Study of the Interaction of Dithranol with Heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin in Solution and in the Solid State

The interaction between dithranol and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TMBCyD) has been investigated in aqueous solution containing isoascorbic acid (0·2% w/v) as antioxidant and in the solid state. The interaction in the solid state was studied by differential scanning calorimetry (DSC), infrared spectroscopy (IR), X-ray powder diffractometry (XPD) and a dissolution-rate method. The extent of complexation between the two substances was poor, as indicated by the low value of the slope of the linear part of the solubility curve. A phase diagram was constructed by measuring the thermal behaviour of various re-solidified physical mixtures of dithranol and of TMBCyD previously subjected to heating until melting of the TMBCyD. The loss of dithranol, owing to sublimation and degradation caused by the thermal treatment used, was less than 10%. In keeping with XPD and IR data, the phase diagram indicated that a complex was formed containing 13·7% dithranol (molar ratio 1:1) which had a congruent melting point at 164°C. The drug dissolution rate from the 1:1 complex was measurable, unlike that of the corresponding physical mixture, and was significantly increased when the complex was dispersed in the glassy matrix of TMBCyD, as it was in re-solidified mixtures containing 2–7% dithranol. The results show that the solubility of dithranol is increased significantly as a consequence of its interaction with TMBCyD, despite the low extent of complexation between the two substances.     

Complexation of Hydrocortison with β-Cyclodextrin and Hydroxypropyl-β-Cyclodextrin

Hydrocortison (HC) forms water-soluble inclusion compounds with β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD), as proved by the equilibrium phase solubility diagrams and by ¹H-NMR spectroscopy. The solubility isotherm of the HC/βCD system is of the BS type, that of the HPβCD system of the AL type. The values of the complex stability constants are K = 4792 M^?1 and 1739 M^?1, respectively. 8 parallel preparations of solid HC/βCD complexes by coprecipitation resulted in a stoichiometric ratio of 0.49:1 which corresponds to a molar ratio of 1:2; the HC content is 13.2±0.2%. The ratio of the HC/HPßCD complex is 0.335 which equals a molar ratio of 1:3; the HC content is 8.6 ± 0.2%. The proof of inclusion formation was performed by X-ray diffractometry and thermoanalytical procedures (DSC, TG, thermofractography). We cannot exclude that some of the HC molecules are not included in the HPßCD cavity.     

Characterization of the complexes of furosemide with 2-hydroxypropyl-β-cyclodextrin and sulfobutyl ether-7-β-cyclodextrin

The purpose of this study was to prepare and characterize complexes of furosemide with 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) and sulfobutyl ether-7-β-cyclodextrin (SBE-7-β-CD). Solid complexes of furosemide with 2-HP-β-CD and SBE-7-β-CD were prepared by using both a freeze–drying and kneading method. Physical mixtures were prepared for comparison. The inclusion complexes were characterized by differential scanning calorimetry, X-ray diffractometry (XRD) and ¹H nuclear magnetic resonance spectroscopy (¹H-NMR). ¹H-NMR, and especially the use of the two-dimensional ROESY spectrum, was used to determine the position of the furosemide molecule inside the cyclodextrin cavity. ¹H-NMR studies showed that furosemide fit into the cyclodextrin torus cavity with its furane ring nearest to the primary hydroxyl side.     

Complexation of the interferon inducer, bropirimine, with hydroxypropyl-β-cyclodextrin

