Improvement of Solubility and Dissolution of 19-Norprogesterone via Inclusion Complexation

In an effort to modify the solubility and dissolution rate of the contraceptive steroid, 19-norprogesterone in order to improve its bioavailability, the cyclodextrin complexation approach was chosen. In solution, the complex formation with -cyclodextrin (-CD), hydroxyethyl -cyclodextrin (HE--CD) and hydroxypropyl -cyclodextrin (HP--CD) was confirmed by using solubility, UV, IR and ¹H-NMR spectrophotometric techniques. The phase solubility diagrams were categorized as A_L-type. The complexing affinity of the CDs investigated were ranked as follows: -CD > HP--CD > HE--CD. The complexation thermodynamic parameters were obtained from the temperature dependence of the dissociation constants. In the solid state, differential scanning calorimetery (DSC) and optical microscopy methods were utilized to characterize the complexes. Dissolution studies showed that such molecularly encapsulated forms offered a marked improvement in the dissolution rate compared to the parent drug.     

Binding of vitamin A byβ-cyclodextrin and heptakis(2,6-O-dimethyl)-β-cyclodextrin

Inclusion complexation of all-trans-retinol, retinal and retinoic acid with -cyclodextrin (-CD) and heptakis(2,6-O-dimethyl)--cyclodextrin (DM--CD) were investigated by means of UV-vis spectroscopy. The association constants (K _a) obtained for vitamin A with DM--CD is greater than with -CD. On the other hand, for the same host compoundK _a values of retinol, retinal and retinoic acid are very close to each other.     

Cucurbituril and β-Cyclodextrin as Hosts for the Complexation of Organic Dyes

The complexation of neutral organic molecules by cucurbituril and-cyclodextrin in formic acid was studied by means ofspectrophotometric titrations. In the case of -cyclodextrin thecomposition of the solvent has almost no influence upon the stability of thecomplexes formed. This situation is completely different for cucurbituril.Due to its interactions with protons the measured stability constants of thecomplexes formed with organic molecules increase with decreasing acidconcentration. At low acid concentrations cucurbituril forms more stablecomplexes with organic molecules than -cyclodextrin.     

Inclusion of Ring A of Cholesterol Inside the β-Cyclodextrin Cavity: Evidence from Oxidation Reactions and Structural Studies

The disposition of cholesterol inside the -cyclodextrin cavity(-CD) was deduced from oxidation of cholesterol secondary alcoholgroups by Ca(OCl)₂ and H₂O₂ in thepyridine–acetic acid system. The amount of cholest-4-ene-3-one formedwas found to be proportional to the concentration of -cyclodextrin,resulting in 56.1% of ketone. The oxidation rate was enhanced by-cyclodextrin and its methyl, polymer and 1 : 1copper(II)–-cyclodextrin derivatives. Detailed investigationsinvolving UV-visible, ¹³C- and ¹H-NMR(T₁, 1D NOE and ROESY) spectroscopic studies were carried out.A binding constant value of 15,385 ± 1500 M^-2 wasobtained for the 2 : 1heptakis-2,6-di-O-methyl--cyclodextrin(DM-CD) : cholesterolcomplex in chloroform from UV studies. Proton and solid state¹³C-CP MAS spectra of the -CD–cholesterol mixtureshowed large magnitude shifts for the protons from the wider end of the-CD cavity as well as those of ring A and ring B of cholesterol. Both1D NOE and ROESY measurements indicated the proximity between ring A andring B protons of cholesterol and the wider end protons of -CD andDM-CD. Besides, analysis of _c,_i and tau;_m from T₁measurements showed not only a lowering of rotational motions but a value of 0.016–0.048 for some of the cholesterol protons, typical of aweak complex. Based on these studies, a probable structure for the 2 : 1complex involving two molecules of -CD/DM-CD was proposed withportions of ring A and ring B being present inside the wider end of the-CD/DM-CD cavity and ring D and the side chain attached atposition 17, projecting into the wider end of the secondCD/DM-CD molecule.     

