Apparent Stability Constants Research Articles

Enhancing Effect of Phenylboronic Acid Compounds and Their Interactions with the Diol Groups of Saccharides in a Capillary Electrophoresis-Chemiluminescence Detection System

In our previous study, we proposed molecular recognition of mono- and disaccharides making use of the interaction between their diol groups and p-iodophenylboronic acid in capillary electrophoresis with a chemiluminescence detection system. Here, to extend our knowledge of molecular recognition, we first examined the enhancing effects of four phenylboronic acid compounds other than p-iodophenylboronic acid i.e., 4-biphenylboronic acid, 4-octyloxyphenyl-boronic acid, 3-octyloxyphenylboronic acid, and 4-dodecyloxyphenylboronic acid, for luminol-hydrogen peroxide-horseradish peroxidase reaction in the capillary electrophoresis-chemiluminescence detection system. Only 4-biphenylboronic acid showed an enhancing effect similar to that of p-iodophenylboronic acid; the effect was determined over the range of 0.5-10 microM in this system. Second, we estimated the apparent stability constants between the diol groups of saccharides (1-methyl-D-glucoside, D-saccharose, and D-fructose) and the boronic acid moieties of the two enhancers, p-iodophenylboronic acid and 4-biphenylboronic acid. The apparent binding constants obtained here provided insight to confirm the principle of molecular recognition for the saccharides examined here.

Assessment of Chelatable Mitochondrial Iron by Using Mitochondrion‐Selective Fluorescent Iron Indicators with Different Iron‐Binding Affinities

Chelatable cellular iron, and chelatable mitochondrial iron in particular, has yet to be well characterized, so the overall strength with which these "loosely bound" iron ions (presumably mainly Fe(II)) are intracellularly/intramitochondrially bound is unclear. We have previously reported the first selective mitochondrial iron indicator: rhodamine B 4-[(1,10-phenanthrolin-5-yl)aminocarbonyl]benzyl ester (RPA). With this compound as a model, we have now developed two additional mitochondrial iron indicators with very different iron-binding affinities and have applied these to the study of the chelatable iron pool in the mitochondria of isolated rat liver cells. With the new indicator rhodamine B 4-[(2,2'-bipyridin-4-yl)aminocarbonyl]benzyl ester (RDA), with 2,2'-bipyridine as chelating unit (log beta(3)=17.5), essentially the same iron concentration (16.0+/-1.9 microM) was determined as with RPA (log beta(3)=21.1), despite the four orders of magnitude difference in Fe(II)-binding affinity. This not only demonstrates the reliability of the procedure, but also confirms that iron complexation by these indicators does not induce any significant release of iron from the iron-storage proteins on the timescale of the experiment. In contrast, the indicator rhodamine B 4-[bis(pyridin-2-ylmethyl)aminomethyl]benzyl ester (PIRO), with an N,N-bis(pyridin-2-ylmethyl)amine group as chelating component (log beta(2)=12.2), could not compete against the array of endogenous ligands. The intramitochondrial concentrations of the three indicators were determined to be in the range of 100 microM: that is, about three orders of magnitude lower than the total concentration of endogenous compounds that might chelate iron ions. It is therefore estimated that chelatable mitochondrial iron ions are bound by endogenous ligands with apparent stability constants (log K(app)) of between 9 and 14.

Synthesis, Structure, and Activity of Supramolecular Mimics for the Active Site and Arg141 Residue of Copper, Zinc−Superoxide Dismutase

