Influence of hydrophilic polymers on celecoxib complexation with hydroxypropyl β-cyclodextrin

Complexation of celecoxib with hydroxypropyl β-cyclodextrin (HPβCD) in the presence and absence of 3 hydrophilic polymers—polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG)—was investigated with an objective of evaluating the effect of hydrophilic polymers on the complexation and solubilizing efficiencies of HPβCD and on the dissolution rate of celecoxib from the HPβCD complexes. The phase solubility studies indicated the formation of celecoxib-HPβCD inclusion complexes at a 1∶1M ratio in solution in both the presence and the absence of hydrophilic polymers. The complexes formed were quite stable. Addition of hydrophilic polymers markedly enhanced the complexation and solubilizing efficiencies of HPβCD. Solid inclusion complexes of celecoxib-HPβCD were prepared in 1∶1 and 1∶2 ratios by the kneading method, with and without the addition of hydrophilic polymers. The solubility and dissolution rate of celecoxib were significantly improved by complexation with HPβCD. The celecoxib-HPβCD (1∶2) inclusion complex yielded a 36.57-fold increase in the dissolution rate of celecoxib. The addition of hydrophilic polymers also markedly enhanced the dissolution rate of celecoxib from HPβCD complexes: a 72.60-, 61.25-, and 39.15-fold increase was observed with PVP, HPMC, and PEG, respectively. Differential scanning calorimetry and X-ray diffractometry indicated stronger drug amorphization and entrapment in HPβCD because of the combined action of HPβCD and the hydrophilic polymers. Published: September 29, 2006     

Physicochemical Properties and Dissolution Studies of Dexamethasone Acetate-β-Cyclodextrin Inclusion Complexes Produced by Different Methods

Inclusion complexes between dexamethasone acetate (DMA), a poorly water soluble drug, and β-cyclodextrin (βCD) were obtained to improve the solubility and dissolution rate of this drug. Phase-solubility profile indicated that the solubility of DMA was significantly increased in the presence of βCD (33-fold) and was classified as A_L-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by different methods (kneading, coevaporation, freeze drying) and physical mixture were characterized by differential scanning calorimetry, thermogravimetry, infrared absorption and optical microscopy. Preparation methods influenced the physicochemical properties of the products. The dissolution profiles of solid complexes were determined and compared with those DMA alone and their physical mixture, in three different mediums: simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 7.4) and distilled water. The dissolution studies showed that in all mediums DMA presented an incomplete dissolution even in four hours. In contrast, the complexes formed presented a higher dissolution rate in simulated gastric fluid (SGF pH 1.2), which indicate that these have different ionization characteristics. According to the results, the freeze–dried and kneaded products exhibited higher dissolution rates than the drug alone, in all the mediums.     

Physicochemical characterization,in vitro dissolution behavior,and pharmacodynamic studies of rofecoxib-cyclodextrin inclusion compounds. Preparation and properties of rofecoxib hydroxypropyl β-cyclodextrin inclusion complex: A technical note

Conclusion  An inclusion complex of rofecoxib and HPβ-CD was prepared successfully by the spray-drying method in a molar ratio of 1∶1. The inclusion complex was found to have improved in vitro drug release compared with the pure drug. The solubility profile of complexes of rofecoxib prepared using HPβ-CD as the complexing agent in a molar ratio of 1∶1 by the spray-drying method in pH 1.2 and pH 7.4 indicated that the acid solubility of rofecoxib was enhanced considerably by formation of an inclusion complex with HPβ-CD. The above results also clearly demonstrated a significant decrease in the gastric ulcerogenic activity of rofecoxib through complexation with cyclodextrins. Even though the physical mixture of rofecoxib with cyclodextrins reduced ulcer formation, it was the spray-dried complex formation approach that minimized gastric ulceration. These findings are extremely important from a commercial point of view as the prepared complex removes a major drawback for rofecoxib in therapy. Published: September 20, 2005     

Physicochemical and molecular modeling studies of cefixime–l-arginine–cyclodextrin ternary inclusion compounds

In an attempt to improve the physicochemical properties of cefixime (CEF), its supramolecular inclusion compounds were prepared with β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) in presence and/or absence of ternary component l-arginine (ARG) using spray drying technique. Initially, the phase solubility studies revealed a stoichiometry of 1:1 molar ratio with an A_L-type of phase solubility curve. The stability constants of binary systems were remarkably improved in presence of ARG, indicating positive effect of its addition. The inclusion complexes were characterized by FTIR, XRPD, DSC, SEM, particle size analysis, and dissolution studies. Further, molecular mechanic (MM) calculations were performed to investigate the possible orientations of CEF inside βCD cavity in presence and/or absence of ternary component. In case of physicochemical studies, the ternary systems performed well as a result of comprehensive effect of ternary complexation and particle size reduction achieved by a spray drying technology.     