Stereoselective Hydrogenation of Thymol over Rh/alumina in the Presence of β:-cyclodextrin and its Derivatives

Stereoselective hydrogenation of thymol over Rh/alumina in the presence of various equivalents of -cyclodextrin (-CD) and itsderivatives in the solid state was studied. Hydrogenation of thymol in the absence of -CD gave 76.8% epimeric alcohols with a menthol/neomenthol (M/N) ratio of 5.6 and an alcohol/ketone ratio of 4.5, whereas the presence of 0.1 equivalent (to thymol) of -CD gave rise to 94.6% of epimeric alcohols with a M/N ratio of 6.3 and an alcohol/ketone ratio of 45.4. The effect of -cyclodextrin and its derivatives on the modification of the yield and the proportion of epimeric alcohols formed were found to be the salient features of this investigation. Inclusion complexation of thymol by -CD studied by UV-Visible spectroscopyindicated a 2:1 stoichiometry ofthymol: -CD complex with a binding constant value of 480 ±40 M^-2.     

Complexation of Oleuropein and trans-Cinnamic Acid with Cyclodextrins

The complexation of oleuropein and trans-cinnamic acid with -, -, and -cyclodextrin has been studied in aqueous model systems by light scaterring. The influence of various parameters (pH, concentration, reaction time, nature of cyclodextrin) has been thoroughly examined. The formation of binary (1:1) inclusion complexes and the higher inclusion ability of -CD for both compounds has been indicated. Trans-cinnamic acid was extracted from olive olive oil following its complexation with -CD at satisfactory recovery levels.     

An Investigation of Inclusion Complexes of Cyclodextrins with Phenylurea Herbicides by Photochemically-Induced Fluorescence. Analytical Applications

The effect of -cyclodextrin (-CD) and hydroxypropyl--cyclodextrin (HP--CD) upon the photochemically-induced fluorescence (PIF) properties of four phenylurea herbicides, including linuron, diuron, isoproturon and neburon has been studied. Photochemical conversion of these nonfluorescent herbicides into strongly fluorescent photoproducts was shown to occur in -CD and HP--CD aqueous media. The influence of pH, UV irradiation time and photoproduct stability on the fluorescence intensity was also investigated. In addition, the stoichiometry and formation constants of the complexes formed between herbicides and -cyclodextrin (-CD) or 2-hydroxypropyl--cyclodextrin (HP--CD) were determined. The formation constant values, ranging from 184 ± 40 to 1498 ± 245 M^-1, were calculated by applying the iterative nonlinear regression (NLR) approach to the PIF data. Linear calibrations graphs were established in the interval 1–12 g/mL, for diuron, linuron and neburon. The IUPAC limits of detection ranged between 580 and 700 ng/mL, according to the compound. Application to the analysis of phenylurea herbicides in spiked river water was also described.     

Enhancement of Oral Bioavailability of Rofecoxib Using β-Cyclodextrin

The purpose of the present work was to investigate the effect ofcomplexation of rofecoxib with -cyclodextrin on its dissolutioncharacteristics and bioavailability. Inclusion complexes of rofecoxibwith -cyclodextrin were made by freeze-drying technique. Phasesolubility studies were conducted as suggested by Higuchi and Connors.The samples were characterized by performing dissolution studies, X-rayDiffraction studies and Differential Scanning Calorimetry. The complexeswere compressed into tablets and compared in-vitro with various marketedformulations. A single dose study on healthy human volunteers was performedin comparison with a marketed formulation of rofecoxib (without-cyclodextrin) to investigate the relative bioavailability.Phase solubility studies confirmed the formation of a 1 : 1complex in solution of rofecoxib with -cyclodextrin. Tablets ofsolid inclusion complexes of rofecoxib with -cyclodextrin preparedby freeze drying technique showed enhanced dissolution rate in distilledwater in comparison with all the marketed formulations analyzed. This isattributed to the increased solubility and wettability along with decreasedcrystallinity caused by complex formation, which is confirmed, by XRD and DSCstudies. The bioequivalence studies performed showed statistically significantenhancement in bioavailability as compared to the marketed formulation.Apparently, tablets containing complexes of rofecoxib with -cyclodextrinshows faster onset of action due to improved solubility, enhanced dissolutionand faster absorption of the molecule. The results of this investigation withrofecoxib in -cyclodextrin lend ample credence to its better oralbioavailability on complexation.     