Bropirimine (ABPP) is an orally active immunomodulator that increases endogenous alpha-interferon and other cytokines used clinically against carcinoma in situ of the bladder. The oral absorption of ABPP is poor because its low solubility in water. The purpose of this study is to develop a technological procedure useful to increase the water solubility of ABPP. To this end, the interaction of ABPP with several cyclodextrin derivatives--, β-, γ- and hydroxypropyl-β-cyclodextrin with a degree of substitution 2.7 (HPβCD) was studied and the effect of the complexation process on the water solubility of the drug was evaluated. The best results were obtained with the hydroxypropyl derivative, HPβCD, that interacts in a 1:1 drug:cyclodextrin molar ratio. The inclusion complex ABPP–HPβCD was characterized in solution by nuclear magnetic resonance (¹H-NMR). The solid inclusion complex was obtained by freeze-drying and characterized by differential scanning calorimetry (DSC), X-ray diffractometry and mass spectrometry. The dissolution rate of ABPP from the HPβCD solid inclusion complex was increased compared to the powdered drug but not differences were found between the complex and a physical mixture with a similar molar ratio. The increase of the dissolution rate of the drug can be attributed to the breakdown in solution of the drug dimers in the presence of the cyclodextrin and to the complex formation.     

Modified β-Cyclodextrin (SBE7-β-CyD) with Viscous Vehicle Improves the Ocular Delivery and Tolerability of Pilocarpine Prodrug in Rabbits

The complexation of pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, with various β-cyclodextrin (β-CyD) derivatives was studied by the phase solubility method. The effects of coadministered sulphobutyl ether β-CyD (SBE7-β-CyD) with and without poly(vinyl alcohol) (PVA) on the miotic response and eye irritation of the prodrug were investigated in pigmented rabbits. The pilocarpine prodrug formed 1:1 inclusion complexes with variably substituted sulphobutyl ether derivatives of β-CyD (SBE4-β-CyD and SBE7-β-CyD), and 1:1 and 1:2 complexes with hydroxypropyl-β-CyD (HP-β-CyD) at pH 7:4. Coadministered SBE7-β-CyD eliminated the eye irritation due to the pilocarpine prodrug, but also decreased the miotic response. Ocular absorption of the prodrug was improved by increasing the viscosity of prodrug/SBE7-β-CyD solution with PVA without inducing any eye irritation. Eye irritation due to viscous prodrug/SBE7-β-CyD solutions was comparable with isotonic NaCl solution. We conclude that administration of pilocarpine prodrug in viscous SBE7-β-CyD solution decreases substantially eye irritation while ocular absorption is not affected.     

Einige N-funktionelle Derivate von N-(α-Tosylaminoacyl)-β-alaninen

Syntheses of dipeptidenitriles 1a-e starting from α-tosylaminoacidchlorides and β-aminopropionitrile and their conversion to the esters of dipeptide-imide acids 2a-d , esters of dipeptide acids 5a-d , to amides of dipeptide acids 6a-d and amidines of dipeptide acids 4a-e are described. Condensations of amidines of tosyldipeptide acids 3a, c with ethyl acetoacetate yield pyrimidines 7a, c .     

Chiral discrimination of phenethylamines with β-cyclodextrin and heptakis(2,3-di-O-acetyl)β-cyclodextrin by capillary electrophoresis and NMR spectroscopy

The resolution of nine sympathomimetic phenethylamine racemates by β-cyclodextrin and heptakis(2,3-di-O-acetyl)β-cyclodextrin has been investigated by capillary electrophoresis and ¹H NMR spectroscopy. The NMR and capillary electrophoresis results showed that β-cyclodextrin probably formed stronger complexes with the amines than did heptakis(2,3-di-O-acetyl)β-cyclodextrin but was a poorer chiral discrimination agent in both techniques. The addition of heptakis(2,3-di-O-acetyl)β-cyclodextrin to the capillary electrophoresis buffer gave baseline resolution of enantiomer peaks for seven of the compounds studied while β-cyclodextrin resolved only three of the racemates.     

