCD inclusion complex (30 mg/kg IH901) into rats, plasma concentrations were determined by LC/MS/MS. The peak concentration ( C max) for the inclusion complex was 2.8-fold higher than that for pure IH901 powder. The BA, calculated from the ratio of the AUC oral to the AUC i.v., for the pure IH901 powder, the IH901–βCD physical mixture, and the inclusion complex was 3.52, 4.34, and 6.57%, respectively. These results indicate that the BA for the inclusion complex was 1.9-fold higher than that for the pure IH901 powder.

Aqueous Solution Inclusion of the Nonionic Surfactant C 12 E 4 in β -Cyclodextrin: Implications of Micellization in Stoichiometry Determination and Model Calculations

The inclusion of α-n-dodecyl-ω-hydroxytetra(oxyethylene), C12E4, in β-cyclodextrin (βCD) has been studied in aqueous solution. Guest encapsulation is recognized by the upfield variations in the chemical shifts of the H3 and H5 inner protons of βCD, and the chemical shift differences of the H5 protons are used for determining the complex stoichiometry (2βCD : 1C12E4) by the continuous variation method. Self-association (micellization) of the surfactant molecules is considered, and the relative amount of surfactant involved in micellar systems at the stoichiometric point estimated. A two-layered integrated molecular orbital and molecular mechanics approach with the PM3 and UFF model chemistries for the guest and host, respectively, was used to perform full geometry optimizations and frequency calculations on the host-guest systems. Energies for the optimized structures were subsequently obtained by single point calculations at the Hartree–Fock level using the STO-3G basis set. These calculations showed that one C12E4 molecule encapsulated by a head-to-head βCD dimer is a stable model system in consonance with the experimentally determined stoichiometry, and that the 1 : 1 complex is not stable with respect to dissociation. In the stable 2 : 1 model system, the guest molecule is appreciably tilted with respect to the βCD dimer axis and presents a gradually bent alkylic chain in clear manifestation of conformational flexibility. Model calculations for βCD inclusion complexes of other oligo(oxyethylene) molecules further indicate that the number and strength of H⋯H intermolecular close contacts reflect the position and conformational flexibility of the guest hydrophobic chain inside βCD.

Pseudorotaxanes of β -Cyclodextrin with Diamino End-functionalized Oligo-phenyl and -benzyl Compounds in Solution and in the Solid State

β-Cyclodextrin forms a 1:1 host:guest inclusion complex ([2]pseudorotaxane) with 4-[2-(4-aminophenyl)ethyl]-benzenamine (1) in water as determined by 1D and 2D NMRexperiments. In the crystalline state, the structure of the complex has revealed a 2:2 stoichiometry, with two βCD molecules forming head-to-head dimers byH-bonds between the secondary O3 hydroxyl groups and enclosing two molecules of the guest. The packing mode of the present complex is encountered for the first time, since it does not belong to any of the four known packing types of the dimeric βCD inclusion complexes. On the other hand,N 1,N 4-bis(4-aminophenyl)-1,4-benzenedimethanamine 2), which is longer than 1 by a phenylene diamine unit, has not afforded any crystals, at present, however it threads into βCD in aqueous solution forming most probably [2]- and [3]pseudorotaxanes. The solution structures and the equilibria in this system are investigated.

Characterization of an inclusion complex of cholesterol and hydroxypropyl- β-cyclodextrin

Interactions between endogenous cholesterol and cyclodextrins have been investigated by several researchers, and they found altered skin penetration of some drugs, membrane disruption, and extraction of cholesterol from the large lipoprotein particles or animal fat. In the present study, an inclusion complex composed of cholesterol and hydroxypropyl- β-cyclodextrin (HP βCD) prepared by lyophilization was investigated and characterized in order to confirm these interactions. Five grams of cholesterol were dispersed in 50 ml of 73.2 mM HP βCD aqueous solution, mixed for 2 days, and the filtrate lyophilized. A phase solubility study was performed by mixing an excess amount of cholesterol with an aqueous solution containing increasing amounts of HP βCD. The amount of cholesterol in solution after mixing for 2 days at 25°C was determined by HPLC. The inclusion complex was characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry, and differential scanning calorimetry (DSC). An A p-type Higuchi phase solubility diagram, DSC, FTIR, and X-ray diffraction demonstrated the formation of an inclusion complex. DSC thermograms indicated that the endothermic peaks of cholesterol and physical mixture of cholesterol with HP βCD due to the fusion of drug crystals, were absent in DSC thermograms obtained on the freeze dried inclusion complex. FTIR spectra indicated that some of the absorption peaks in the lyophilized inclusion complex were different from that of the physical mixture of cholesterol and HP βCD. X-ray diffraction patterns showed that the pure cholesterol and a physical mixture of cholesterol and HP βCD exhibited crystalline characteristics whereas the lyophilized inclusion complex and HP βCD displayed amorphous characteristics. The results indicated that the formation of a cholesterol/HP βCD inclusion complex is more water soluble than cholesterol alone.

Drugs, in cyclodextrins, in liposomes: a novel approach to the chemical stability of drugs sensitive to hydrolysis

The entrapment in multilamellar liposomes of the inclusion complexes of cyclodextrins with drugs sensitive to hydrolysis, is being examined. The anti-inflammatory drug indomethacin (IND), rapidly hydrolyzed in alkaline media, can be stabilized 75-fold when its inclusion complex with the hydroxypropylated derivative of β-cyclodextrin (HP βCD) is entrapped in multilamellar liposomes. These liposomes were composed of egg phosphatidylcholine and cholesterol of 1:1 molar ratio and were prepared according to the dehydration-rehydration method. The molar ratio for the IND:HP βCD inclusion complex was estimated to be 1:1 using the continuous variation method based on the 1H NMR data. Furthermore, the binding constant (K 11) of the IND:HP βCD complex was estimated kinetically and by 1H NMR.

Application of solvent extraction and synchronous spectrofluorimetry to the determination of the formation constant for a 1:1 complex of carbazole with?-cyclodextrin in water-dimethyl sulfoxide medium

Extraction of carbazole in heptane was performed at 25±1°C with an aqueous dimethyl sulfoxide (DMSO) medium containing β-cyclodextrin (βCD) at consecutive concentrations in the range of 0–10 mM. The fluorescence intensity of carbazole remaining in the heptane phase was measured by synchronous scanning fluorimetry. The apparent formation constant (Kf) for a 1:1 carbazole: βCD inclusion complex in water-DMSO medium was determined by using a linear plot of the distribution ratio calculated from the fluorescence intensities vs. the β-CD concentration. The values thus obtained ranged from 477 M−1 in a 10% v/v DMSO medium to 12.1 M−1 in a 60% v/v medium. Good linear relationships were observed between logKf and the DMSO concentration ([DMSO]), and also between logKf and the logarithm of the distribution coefficient (Kd) for carbazole. The formation constant in 100% water was estimated to be approximately 1.0×103 M−1 on the basis of the logKf vs. [DMSO] and the logKf vs. logKd correlations.