Effect of Cyclodextrins on the Chemical Stability of ST1435, a Contraceptive Steroid Progestin, in Aqueous Solution

The influence of cyclodextrins (CDs) on the chemical stability of the contraceptive steroid progestin, ST1435, in aqueous solution has been studied using reversed phase high performance liquid chromatography. The effects of CD structure, temperature, and CD concentration on the rate of degradation were investigated. It was found that the drug degraded to different extents following a pseudo-first order reaction mechanism. The presence of the host molecules affected the degradation rate as a result of complexation which might result in protection of the labile moiety of the drug molecule against degradation. Hydroxypropyl--cyclodextrin (HP--CD) and hydroxyethyl--cyclodextrin (HE--CD) retarded the degradation in contrast to -cyclodextrin (-CD) which accelerated the steroid degradation. The stabilizing action of HP--CD is larger than that of HE--CD. The degradation rate increased upon increasing temperature and the Arrhenius equation is valid. Lineweaver-Burk equation analysis indicated that the steroid included inside the CD cavity degraded three times more slowly than did the free ST1435 in solution. This equation further supported the formation of a 1 : 1 inclusion complex between ST1435 and HP--CD with a stability constant of 934.5 M-1 at 65°C.     

Solubility Study of Nimodipine Inclusion Complexation with α- and β-Cyclodextrin and some Substituted Cyclodextrins

The solubility of nimodipine was measured in aqueous solutions of the following cyclodextrins: -cyclodextrin (-CD), hydroxypropyl--CD (HP--CD), -cyclodextrin (-CD), random substituted methyl--CD (M--CD), three hydroxypropyl--CDs (HP--CD) with mutually different average degree of substitution, and hydroxypropyl--cyclodextrin (HP--CD). From the determined linear solubility diagrams the values of the binding constant K₁₁ of the inclusion complexes of nimodipine with the respective CDs were evaluated. The -CDs efficiently solubilized sparingly soluble nimodipine, the highest value of K₁₁ was found for M--CD (1680 M^-1), followed by -CD (550 M^-1) and HP--CDs, where the higher degree of substitution lowered K₁₁. Only slight solubilization of nimodipine was observed in the solutions of the -CDs and HP--CD.     

Biological Activities of Violacein, a New Antitumoral Indole Derivative, in an Inclusion Complex with β-Cyclodextrin

Violacein is a poorly water-soluble antitumoraland antibacterial drug. The solubility can be enhanced by complexation with-cyclodextrin. The inclusion complex was prepared by the co-precipitation method in molarratios of 1 : 1 and 1 : 2 of violacein/-cyclodextrin, respectively. The acutetoxicity (E. coli strain) of violacein did not changeup to 400 M, either in thepresence or absence of cyclodextrin. Cytotoxicity (V-79 cellculture) through DNA and MTT assays was significantlydecreased in the presence of the 1 : 2 molar ratio complex.Studies on erythrocyte lipid peroxidation by the thiobarbituricacid (TBA) methodshowed that violacein and violacein/-CD (1 : 2) at100 M cause 50% and 80% inhibition, respectively. At 500 M theviolacein/-CD complexinhibited lipid peroxidation completely; however, withfree violacein only 65% inhibition was reached at that concentration.     