Comparative interaction of 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin with itraconazole: Phase-solubility behavior and stabilization of supersaturated drug solutions

Cyclodextrins can increase the apparent solubility and dissolution rate of poorly water-soluble drug candidates improving their biopharmaceutical performance. The current data assess the ability of hydrophilic cyclodextrins to solubilize compounds via stabilization of supersaturated drug solutions presumably by inhibition of nucleation and arresting crystal growth. To these points, the effects of 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutylether-beta-cyclodextrin (SBEbetaCD) on equilibrium solubility was assessed via phase-solubility analysis as were the interactions of these excipients on drug solubility under conditions favoring supersaturation. Phase-solubility analysis indicated that different profiles were generated as a function of the cyclodextrin examined and the pH of the complexing medium. When kinetic solubility measurements were completed, the cyclodextrins were found to stabilize concentrations of itraconazole significantly in excess of their equilibrium solubility when supersaturated solutions were formed using the co-solvent/solvent quench approach. These solutions were stable over 240 min falling in concentration at the 24 h time point of the experiment unlike those formed using surfactants and other polymers which demonstrated a rapid decrease in concentration over time. These data suggest that hydrophilic cyclodextrins might be useful formulation adjuncts in supersaturating drug delivery systems.     

Multimodal molecular encapsulation of nicardipine hydrochloride by β-cyclodextrin, hydroxypropyl-β-cyclodextrin and triacetyl-β-cyclodextrin in solution. Structural studies by H NMR and ROESY experiments

Proton nuclear magnetic resonance spectroscopy (¹H NMR), which has become an important tool for in vitro study of cyclodextrin (CD) complexes, was used to study and structurally characterize the inclusion compounds formed in solution between nicardipine hydrochloride (NC) and β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD) and triacetyl-β-cyclodextrin (TAβCD). The large variation of chemical shifts from protons located around the interior of the hydrophobic cavity (i.e. H-3, H-5 and H-6) coupled with minimal variation of shifts from protons located on the outer sphere of the βCD (i.e. H-1, H-2 and H-4) provided clear evidence of inclusion complexation. In the presence of the different CDs, the aromatic protons of NC were the most affected, suggesting a strong involvement of the phenyl groups in the inclusion mechanism. The application of continuous variation method indicated the presence of complexes with a 1:1 host/guest stoichiometry for all the studied CDs. Two-dimensional rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiments were carried out to further support the proposed inclusion mode. Inspection of the ROESY spectra allowed the establishment of spatial proximities between several aromatic hydrogens of the guest and the CD protons, indicating that the inclusion occurs by accommodation of the two aromatic groups of NC. All the experimental data were further rationalized to elaborate possible three-dimensional geometric models of inclusion complexes. From the aforementioned observations, we concluded there is no preference for inclusion of a particular aromatic ring. Instead, two types of 1:1 complexes with different inclusion structures may exist simultaneously in solution, being alternatively included through the wider side of the cavity, i.e. the so-called multimodal inclusion occurs in the interaction of NC with the different CDs.     

Inclusion complexation of glibenclamide with 2-hydroxypropyl-β-cyclodextrin in solution and in solid state

Phase solubility diagrams have been used to investigate complexation between 2-hydroxypropyl-β-cyclodextrin (HPBCD) and glibenclamide (GM) in aqueous medium. More stable GM-HPBCD complexes were formed in alkaline medium (in which the drug is in ionized form) than in acid medium (in which the drug is in non-ionized form). The formation of solid GM-HPBCD inclusion complexes has been evaluated by using kneading, spray-drying and freeze-drying methods. Characterization of the resulting mixtures by X-ray diffraction, infrared spectroscopy and differential scanning calorimetry indicated that inclusion complexes can be obtained by spray drying and freeze drying but not by kneading. According to the phase solubility results, drug solubility in alkaline medium was greatly improved by inclusion with HPBCD, whereas in acid medium inclusion with HPBCD had no appreciable effect. Cyclodextrin complexation of ionized drug molecules in alkaline medium resulted in greater total solubilization, i.e., solubilization of the drug due to both cyclodextrin complexation and ionization.     