Effects of the Preparation Method on the Formation of True Nimodipine SBE-β-CD/HP-β-CD Inclusion Complexes and Their Dissolution Rates Enhancement

The aims of this study were to enhance the solubility and dissolution rate of nimodipine (ND) by preparing the inclusion complexes of ND with sulfobutylether-b-cyclodextrin (SBE-β-CD) and 2-hydroxypropyl-b-cyclodextrin (HP-β-CD) and to study the effect of the preparation method on the in vitro dissolution profile in different media (0.1 N HCl pH 1.2, phosphate buffer pH 7.4, and distilled water). Thus, the inclusion complexes were prepared by kneading, coprecipitation, and freeze-drying methods. Phase solubility studies were conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were investigated with differential scanning calorimetry (DSC), X-ray diffractometry (X-RD), and Fourier transform infrared spectroscopy (FT-IR). Stable complexes of ND/SBE-β-CD and ND/HP-β-CD were formed in distilled water in a 1:1 stoichiometric inclusion complex as indicated by an A_L-type diagram. The apparent stability constants (Ks) were 1334.4 and 464.1 M⁻¹ for ND/SBE-β-CD and ND/HP-β-CD, respectively. The water-solubility of ND was significantly increased in an average of 22- and 8-fold for SBE-β-CD and HP-β-CD, respectively. DSC results showed the formation of true inclusion complexes between the drug and both SBE-β-CD and HP-β-CD prepared by the kneading method. In contrast, crystalline drug was detectable in all other products. The dissolution studies showed that all the products exhibited higher dissolution rate than those of the physical mixtures and ND alone, in all mediums. However, the kneading complexes displayed the maximum dissolution rate in comparison with drug and other complexes, confirming the influence of the preparation method on the physicochemical properties of the products.     

Inclusion interactions of cyclodextrins and crosslinked cyclodextrin polymers with linalool and camphor in Lavandula angustifolia essential oil

In the present study, we investigated the feasibility of preparation of novel controlled release systems for the delivery of essential oil used as ambient odors. The inclusion interactions of cyclodextrins (CDs) and β-cyclodextrin polymers with linalool and camphor in Lavandula angustifolia essential oil were investigated by static headspace gas chromatography (SH-GC). The stability constants with monomeric CD derivatives were determined for standard compounds and for the compounds in essential oil. All studied CDs and CD polymers reduce the volatility of the aroma compounds and stable 1:1 inclusion complexes are formed. The retention capacity of the CD derivatives was measured in static experiments. The feasibility of preparation of novel controlled release systems for the delivery of fragrances was investigated by multiple headspace extraction (MHE) experiments.     

Preparation and Solid-State Characterization of Inclusion Complexes Formed Between Miconazole and Methyl-β-Cyclodextrin

The aim of this study is to confirm the formation of inclusion complexes between miconazole (MCZ) and two derivatives of beta-cyclodextrin, methyl-beta-cyclodextrin (MβCD) and 2-hydroxypropyl-beta-cyclodextrin (HPβCD) in aqueous solution by phase solubility studies. Inclusion complexes with MβCD in the solid state were then prepared by different methods, i.e., kneading, coevaporation (COE), spray-drying (SD), and lyophilization (LPh). The physicochemical properties of these complexes were subsequently studied by means of differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction techniques. Phase solubility diagrams with MβCD and HPβCD were classified as A_P type, indicating the formation of 1:1 and 1:2 stoichiometric inclusion complexes. The apparent stability constants (K_S) calculated from the phase solubility diagram were 145.69 M⁻¹ (K _1:1) and 11.11 M⁻¹ (K _1:2) for MβCD and 126.94 M⁻¹ (K _1:1) and 2.20 M⁻¹ (K _1:2) for HPβCD. The method of preparation of the inclusion complexes in the solid state was shown to greatly affect the properties of the formed complex. Hence, the LPh, SD, and COE methods produce true inclusion complexes between MCZ and MβCD. In contrast, crystalline drug was still clearly detectable in the kneaded (KN) product.     