Two supramolecular complexes, [Cu(L)(H2O)2(beta-CD)](ClO4)2.10.5H2O.CH3OH (1) and [Cu(L)(H2O)2(beta-GCD)](HClO4)(ClO4)2.10H2O (2) (L = 4-(4'-tert-butyl-benzyl)diethylenetriamine, beta-CD = beta-cyclodextrin, and beta-GCD = mono-6-deoxy-6-guanidinocycloheptaamylose cation), have been synthesized. The structure of 1 has been characterized by X-ray crystallography. The 4-tert-butyl-benzyl of [Cu(L)(H2O)2]2+ moiety in 1 as a guest inserts into the hydrophobic cavity of the beta-CD as a host along the primary hydroxyl side. On the basis of the structure data of 1, complex 2 was modeled, which showed that the distance between the Cu and C atom of the guanidinium is 5.2 A, comparable to the corresponding distance in bovine erythrocyte Cu, Zn-SOD (5.9 A) (SOD = superoxide dismutase). Apparent inclusion stability constants of the host and the guest were measured to be 0.66 (+/-0.01) x 104 and 1.15 (+/-0.03) x 104 M-1 for 1 and 2 respectively. The electronic absorption bands and electronic reflection bands of each complex are almost the same, indicating an identical structure of the complex in aqueous solution and in solid state. The two complexes showed quasi-reversible one-electron Cu(II)/Cu(I) redox waves with redox potentials of -0.345 and -0.338 V for 1 and 2, respectively. Their SOD-like activities (IC50) were measured to be 0.30 +/- 0.01 and 0.17 +/- 0.01 microM by xanthine/xanthine oxidase-NBT assay. The enhanced SOD activity of 2 by approximately 40% compared with 1 suggests that the guanidyl cation in the host of the supramolecular system of 2 can effectively mimic the side chain of Arg141 in the enzyme, which is known to be essential for high SOD activity possibly through steering of the superoxide substrate to and from the active copper ion.

Effect of alkylimidazolium substituents on enantioseparation ability of single-isomer alkylimidazolium-β-cyclodextrin derivatives in capillary electrophoresis

A family of 6-mono(3-alkylimidazolium)-β-cyclodextrins with one primary hydroxyl group replaced by an alkylimidazolium cation has been developed. The effect of alkyl substitutents on the enantioresolution ability of these single-isomer cyclodextrins towards dansyl amino acids has been studied by capillary electrophoresis. Systematical investigations on the effect of buffer pH and selector concentration on the enatioseparation show that chiral selectors with a shorter alkyl chain (R = C n H 2 n+1 , n ≤ 4) presented more powerful chiral recognition ability. These newly introduced single-isomer β-cyclodextrin derivatives proved to be effective chiral selectors for most selected dansyl amino acids at low buffer pH (e.g. pH 5.0) with selector concentration no less than 3 mM. The apparent complex stability constants between alkylimidazolium β-CDs and dansyl amino acids were also theoretically determined by using the mobility difference model proposed by Wren and Rowe. The side alkyl chains from both dansyl amino acids and alkylimidazolium β-CDs displayed significant effect on the apparent complex stability constants. Both the optimum selector concentrations calculated according to the model, however, were much lower than the experimental values giving the maximum chiral resolution of enantiomers.

Synthesis of a novel bistriazene reagent 4,4′- bis[3-(4-phenylthiazol-2-yl)triazenyl]biphenyl and its highly sensitive color reaction with mercury(II)

We report the synthesis of a novel bistriazene, 4,4′- bis(3-(4-phenylthiazol-2-yl)triazenyl)biphenyl (BPTTBP), and its highly sensitive color reaction with Hg 2+. The new reagent was synthesized in good yield by coupling 2-amino-4-phenylthiazole with 4,4′-biphenyldiamine bisdiazonium salt. Using a blend of surfactants N-cetylpyridinium chloride (CPC) and polyethylene glycol n-octanoic phenyl ether (OP) as a micelle sensitizer, the red colored reagent assembles with Hg 2+ in pH 9.8 borate buffer according to a 1:1 stoichiometry, forming a blue oligomeric/polymeric chelating complex with a high apparent stability constant (1.1 × 10 8 M −1). Whereas the maximum absorption of reagent occurs at 510 nm with an extinct coefficient of 1.35 × 10 4 M −1 cm −1, the complex absorbs at 611 nm, with an apparent extinct coefficient of 1.04 × 10 5 M −1 cm −1. Beer's law is obeyed in the range of 0–15 μg/25 mL Hg 2+, and Sandell's sensitivity is 1.92 × 10 −3 μg/cm 2. In the presence of thiourea and Na 4P 2O 7 as masking agents, the method was found free from interferences of foreign ions commonly occurring with mercury. The optimized protocol has been successfully applied to spectrophotometric determination of mercury in waste water samples. The features of the new reagent associated with its special structure were discussed, and an unprecedented “domino effect” was proposed to account for its unique chelating stoichiometry with Hg 2+.