Conformational investigation of α,β-dehydropeptides VII*. Conformation of Ac-Pro-ΔAla-NHCH3 and Ac-Pro-(E)-ΔAbu-NHCH3: comparison with (Z)-substituted α,β-dehydropeptides†

The crystal structure and solution conformation of Ac-Pro-ΔAla-NHCH₃ and the solution conformation of Ac-Pro-(E)-ΔAbu-NHCH₃ were investigated by X-ray diffraction method and NMR, FTIR and CD spectroscopies. Ac-Pro-ΔAla-NHCH, adopts an extended-coil conformation in the crystalline state, with all-trans peptide bonds and the ΔAla residue being in a C₅ form, φ₁=– 71.4(4), ψ₁=– 16.8(4), φ₂=– 178.4(3) and ψ₂= 172.4(3)°. In inert solvents the peptide also assumes the C₅ conformation, but a γ-turn on the Pro residue cannot be ruled out. In these solvents Ac-Pro-(E)- ΔAbu-NHCH₃ accommodates a βII-turn, but a minor conformer with a nearly planar disposition of the CO—NH and C=C bonds (φ₂～0°) is also present. Previous spectroscopic studies of the (Z)-substituted dehydropeptides Ac-Pro-(Z)- ΔAbu-NHCH, and Ac-Pro-ΔVal-NHCH₃ reveal that both peptides prefer a βII-turn in solution. Comparison of conformations in the family of four Ac-Pro-ΔXaa-NHCH₃ peptides let us formulate the following order of their tendency to adopt a β-turn in solution: (Z)- ΔAbu > (E)- δAbu > ΔVal; ΔAla does not. None of the folded structures formed by the four compounds is stable in strongly solvating media. © Munksgaard 1996.     

Pharmacological profiles of β-funaltrexamine (β-FNA) and β-chlornaltrexamine (β-CNA) on the mouse vas deferens preparation

The profiles of action of β-funaltrexamine (β-FNA) and β-chlornaltrexamine (β-CNA) have been assessed in the mouse vas deferens preparation. β-FNA, but not β-CNA, demonstrated a reversible agonist action that appeared to be mediated via κ-receptor interaction. β-CNA produced an irreversible antagonism of μ-, κ- and δ-mediated agonist actions, whereas β-FNA irreversibly antagonized μ-mediated agonist effects only. This selective action of β-FNA could also be seen following administration in vivo. β-CNA and particularly β-FNA should prove valuable in the elucidation of multiple opioid receptors.     

Effects of N-substituted analogs of (−)-α-acetylmethadol and (−)-α-methadol on schedule-controlled behavior

The behavior of the pigeon maintained under a variable-interval schedule of food presentation was used to compare the activity of four novel N-substituted acetylmethadol and methadol analogs with that of methadone and (-)-α-acetylmethadol (LAAM). All of the acetylmethadol and methadol analogs had narcotic agonist activity, as defined by the reversibility of their behavioral effects by naloxone. The effect of the N-substituted analogs on variable-interval responding was similar to that of methadone and LAAM, but all these compounds had a slower onset of action than methadone and a shorter duration of action than LAAM. None of the N-substituted analogs showed narcotic antagonist activity when tested against methadone.     

Interaction of 6-p-toluidinylnaphthalene-2-sulphonate with β-cyclodextrin

The present study examines the complexation of β-cyclodextrin (β-CD) with 6-p-toluidinylnaphthalene-2-sulfonate (TNS), a fluorescent probe for exploring hydrophobic regions of several biological substances. The complexation was monitored in aqueous solution by ultraviolet spectrophotometry. At first, the stoichiometry of the formed complex was examined by applying the continuous variation (Job plot) method. Next, the kinetic of the complex formation as well as the determination of the stability constant were calculated by monitoring the spectrophotometric properties of TNS in the presence of increasing concentrations of β-CD applying both linear and nonlinear models. The results suggested that TNS forms a stable complex with β-CD with a stability constant of 1109 M⁻¹ and 1:1 molar ratio, at least at the examined concentrations.     