Formulation and Preliminary in vivo Testing of Rufloxacin-Cyclodextrin Ophthalmic Solutions

Aim of the present work was to investigate the effect of somecyclodextrins (CDs) on the solubility and ocular bioavailability of rufloxacin base (RUF), with theultimate goal of developing an ophthalmic formulation. Phase solubility studies of RUF inpH 7.4 buffer were carried out in the presence of -cyclodextrin (-CD),hydroxypropyl--cyclodextrin (HP--CD) and -cyclodextrin(-CD). The effect of hydroxypropyl methylcellulose (HPMC) on RUF solubility was evaluated after heating the solutionscontaining HP--CD at 120 °C.A significant enhancement of RUF solubility was achieved by associatingthe drug with CDs, particularly HP--CD. This CD formed with RUF a less stablecomplex than that formed by -CD, but did not suffer the solubility limitations ofthe parent CD, and showed a higher solubilizing capacity than -CD. Addition of 0.25%(w/v) HPMC to solutions containing HP--CD increased the solubilizing effect of this CD,thus allowing reduction of the amount necessary for solubilization of 0.3% (w/v) RUF.Preliminary pharmacokinetic data in rabbits indicated that theocular bioavailability of 0.3% (w/v) RUF solubilized by HP--CD was higher when compared witha 0.3% (w/v) RUF suspension used as reference.     

Sodium Dithionite Reduction of 2S,5R-(-)-menthone and R-(+)-pulegone in the Presence of β-Cyclodextrin and Hydroxypropyl-β-cyclodextrin

Menthone on reduction with sodium dithionite,showed a good amount of mentholformation in the water/DMF system, withincreasing -cyclodextrin (-CD)concentration from 47.0% for 0.1 equivalent of-CD to 93.5% for 1 equivalentof -CD. Increasing hydroxypropyl--cyclodextrin(HP-CD) gave higher menthol/neomenthol (M/N) ratiosfrom 2.8 to 3.5. In the case of pulegone,increasing -CD showed an increase in the formationof menthols in thewater/DMF system from 13.3% for 0.1 equivalent of-CD to 78.1% for 1equivalent of -CD with greater proportions ofneomenthol and neoisomenthol.However, HP-CD which showed only marginalenhancement in the formationof menthol from menthone (32.1–41%), exhibiteda greater proportion of mentholformation in the case of pulegone (55.1%).However, the phase-transfer capabilityof HP-CD was not found to be significant.     

In vitro nitrosation of ephedrine in the presence of cyclodextrins

-, and -cyclodextrin and heptakis-2,6-di-O-methyl--cyclodextrin enhance the nitrosation rate of l-ephedrine if the nitrosation assay procedure (NAP test) is applied. During this reaction with -cyclodextrin a solid inclusion compound of -cyclodextrin andN-nitrosoephedrine precipitates. Solubilities and stabilities of inclusion compounds of the cyclodextrins with ephedrine and nitrosoephedrine, respectively, explain especially the catalytic effects of some cyclodextrins on ephedrine.Part of the PhD thesis of V. Wedelich, Freie Universität Berlin, 1985.     

Influence of cyclodextrins on nitrosation of drugs

The World Health Organization issued a nitrosation procedure (NAP Test) which allows to carry out nitrosation under standard conditions. It has proved that the in vitro reaction rates of the fast nitrosatable drugs piperazine, cimetidine and ethambutol are not influenced by -, - and -cyclodextrin. On the contrary, -, -cyclodextrin and heptakis-2,6-di-O-methyl--cyclodextrin enhance the nitrosation of the slower nitrosatable 1-ephedrine and fencamfamine significantly. This possible reaction must be considered if nitrosatable drugs are formulated with cyclodextrins to be administered to human beings.     