Investigation and Physicochemical Characterization of Clarithromycin–Citric Acid–Cyclodextrins Ternary Complexes

ABSTRACTThe purpose of this study was to investigate the effect of citric acid (CA) on the complexation of clarithromycin (CLM) with β-cyclodextrin (βCD) in aqueous solutions and in the solid state. A phase solubility study revealed a positive effect of CA on the drug solubility. A Bs-type solubility with an apparent stability constant (Kc) of 102.4 M−1 was obtained for CLM in βCD solution and 161.2 M−1 for CLM in 6 mM βCD solution. Solid ternary complexes were prepared by coevaporation and lyophilization. CLM–βCD–CA interactions were studied in the solid state by differential scanning calorimetry (DSC), infrared spectroscopy, scanning electron microscopy and X-ray diffractometry. A part of the guest molecule was located in the βCD host cavity. The results obtained suggest that the lyophilization method yields a higher degree of amorphous entity than coevaporation.

Molecular Complex Consisting of Two Typical External Medicines: Intermolecular Interaction between Indomethacin and Lidocaine

The molecular complex formed between indomethacin (IDM) and lidocaine (LDC), which are typical external medicines, was studied. A thermal analysis, microscopic study and phase solubility technique suggested intermolecular interaction between IDM and LDC. The phase solubility profiles with IDM and LDC were classified as A(L)-type, indicating the formation of a 1 : 1 stoichiometric molecular complex. The apparent stability constant (K(S)), calculated from the slope and the intercept, was 4478.9 M(-1). A molecular ion peak was detected at 592.2 (m/z) from fast-atom bombardment-MS measurements, which was in accordance with the sum of the molecular weight for IDM (M(W): 357.81) and LDC (M(W): 234.38). The changes of IR spectra in the C=O stretching region showed that each intact hydrogen bond network was collapsed in the IDM-LDC system and strong interaction between IDM and LDC formed after their kneading. From the (1)H-NMR analyses, it was estimated that the dominant interactive site was the IDM carboxylic acid group which associated with the LDC diethyl amino group non-covalently.

ION-EXCHANGE STUDY OF THE COMPLEX FORMATION OF SOME CONDENSED PHOSPHATE OLIGOMERS WITH Al3+ AND Cu2+ ION

In this paper, the complex formations of cyclo-polyphosphates and linear polyphosphates with copper(II), and aluminum ions were investigated by both cation- and anion-exchange methods. From the apparent stability constants of cyclo-polyphosphate complexes, it was shown that their complex formations with both cations are due to electrostatic forces. On the other hand, the complex formations between linear polyphosphates and cations might be ascribed to the covalent bond.

Interaction of Omeprazole with a Methylated Derivative of β-Cyclodextrin: Phase Solubility, NMR Spectroscopy and Molecular Simulation