Influence of hydrophilic polymers on celecoxib complexation with hydroxypropyl beta-cyclodextrin

Complexation of celecoxib with hydroxypropyl beta-cyclodextrin (HPbetaCD) in the presence and absence of 3 hydrophilic polymers-polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG)-was investigated with an objective of evaluating the effect of hydrophilic polymers on the complexation and solubilizing efficiencies of HPbetaCD and on the dissolution rate of celecoxib from the HPbetaCD complexes. The phase solubility studies indicated the formation of celecoxib-HPbetaCD inclusion complexes at a 1:1M ratio in solution in both the presence and the absence of hydrophilic polymers. The complexes formed were quite stable. Addition of hydrophilic polymers markedly enhanced the complexation and solubilizing efficiencies of HPbetaCD. Solid inclusion complexes of celecoxib-HPbetaCD were prepared in 1:1 and 1:2 ratios by the kneading method, with and without the addition of hydrophilic polymers. The solubility and dissolution rate of celecoxib were significantly improved by complexation with HPbetaCD. The celecoxib-HPbetaCD (1:2) inclusion complex yielded a 36.57-fold increase in the dissolution rate of celecoxib. The addition of hydrophilic polymers also markedly enhanced the dissolution rate of celecoxib from HPbetaCD complexes: a 72.60-, 61.25-, and 39.15-fold increase was observed with PVP, HPMC, and PEG, respectively. Differential scanning calorimetry and X-ray diffractometry indicated stronger drug amorphization and entrapment in HPbetaCD because of the combined action of HPbetaCD and the hydrophilic polymers.     

Enhancement of Oral Bioavailability of Cilostazol by Forming its Inclusion Complexes

The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like β-CD, γ-CD, and the hydrophilic β-CD derivatives, DM-β-CD and HP-β-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The dissolution rate of cilostazol was markedly augmented by the complexation with DM-β-CD. DSC and XRD curves showed sharp endothermic peaks indicating the reduction in the microcrystallinity of cilostazol. Selected inclusion complex was also stable at ambient temperature up to 6 months. The in vivo study revealed that DM-β-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol–cyclodextrins complexes, cilostazol–DM-β-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.     

Volatile constituents of Trichothecium roseum

In the course of investigation of Trichothecium roseum (Fungi Imperfecti) for its attractancy against Tyrophagus putrescentiae (cheese mite), the twenty following volatile compounds produced at a very low concentration by the microfungus were identified by gc, gc/ms, gc/c.i.ms and tlc: 3-methyl-1-butanol, 3-octanone, 1-octen-3-one, 3-octanol, octa-1,5-dien-3 one, 1-octen-3-ol, 6-methyl-5-hepten-2-ol, octa-1,5-dien-3 ol, furfural, linalool, linalyl acetate, terpineol (alpha and beta) citronellyl acetate, nerol, citronellol, phenylacetaldehyde, benzyl alcohol geranyl acetate, 1-phenyl ethanol and nerolidol. Octa-1,5-dien-3-ol and octa-1,5-dien-3-one have not been previously isolated from fungi; octa-1,5-dien-3-ol is the most potent attractant amount the volatile compounds detected by gc.     

Investigations of animal blood samples after fragrance drug inhalation by gas chromatography/mass spectrometry with chemical ionization and selected ion monitoring.

The fragrance compounds linalool (1) and linalyl acetate (2) could be detected, identified and quantified (1: 7-9 ng ml-1; and 2: 1-2 ng ml-1 and 4-5 ng ml-1 as free linalool) in blood samples after inhalation in animal experiments (mice) by gas chromatography/mass spectrometry (GC/MS) with chemical ionization (CI) (ammonia); selected ion monitoring (SIM) mode (1: m/z 81, 137 and 154; 2: 47, 57 and 137) and GC/flame ionization detection (FID). The inhalation of these monoterpenes in concentrations of 5 mg l-1 air leads to a significant reduction of the motility of the test animals down to 30-40% with respect to the control group.     