Solubility Enhancement of Low Soluble Biologically Active Compounds by β-Cyclodextrin and Dimethyl-β-cyclodextrin

The solubility enhancement of triflumizole by complexation with -cyclodextrin and with dimethyl--cyclodextrin is compared with respect to the different physico-chemical properties of the host molecules. Although the inclusion reaction constants are rather similar for both complexation reactions, a completely different temperature dependence of the host-guest interaction is observed, which indicates a change of the reaction mechanisms. Moreover, the influence of ethanol as cosolvent is studied.     

Nitrosation of mefenorex in the presence of cyclodextrins

- and -Cyclodextrin (CD) and heptakis-2,6-di-O-methyl--cyclodextrin (DIMEB) form soluble inclusion compounds with mefenorex (MEF); with -CD a partial inclusion occurs. No solid inclusion compound could be obtained with the four CDs. -, -CD and DIMEB, but not -CD, enhance the nitrosation rate of MEF if the nitrosation assay procedure (NAP test) is applied. During this reaction with - and -CD, solid inclusion compounds of the CDs and nitrosomefenorex (NMEF) precipitate.Part of the Ph.D. thesis of V. Wedelich, Freie Universität Berlin, 1985.     

Reduction of photohemolytic activity of benoxaprofen byβ-cyclodextrin complexations

Inclusion complexations of benoxaprofen (BXP) with-cyclodextrin (-CyD) and heptakis (2,6-di-O-methyl)--CyD (DM--CyD) were studied by the solubility method and CD and¹H-NMR spectroscopy. Both -CyDs decelerated the photodecarboxylation of BXP, and suppressed the BXP-photosensitized hemolysis, where the inhibitory effect of DM--CyD was larger than that of -CyD. This order was well correlated with the magnitude of the stability constants of BXP--CyD complexes. The peroxidation of lipid components in erythrocyte ghosts induced by BXP was also suppressed particularly by DM--CyD. The protective effect of -CyDs on the BXP-induced photohemolysis seems to be due to the suppression in the photochemical reactions of BXP yielding toxic transient species, together with the inhibition in attacks of the transient species to the membrane, through inclusion complexation.     

Complexation of 6-Deoxy-6-(aminoethyl)amino-β-cyclodextrin with Sodium Cholate and Sodium Deoxycholate

In order to study its guest binding and the inclusion phenomena, 6-deoxy-6-(aminoethyl)amino--cyclodextrin (CDN) was synthesised and its binding properties examined. The complexation phenomena of sodium cholate (NaC) and sodium deoxycholate (NaDC) with CDN has been monitored by the NMR method using ¹³C chemical shift data. The method of continuous variation Job's method has been used to determine the stoichiometry of these supramolecular complexes. The Job's plot confirms the 1 : 1 supramolecular complex for NaC: CDN and the 1 : 2 supramolecular complex for NaDC: CDN. The interaction of NaC and NaDC with CDN has been obtained through two-dimensional Rotational Nuclear Overhauser Effect Spectroscopy (ROESY) NMR. Equilibrium constants were also obtained from ¹³C chemical shift data (C-1, C-3 & C-4) at different pH values (7, 9, & 11).     

Study on Interactions of Several Psychopharmaceutical Drugs with β-Cyclodextrin by Affinity Capillary Electrophoresis and their Application in Separation

The binding of psychopharmaceutical drugs by -cyclodextrin (-CD) changed their effective electrophoretic mobilities. Based on this phenomenon the interactions between some psychopharmaceutical drugs and -cyclodextrin were studied and the binding constants of -CD with tiapride, imipramine, clomipramine, amitriptyline, trifluoperazine, perphenazine and carbamazepine were determined by affinity capillary electrophoresis. The presence of -CD improved the separation of these psychopharmaceutical drugs. Organic modifier was used as another kind of additive to be added in the running buffer to improve further the separation. 70 mM pH 7.2 phosphate buffer solution containing 12 mM -cyclodextrin and 15% (v/v) acetone was selected as optimal running buffer for separation by capillary electrophoresis.