Elevation of serum 17-β-estradiol in channel catfish following injection of 17-β-estradiol, ethynyl estradiol, estrone, estriol and estradiol-17-β-glucuronide

17-β-Estradiol is naturally converted in numerous organisms to various derivatives/metabolites, which may be excreted from the organism into its immediate external environment. There is a paucity of data regarding the biological effects of these derivatives/metabolites on aquatic organisms. Male channel catfish (200–500 g, N=5, 12–18 months) were injected with 1 mg/kg 17-β-estradiol (E2), ethynyl estradiol (EE2), estrone, estriol or E2-17-β-glucuronide with subsequent measurements of vitellogenin (Vtg) and serum E2 concentrations 7 days post injection. EE2 and E2 gave the largest magnitude of Vtg response followed by estrone and estriol. Exposure to EE2, estrone, and E2-17-β-glucuronide all induced significant increases in serum E2 concentrations. This study indicates that metabolites of E2 are also estrogenic and may potentially disrupt estrogen feedback loops within aquatic organisms.     

Density functional calculations on meloxicam–β-cyclodextrin inclusion complexes

The geometries of the cyclodextrin (CD) inclusion complexes with various tautomeric forms of meloxicam in gas phase were determined by DFT calculation (B3LYP/6-31G (d,p)). The interaction energies were estimated including basis set superposition error (BSSE) correction. Two orientations of the meloxicam guest were considered: the benzene ring located near the narrow rim and at the wider rim of the β-cyclodextrin, respectively. The calculations show that in all cases the molecules are located inside the CD cavity. The preferred complexation orientation is that one, in which the benzene ring of meloxicam is located near the wider rim with the secondary hydroxyl groups of the CD. The stabilization energies for the encapsulation of the meloxicam guest molecules show an overall affinity ranking for the meloxicam guest molecule in the following order: anionic (deprotonated) form > zwitterionic form  enolic form > cationic (protonated) form. A comparison of the enolic and zwitterionic neutral forms shows, that the zwitterionic structure is better stabilized upon complexation due to the geometry of two extra hydrogen bonds between host and guest.     

Structure elucidation of the tetrahydrocannabinol complex with randomly methylated β-cyclodextrin

The low aqueous solubility of the bioactive cannabinoid tetrahydrocannabinol (THC) is a serious obstacle for the development of more efficient administration forms. In this study the aqueous solubility of THC was tested in the presence of -, β- and γ-CD, and randomly methylated β-CD (RAMEB). It was found that only RAMEB was able to increase the aqueous solubility of THC to a significant level. A THC concentration of about 14 mg/ml was reached by using a 24% (187 mM) RAMEB solution, which means an increase in solubility of four orders of magnitude. The resulting THC/RAMEB complex was investigated through phase-solubility analysis, complemented by ¹H NMR, NOESY- and UV-studies in order to obtain details on the stoichiometry, geometry and thermodynamics of the complexation. The binding ratio of THC to CD was found to be 2:1, with the second THC molecule bound by non-inclusion interactions. Based on the obtained results a model for the complex structure is presented. Stability of the complex under laboratory room conditions was tested up to 8 weeks. Results show that complexation with RAMEB seems to be promising for the development of water-based THC formulations.     

Anti-inflammatory,Analgesic and Ulcerogenic Properties of S-(+)-Ibuproxam,Racemic Ibuproxam-β-cyclodextrin and S-(+)-Ibuproxam-β-cyclodextrin

The anti-inflammatory, analgesic and gastric mucosal damage-inducing activities of S-(+)-ibuproxam, and S-(+)-ibuproxam-β-cyclodextrin, new propionic acid derivatives, and racemic ibuproxam-β-cyclodextrin were investigated in three animal models and compared with those of racemic ibuproxam, racemic ibuprofen and its optical enantiomer S-(+)-ibuprofen. The anti-inflammatory activities of racemic ibuprofen, S-(+)-ibuprofen and racemic ibuproxam in carrageenan-induced paw oedema in rats were almost equipotent and slightly greater than those of S-(+)-ibuproxam and S-(+)-ibuproxam-β-cyclodextrin, and significantly greater than that of racemic ibuproxam-β-cyclodextrin. In abdominal constriction tests in mice, the analgesic effects of racemic ibuproxam, S-(+)-ibuproxam, racemic ibuproxam-β-cyclodextrin and S-(+)-ibuproxam-β-cyclodextrin were significantly less pronounced than those of racemic ibuprofen and S-(+)-ibuprofen. Ulcerogenic activity of S-(+)-ibuproxam-β-cyclodextrin in rats was found to be significantly weaker than that of racemic ibuproxam-β-cyclodextrin, racemic ibuproxam and S-(+)-ibuproxam and, most notably, weaker than those of racemic ibuprofen ans S-(+)ibuprofen. These results indicate that S-(+)-ibuproxam-β-cyclodextrin could be a novel potent anti-inflammatory and analgesic agent with a therapeutic index more favourable than that of the classical non-steroid anti-inflammatory drugs ibuprofen and ibuproxam.     