A 5,7-Dimethoxyflavone/Hydroxypropyl-β-Cyclodextrin Inclusion Complex with Anti-Butyrylcholinesterase Activity

This study aimed to improve the water solubility of 5,7-dimethoxyflavone (5,7-DMF) isolated from Kaempferia parviflora by complexation with 2-hydroxypropyl-β-cyclodextrin (HPβ-CD). The phase solubility profile of 5,7-DMF in the presence of HPβ-CD was classified as A_L-type and indicated a 1:1 mole ratio. Differential scanning colorimetry, X-ray diffraction, NMR and SEM analyses supported the formation of a 5,7-DMF/HPβ-CD inclusion complex involving the A ring of 5,7-DMF inside the HPβ-CD cavity. This is the first example of CD inclusion with the A ring of non-hydroxyl flavones. The stability and binding constants of the complexes were determined using the phase solubility and UV-vis absorption spectroscopy, respectively. The water solubility of 5,7-DMF was increased 361.8-fold by complexation with HPβ-CD and overcame the precipitation problem observed in aqueous buffers, such as during in vitro anti-butyrylcholinesterase activity assays. The 1:1 mole ratio of the 5,7-DMF/HPβ-CD complex showed a 2.7-fold higher butyrylcholinesterase inhibitory activity (in terms of the IC₅₀ value) compared to the non-complexed compound.     

Enhanced antibacterial and anti-quorum sensing activities of triclosan by complexation with modified β-cyclodextrins

Triclosan (TCS), an antimicrobial agent widely used in consumer and medical products, was complexed with 2-hydroxypropyl-β-cyclodextrin (HPβCD) and methyl-β-cyclodextrin (MβCD). Phase-solubility studies indicated that inclusion complexes of 1:1 stoichiometry were formed and allowed estimation of the associated equilibrium constants and free-energy changes. At the highest cyclodextrin concentrations investigated, an almost 20-fold increase in the apparent water solubility of TCS was determined. Susceptibility tests against Escherichia coli and Staphylococcus aureus showed that the TCS–HPβCD and TCS–MβCD complexes exhibited antibacterial properties higher than those of uncomplexed TCS. The two complexes were also found capable of interfering with cell-to-cell communication mechanisms in the C. violaceum model system relying on N-acylhomoserine lactone autoinducers. The inhibitory activity of TCS increased significantly upon inclusion of the drug in HPβCD or MβCD, with small differences between the two CDs. The results obtained suggest that the investigated complexes could be used for treating infections caused by TCS-susceptible pathogens or for preventing biofilm formation on indwelling medical devices such as catheters, stents and orthopedic implants.     

Solubility and Stability of ??-Cyclodextrin?CTerpineol Inclusion Complex as Affected by Water

In the present work, inclusion complexes of α-terpineol (Terp) and β-cyclodextrin (BCD) were prepared by the coprecipitation method. Phase solubility studies were performed and thermodynamic parameters involved in the complex formation were calculated. The solubility of Terp increased linearly as the concentration of BCD was increased, confirming the 1:1 stoichiometry of the complex. The stability constants decreased along with increasing temperature. The negative value of the enthalpy and of the Gibbs free energy demonstrated that the process is exothermic and spontaneous. Since complexation gives more ordered systems, the negative value obtained for the entropy change evidenced the encapsulation of Terp. Terp was completely encapsulated in BCD at the preparation conditions and studied molar ratios, as confirmed in the freeze-dried samples by differential scanning calorimeter. The presence of Terp greatly modified the BCD water sorption curves, and the amount of adsorbed water was lower for the complexes. The limited water solubility of Terp could be overcome by the formation of BCD inclusion complexes, and the complexes were stable at different storage conditions (relative humidities 11–97% and 25 °C). The obtained phase solubility data are useful for food or pharmaceutical products formulation involving cyclodextrins and stability predictions.     

Triamcinolone solubilization by (2-hydroxypropyl)-β-cyclodextrin: A spectroscopic and computational approach

The molecular foundations of the use of (2-hydroxypropyl)-β-cyclodextrin (HPβCD) as solubility promoter of triamcinolone acetonide (TrA), a corticosteroid with very low aqueous solubility, was investigated by a multidisciplinary spectroscopic and computational approach. Aqueous solutions of TrA and HPβCD were investigated by UV and NMR spectroscopies. The association constant was determined by phase solubility diagrams and by the Foster-Fyfe method whereas the nature of the drug/cyclodextrin aggregates was probed by using the NMR DOSY technique. ROE measurements in solution led to stereochemical information regarding the nature of inclusion processes. TrA/HPβCD powders were prepared and investigated by Raman spectroscopy supported by computational methods. A molecular interaction of the hydroxyacyl chain with cyclodextrin, not identified in solution, was detected. Raman imaging experiments confirmed the attainment of a molecularly homogeneous system when the TrA/HPβCD molar ratio was 1:7 whereas TrA crystallized for mixtures richer in TrA (1:3.5) forming domains with size in the range of 10-15μm. We demonstrate that the combined use of several spectroscopical techniques with specific responsivities allows a detailed depiction of drug/cyclodextrin interaction useful in the development of novel pharmaceutical formulation.     