Cyclodextrins are known to be good solubility enhancers for several drugs, improving bioavailability when incorporated in pharmaceutical formulations. In this work we intend to assess and characterize the formation of inclusion complexes between omeprazole (OME) and a methylated derivative of beta-cyclodextrin, methyl-beta-cyclodextrin (MbetaCD). A comparison with results obtained from the most commonly used natural cyclodextrin, beta-cyclodextrin (betaCD) is also presented in most cases. The interaction of OME with the mentioned cyclodextrins in aqueous solutions was studied by phase solubility studies, 1D (1)H and 2D rotating frame nuclear overhauser effect NMR spectroscopy (ROESY) and Molecular Dynamics. The solubility of OME was significantly increased by formation of inclusion complexes with each cyclodextrin. Phase solubility studies and continuous variation plots revealed that OME forms an inclusion complex in a stoichiometry of 1:1 with both cyclodextrins. (1)H NMR and ROESY spectra of the inclusion complexes indicated that the benzimidazole moiety is included within the cyclodextrins cavities. Molecular dynamics showed that OME is more deeply included in the MbetaCD than in betaCD cavity, in agreement with a larger apparent stability constant (K (S)) obtained for the inclusion complex with MbetaCD. MbetaCD proved to be an efficient enhancer of OME solubility, thus possessing characteristics for being an useful excipient in pharmaceutical formulations of this drug.

Sorption of Thiocyanate Silver Complexes and Determination of Silver by Diffuse Reflectance Spectroscopy

The present paper is focused on sorption concentration of silver (I) on some complex-forming ion exchangers in the initial thiocyanate form and subsequent determination of Ag(I) in the phase of anion exchanger AN-25 by diffuse reflectance spectroscopy. The sorption and kinetic characteristics of the sorbents were investigated. The apparent stability constants of thiocyanate silver complexes in the ion exchanger phase were calculated. The sorption-spectroscopic method is proposed for Ag(I) determination in aqueous solutions. The calibration curve is linear in the concentration range of 10-200 mg/L (sample volume is 10.0 mL) and the detection limit is 2 g/mL. The presence of (macrocomponents) as well as of Ni (II), Co (II), Cu (II) do not hinder the determination of silver (I).

Study of the interaction between S(−) bupivacaine and 2-hydroxypropyl-β-cyclodextrin

Local anesthetics are substances able to induce pain relief by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of nervous impulses. S(−) bupivacaine ( S(−) bvc) is an amide type local anesthetic widely used in surgery and obstetrics for sustained peripheral and central nerve blockade. The present work focuses on the characterization of an inclusion complex of S(−) bvc in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The complexation with HP-β-CD has been investigated using reversed-phase liquid chromatography and solubility isotherms. The retention behavior was analyzed on a reversed phase C 18 column and the mobile phase used was acetonitrile–phosphate buffer pH 7.4 (10 mM), (45/55, v/v), in which HP-β-CD was incorporated as a mobile phase additive. The decrease in the retention times with increasing concentration of HP-β-CD enables the determination of the complex apparent stability constants by HPLC as a function of temperature. The solubility isotherms were studied as a function of pH (7.4 and 10.5) and temperature. The pH study showed that S(−) bvc reaches a concentration at least 1.5 and 4.5 times higher (pH 7.4 and 10.5, respectively) than the one presented by the free drug in water. The calculated values for the apparent stability constant ( K) are 13.1 ± 2.8 and 95.4 ± 11.8 M −1 for pH 7.4 and 10.5, respectively, thus indicating the formation of a stable complex. In addition, the study of the apparent stability constant by HPLC and solubility isotherm gives thermodynamics information about the interaction between S(−) bvc and HP-β-CD. The application of the continuous variation method indicated the presence of a complex with 1:1 S(−) bvc:HP-β-CD stoichiometry. This is an important study for the characterization of potential formulations to be used as therapeutic options for the treatment of pain.

Evaluation of Powdered Infant Formula Milk as Chelating Agent for Copper under Simulated Gastric Conditions of a Baby’s Stomach