Complexation of ursodeoxycholic acid with β-cyclodextrin–choline dichloride coprecipitate

The inclusion complexes of ursodeoxycholic acid (UDCA) with β-cyclodextrin (βCD) coprecipitated with choline dichloride (CDC) or β-cyclodextrin were investigated to evaluate the effect of the presence of choline for UDCA inclusion in βCD. The inclusion complexes were investigated in solution by phase solubility diagrams and ¹H NMR spectrometry and in solid state (kneading, freeze-drying, sealed heating and spray-drying) by DSC, SEM, HSM, XRD and IR spectroscopy. Stability constants were determined at pH 5.5 and 7.0 to simulate the environmental pH of the first intestinal tract and at different temperatures (25, 30 and 37°C) to obtain the thermodynamic parameters of inclusion. Both βCD–CDC and βCD increased the water solubility of UDCA particularly βCD–CDC. All complexes showed a high dissolution rate particularly the spray-dried complexes obtained in the presence of βCD–CDC.     

Conformational investigation of α,β-dehydropeptides. IX. N-Acetyl-(E)-α,β-dehydrobutyrine N′-methylamide: stereoelectronic properties from infrared and theoretical studies*

Abstract: : The Fourier transform infrared spectra of Ac-(E)-ΔAbu-NHMe were analyzed to determine the predominant solution conformation (s) of this (E)-α,β-dehydropeptide-related compound and the electron density perturbation in its amide groups. The measurements were performed in dichloromethane and acetonitrile in the region of mode v_s (N–H), amide I, amide II and v_s (C^α= C^β). The equilibrium geometrical parameters, calculated by a method based on the density functional theory with the B3LYP functional and the 6–31G* basis set, were used to support spectroscopic interpretation and gain some deeper insight into the molecule. The experimental and theoretical data were compared with those of three previously described molecules: isomeric Ac-(Z)-ΔAbu-NHMe, Ac-ΔAla-NHMe, which is deprived of any β-substituent, and saturated species Ac-Abu-NHMe. The titled compound assumes two conformational states in equilibrium in the DCM solution. One conformer is extended almost fully and like Ac-ΔAla-NHMe is C₅ hydrogen-bonded. The other adopts a warped C₅ structure similar to that of Ac-(Z)-ΔAbu-NHMe. The C₅ hydrogen bond, unlike the H-bond in Ac-ΔAla-NHMe, is disrupted by acetonitrile. The resonance within the N-terminal amide groups in either of the (E)-ΔAbu conformers is not as well developed as the resonance in Ac-Abu-NHMe. However, these N-terminal groups, compared with the other unsaturated compounds, constitute better resonance systems in each conformationally related couple: the C₅ hydrogen-bonded Ac-(E)-ΔAbu-NHMe/Ac-ΔAla-NHMe and the warped C₅ Ac-(E)-ΔAbu-NHMe/Ac-(Z)-ΔAbu-NHMe. The resonance within the C-terminal groups of the latter couple apparently is similar, but less developed than the resonance in Ac-Abu-NHMe. The electron distribution within the C-terminal group of the hydrogen-bonded C₅ (E)-ΔAbu conformer apparently is determined mainly by the electron influx from the C^α= C^β double bond.