Linalool and linalool oxide production in transgenic carnation flowers expressing the Clarkia breweri linalool synthase gene

Most modern cut-flower cultivars, including those of carnation(Dianthus caryophyllus), lack distinct fragrance.Carnationcv. Eilat flowers produce and emit various fragrance compounds, includingbenzoic acid derivatives and sesquiterpenes, but not monoterpenes. Based onGC-MS analysis, benzoic acid, benzyl benzoate, phenylethyl benzoate, methylbenzoate, cis-3-hexenyl benzoate and -caryophylleneare the major fragrance compounds, representing ca. 60% of the total volatilesgenerated by these flowers. The level of these compounds increases dramaticallyduring petal development. To evaluate the possibility of producing monoterpenesin carnation cv. Eilat, we generated transgenic plants expressing the linaloolsynthase gene from Clarkia breweri under the regulation ofthe CaMV 35S constitutive promoter. The product of this gene catalyzes theproduction of the monoterpene linalool from geranyl diphosphate. HeadspaceGC-MSanalysis revealed that leaves and flowers of transgenic, but not controlplants,emit linalool and its derivatives, cis- andtrans-linalool oxide. GC-MS analysis of petal extractrevealed the accumulation of trans-linalool oxide but notlinalool. The emission of linalool by the transgenic flowers did not lead todetectable changes in flower scent for human olfaction.     

Physicochemical Characterization of Efavirenz–Cyclodextrin Inclusion Complexes

Efavirenz (EFV) is an oral antihuman immunodeficiency virus type 1 drug with extremely poor aqueous solubility. Thus, its gastrointestinal absorption is limited by the dissolution rate of the drug. The objective of this study was to characterize the inclusion complexes of EFV with β-cyclodextrin (β-CD), hydroxypropyl β-CD (HPβCD), and randomly methylated β-CD (RMβCD) to improve the solubility and dissolution of EFV. The inclusion complexation of EFV with cyclodextrins in the liquid state was characterized by phase solubility studies. The solid-state characterization of various EFV and CD systems was performed by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy analyses. Dissolution studies were carried out in distilled water using US Pharmacopeia dissolution rate testing equipment. Phase solubility studies provided an A_L-type solubility diagram for β-CD and A_P-type solubility diagram for HPβCD and RMβCD. The phase solubility data enabled calculating stability constants (K _s) for EFV-βCD, EFV-HPβCD, and EFV-RMβCD systems which were 288, 469, and 1,073 M⁻¹, respectively. The physical and kneaded mixtures of EFV with CDs generally provided higher dissolution of EFV as expected. The dissolution of EFV was substantially higher with HPβCD and RMβCD inclusion complexes prepared by the freeze drying method. Thus, complexation with HPβCD and RMβCD could possibly improve the dissolution rate-limited absorption of EFV.     

Reversible vesicles based on one and two head supramolecular cyclodextrin amphiphile induced by methanol

Reversible vesicles based on supramolecular inclusion of hydroxypropyl-β-CD (HPβCD) and N,N′-bis(ferrocenylmethylene)-diaminohexane (BFD) were prepared in water and methanol-water mixtures. The inclusion stoichiometry of HPβCD with BFD was in a molar ratio of 2:1, which could be named as ‘two head’ supramolecular amphiphile when the solvent was water. However, the inclusion stoichiometry of HPβCD with BFD would tend to be a molar ratio of 1:1 based on introduction of methanol to the solvent, especially when the volume ratio of methanol and water was more than 1:4, which could be named as ‘one head’ supramolecular amphiphile. The inclusion compounds could switch between ‘one head’ and ‘two head’ conformations by changing the methanol concentration of the solvents. The vesicles were also found to be responsive to the stimulus of external molecules. When the inclusion ability between HPβCD and an external guest was relatively stronger, the vesicles were easily destroyed. Furthermore, the vesicles disappeared after adding an oxidizing agent. NMR was used to confirm the conformation of the mixture of HPβCD and BFD in water. The structure and morphology of the vesicles were characterized by TEM and DLS. The vesicles may be used in smart materials, drug delivery and molecular recognition.