The objective of this study was to determine the complexing capacity of four types of powdered commercial milks with copper(II) using square wave adsorptive stripping voltammetry. Two were types of cow milk adapted for babies under one year (A and B), one was soymilk (C) and the other was normal milk (D). Milk solutions were prepared following the instructions shown on the milk container, and they were mixed with a pepsin solution simulating a baby's stomach conditions (pepsin and salts concentration, pH and temperature). Complexing capacity was determined by titrating milk samples with aliquots of a standard copper solution until the peak current due to solvated or free copper ions was increasing. Assuming a 1:1 copper-milk complex, the apparent stability constant was found using the pseudopolarogram method. The log K'(Cu-milk) values were 4.9, 5.0, 3.0 and 5.1 for A, B, C and D types of milk, respectively. Voltammograms of the milk solution as a function of copper added show that the binding properties of the four types of powdered milk studied were different and that saturation of the four types, occurs at different copper concentrations. Concentrations obtained were: 4.9, 5.8, 1.1 and 10.1 mM for A, B, C and D types, respectively. The best complexing agent was the solution prepared with powdered milk D and the worst was that of C. This is important for the bioavailability of this element as a micronutrient.

Determinations of the inclusion complex between gossypol and β-cyclodextrin

Features of the inclusion complex between gossypol (Gos) and β-cyclodextrin (CD), such as its aqueous solubility, association constant, characteristics in the solid state and crystalline morphology, as well as the stoichiometry of this complex have been determined. The phase–solubility diagram drawn using UV detections belongs to an AN-type. Fluorescence detection and calculation with the modified Benesi–Hidebrond equation provide an 1:2 stoichiometry for the complex. Its apparent stability constant has been determined to be 3203 M −1 by fluorescence technique and confirmed by the calculation from UV spectroscopy. X-ray powder diffractions (XRD) and Scanning Electron Microscopy (SEM) observations showed a clear difference in the crystal morphology of the complex from those of both Gos and β-CD.

The stability and solubility of cadmium(II)-8-oxyquinoline complexes in water and micellar solutions of sodium dodecyl sulfate

The formation of cadmium 8-oxyquinoline (HOx) complexes in water and a 0.01 M aqueous solution of sodium dodecyl sulfate (293 K, 0.01) was studied by pH-metric titration. Mathematical simulation of the most probable equilibria gave complex formation constants logβ1 = 6.17 ± 0.32 (CdOx+) and logβ2 = 14.60 ± 0.14 (CdOx2) in aqueous solution and apparent stability constants logβ1 = 8.64 (CdOx+) and logβ2 = 17.59 (CdOx2) in a solution of dodecyl sulfate. The solubility of cadmium dioxyquinolate in water at pH from 3 to 6 and a micellar sodium dodecyl sulfate medium was determined by the method of saturated solutions. The solubility product pLp = 21.3 ± 0.9 (H2O, 293 K) was calculated by modeling the solution of CdOx2 with taking into account all acid-base interactions and complex formation reactions.

Characterization of Complexes Between Naftifine and Cyclodextrins in Solution and in the Solid State

Naftifine (NF) is an antifungal drug poorly soluble in basic aqueous solutions. Complexation with cyclodextrins (CDs) improves the physicochemical characteristics of many drugs. The aim of this work is to characterize the interactions between NF and alpha-CD, beta-CD, hydroxypropylbeta-CD, methylbeta-CD, and gamma-CD. The studies have been developed in pH 12 aqueous solutions at 25 degrees C and in the solid state. The apparent stability constants of the complexes have been determined from phase-solubility diagrams. In the solid state, crystalline and amorphous complexes have been characterized using X-ray diffraction patterns, thermal analysis, and Fourier transform infrared spectroscopy. The solubility of NF improves with all the CDs studied, with the exception of alpha-CD. Different types of diagrams have been found depending on the CD used. The interaction between NF and hydroxypropylbeta-CD is stronger than that with beta-CD due to the specific properties of the substituents. The coevaporation method can be said the best method in preparing the solid complexes, except for NF-alpha-CD; again, there is no evidence of complexation. Furthermore, the presence of different types of CD structures upon complexation (i.e., cage or channel) has been discussed. Dissolution rate studies have been performed, and a positive influence of complexation in the solid state has been observed.

Solubility and Dissolution Rate of Progesterone-Cyclodextrin-Polymer Systems

ABSTRACTThis contribution focused on the solubility improvement of the poorly water-soluble steroid hormone progesterone which, in its natural state, presents a reduced oral bioavailability. In the first part of this study, two simple, reproducible methods that were candidates for use in the preparation of inclusion complexes with cyclodextrins were investigated. Solubility capacities of the progesterone complex with hydroxypropyl-β-CD (HPβ-CD), hydoxypropyl-γ-CD (HPγ-CD), permethyl-β-CD (PMβ-CD), and sulfobutylether-β-CD (SBEβ-CD), prepared by the freeze-drying and precipitation methods, were evaluated by Higuchi phase solubility studies. The results showed that HPβ-CD and PMβ-CD were the most efficient among the four cyclodextrins for the solubilization of progesterone, with the highest apparent stability constants. Therefore, dissolution studies were conducted on these latest progesterone/cyclodextrin complexes and physical mixtures. Two additional natural cyclodextrins, β-CD and γ-CD, were taken as references. Hence, the influence of more highly soluble derivatives of β‐CD (HPβ-CD, PMβ-CD) on the progesterone dissolution rate, in comparison to pristine β-CD, alongside an increase in the cavity width for γ-CD versus β-CD, were investigated. The dissolution kinetics of progesterone dissolved from HPβ-CD, PMβ-CD, and γ-CD revealed higher constant rates in comparison to β-CD. Therefore, the aim of the second part of this study was to investigate the possibility of improving the dissolution rate of progesterone/β-CD binary systems upon formation of ternary complexes with the hydrophilic polymer, PEG 6000, as β-CD had the smallest progesterone solubility and dissolution capacity among the four cyclodextrins studied (β‐CD, HPβ-CD, HPγ-CD and PMβ-CD). The results indicated that dissolution constant rates were considerably enhanced for the 5% and 10% progesterone/β-CD complexes in PEG 6000.The interaction of progesterone with the cyclodextrins of interest on the form of the binary physical mixtures, complexes, or ternary complexes were investigated by differential scanning calorimetry (DSC) and Fourier transformed-infrared spectroscopy (FT-IR). The results proved that progesterone was diffused into the cyclodextrin cavity, replacing the water molecules and, in case of ternary systems, that the progesterone β-cyclodextrin was well dispersed into PEG, thus improving progesterone bioavailability for subsequent oral delivery in the same way as derivatized cyclodextrins. The present work proves that ternary complexes are promising systems for drug encapsulation.

Melarsoprol–cyclodextrins inclusion complexes

Melarsoprol, a water-insoluble drug, is mainly used in the treatment of trypanosomiasis and has demonstrated an in vitro activity on myeloid and lymphoid leukemia derived cell lines. It is marketed as a very poorly tolerated non-aqueous solution (Arsobal ®). The aim of our work was to develop melarsoprol–cyclodextrin complexes in order to improve the tolerability and the bioavailability of melarsoprol. Phase-solubility analysis showed A L-type diagrams with β-cyclodextrin (βCD), randomly methylated β-cyclodextrin (RAMEβCD) and hydroxypropyl-β-cyclodextrin (HPβCD), which suggested the formation of 1:1 inclusion complexes. The solubility enhancement factor of melarsoprol (solubility in 250 mM of cyclodextrin/solubility in water) was about 7.2 × 10 3 with both β-cyclodextrin derivatives. The 1:1 stoichiometry was confirmed in the aqueous solutions by the UV spectrophotometer using Job's plot method. The apparent stability constants K 1:1, calculated from mole–ratio titration plots, were 57 143 ± 4 425 M −1 for RAMEβCD and 50 761 ± 5 070 M −1 for HPβCD. Data from 1H-NMR and ROESY experiments provided a clear evidence of inclusion complexation of melarsoprol with its dithiaarsane extremity inserted into the wide rim of the cyclodextrin torus. Moreover, RAMEβCD had a pronounced effect on the drug hydrolysis and the dissolution rate of melarsoprol. However, the cytotoxic properties of melarsoprol on K562 and U937 human leukemia cell lines was not modified by complexation.

Improvement of Solubility and Stability of Valsartan by Hydroxypropyl-\boldbeta-Cyclodextrin

Aim of the present work was to investigate the effect of hydroxypropyl-β-cyclodextrin (HP-β-CD) on the solubility, dissolution rate and stability of Valsartan (VAL), a drug used orally for the treatment of hypertension. Phase solubility studies demonstrated the ability of the HP-β-CD to complex VAL and to increase drug solubility. The dissolved amount of VAL increased linearly with the addition of HP-β-CD according to an AL type plot. The apparent stability constant of the complex, calculated supposing a 1:1 stoichiometry, was 296±7 M−1. VAL/HP-β-CD interactions were also studied by 13C-NMR spectroscopy. Equimolar VAL/HP-β-CD solid systems were prepared by physical-mixing and freeze-drying, and their properties in the solid state studied by DSC and FT-IR analysis. The results provided clear indications of the formation of a new solid phase corresponding to the inclusion complex in the freeze-dried sample. The dissolution profiles of the drug from each solid system were affected by its physico-chemical properties, the freeze-dried being the most rapidly dissolving form. The thermal stability of the complex was studied, also determining the number and identity of the decomposition products of the drug. The stability studies revealed that the VAL/HP-β-CD complex significantly decreases the rate of VAL degradation. These results suggest that CD technology would be a very useful method to overcome the solubility and the stability problems of VAL.

Evaluation of cyclodextrin solubilization of drugs

The most common stoichiometry of drug/cyclodextrin complexes is 1:1, i.e. one drug molecule forms a complex with one cyclodextrin molecule, and the most common method for stoichiometric determination during formulation studies is the phase-solubility method. However, in recent years it has becoming increasingly clear that solubilizing effects of cyclodextrins are frequently due to the formation of multiple inclusion and non-inclusion complexes. The aqueous solubility of 38 different drugs was determined in pure aqueous solution, aqueous buffer solutions and aqueous cyclodextrin solutions, and the apparent stability constant ( K 1:1) of the 1:1 drug/cyclodextrin complexes calculated by the phase-solubility method. For poorly soluble drugs (aqueous solubility <0.1 mM) the intrinsic solubility ( S 0) is in general much larger than the intercept of the phase-solubility diagram ( S int) resulting in non-linearity of otherwise linear ( A L-type) phase-solubility diagram. This can lead to erroneous K 1:1-values. A more accurate method for determination of the solubilizing efficiency of cyclodextrins is to determine their complexation efficiency (CE), i.e. the concentration ratio between cyclodextrin in a complex and free cyclodextrin. CE is calculated from the slope of the phase-solubility diagrams, it is independent of both S 0 and S int, and more reliable when the influences of different pharmaceutical excipients on the solubilization are being investigated.

Spectral properties and supramolecular inclusion complexes of β-cyclodextrin with flexible amphiphilic and rigid compounds

Spectral properties and inclusion complexes of β-cyclodextrin (β-CD) with nonionic amphiphiles and rigid 1-bromonaphthalene (BrN) was investigated in detail. Fluorescence and 1H NMR measurements give new insights into inclusion of the hydrophobic moiety of amphiphiles into the cavity of β-CD. Their apparent stability constants were well correlated with the structure of the hydrophobic moiety of amphiphiles. The long and flexible hydrophobic moiety may occupy the cavity in the compressed manner. The phosphorescence quenching and the binding strength of BrN in ternary complexes indicate that the inclusion depth and the rigidity of BrN in the cavity of β-CD are predominant factors in determining its phosphorescence. Further inclusion of rigid BrN into the cavity drives the built-in phenyl group of amphiphiles to expose to bulk water phase to a greater extent. Comparative analyses of molecular sizes and models reveal that the flexible hydrocarbon chain of an amphiphile in supramolecular inclusion complexes was located inside the crowded cavity of β-CD due to the filling of rigid BrN into the cavity.