Effect of self-aggregation of γ-cyclodextrin on drug solubilization

The purpose of this study was to investigate the physicochemical properties of drug-saturated aqueous cyclodextrin (CD) solutions. Phase solubility profiles of different drugs were determined in aqueous solutions containing γ-cyclodextrin (γCD) and/or hydroxypropyl-γ-cyclodextrin (HPγCD) in absence or presence of water-soluble polymers. ¹H-NMR and turbidity analysis were performed as well as permeation studies. Phase solubility diagrams showed that the observed γCD content (1–20% w/v) was only slightly different from the theoretical values for aqueous solutions that had been saturated with indomethacin, diclofenac sodium or amphotericin B, all displayed A-type profiles, while it was less than the theoretical value in solutions that had been saturated with corticosteroids (hydrocortisone and dexamethasone) that displayed B_S-type profiles. In the latter case self-assemble of drug/CD complexes decreased the overall CD solubility. Water-soluble polymers enhanced aqueous solubility of the drugs tested by stabilizing the drug/CD complexes, i.e. enhancing their stability constants, without affecting the observed aqueous γCD solubility. When the drug solubility leveled off (the B_S-type profiles) the amount of dissolved γCD increased and approached the theoretical values. Hydrocortisone formed partial inclusion complex with γCD and HPγCD and no non-inclusion or aggregates could be detected in diluted solutions by ¹H-NMR. Both permeation and turbidity studies showed that formation of dexamethasone/γCD complex promoted CD aggregation. All these observations indicate that CD aggregate formations play a role in CD solubilization of lipophilic and poorly water-soluble drugs and that the water-soluble polymers enhance the complexation efficiency of γCD and HPγCD by stabilizing the self-assembled drug/CD nanoparticles and promote non-inclusion complex formation.     

Inclusion complexes of <Emphasis Type="Italic">p</Emphasis>-hydroxybenzoic acid esters and γ-cyclodextrin

The alkyl esters of p-hydroxybenzoic acid (parabens) are commonly used as preservatives in cosmetics, food products and pharmaceutical formulations because of their wide range antimicrobial activity. However, the usage of parabens in aqueous media has been hampered, especially parabens with long alkyl chains, due to their low aqueous solubility. One approach to increase their solubility is cyclodextrins (CDs) complexation to form water-soluble inclusion complexes. γCD has the widest hydrophobic central cavity and the highest water solubility among natural CDs. Hence, inclusion complexes between γCD and parabens of various alkyl chain lengths were investigated. Results from phase-solubility studies show that methyl- and ethylparaben form various complexes of paraben/γCD (i.e. 1:1, 2:1, etc.) while the 1:1 complex was dominant in propyl- and butylparaben/γCD complex solution. Moreover, the effect of the paraben complexation on the critical aggregation concentration (cac) of γCD in aqueous solutions was determined. It was found that the longer the paraben alkyl chain was the more influence it had on the γCD cac. In pharmaceutical formulations the mixture of parabens (i.e. binary, ternary and quaternary) has been used to maximize antimicrobial effect. It is important to determine how mixtures of parabens affect the solubility of γCD and its cac values upon formation of inclusion complexes. Competition of the different parabens for a space in the γCD central cavity was evaluated by comparing the γCD cac values obtained in presence of the individual parabens and their mixtures.     

Gamma-cyclodextrin on enhancement of water solubility and store stability of nystatin

The water solubility of nystatin was found enhanced by forming inclusion complex with gamma-cyclodextrin (γ-CD). Further discovery of a pleased surprise showed that the phase solubility curves of nystatin in β- and γ-CD aqueous solution were A_L type, while B_S type for α-CD, indicating 1:1 inclusion complexes were formed between β-CD, γ-CD and nystatin, but no inclusion complexes for α-CD, in addition, CDs with much larger ring would be more suitable for forming inclusion complexes with macrolide antibiotics. The aqueous solubility of nystatin in γ-CD solution was investigated increased with γ-CD concentration increasing. At the concentration of 24 g/100 ml for γ-CD aqueous solution, which is near to the saturated solution, water solubility of nystatin was found to be 104 μg/ml, which was 103 folds over original nystatin. Inclusion constants for γ-CD–nystatin complexes were 0.539 l/mmol, which is larger than that of β-CD–nystatin complex (0.375 l/mmol). The inclusion complex of γ-CD with nystatin was prepared and detected by infrared spectrum, results showing that the ester linkage and diene were included in the cavity of CDs, while conjugate arachidonic, carboxyl and amino group were left outside of CDs. Storing experiment showed that forming of the inclusion complexes greatly enhanced the stability of nystatin against light and oxygen.     

Cyclodextrin solubilization of celecoxib: solid and solution state characterization

The low aqueous solubility of celecoxib (CCB) hampers its oral bioavailability and permeation from aqueous environment through biological membranes. The aim of this study was to enhance the aqueous solubility of CCB by complexation with cyclodextrin (CD) in the presence of water-soluble polymer. The effects of different CDs (αCD, βCD, γCD, 2-hydroxypropyl-β-cyclodextrin and randomly methylated β-cyclodextrin (RMβCD)) and mucoadhesive, water-soluble polymers (hydroxypropyl methylcellulose (HPMC), chitosan and hyaluronic acid) were investigated. The phase solubility profiles and CCB/CD complex characteristics were determined. RMβCD exhibited the greatest solubilizing effect of the two CDs tested. However, γCD was also selected for further investigations due to its safety profile. Addition of polymer to the aqueous CD solutions enhanced the CD solubilization. Formation of CCB/RMβCD/HPMC and CCB/γCD/HPMC ternary complexes resulted in 11 and 19-fold enhancement in the apparent complexation efficiency in comparison to their CCB/CD binary complex, respectively. The size of ternary complex aggregates in solution were determined to be from about 250 to about 350 nm. The data obtained from Fourier transform infra-red, differential scanning calorimetry and powder X-ray diffraction indicated presence of CCB/CD inclusion complexes in the solid state. Proton nuclear magnetic resonance data demonstrated that CCB was partially and totally inserted into the hydrophobic central cavities of RMβCD and γCD.     

Complexation of triptolide and its succinate derivative with cyclodextrins: affinity capillary electrophoresis, isothermal titration calorimetry and 1H NMR studies

The complexation of the triptolide PG490 and its succinate derivative PG490-88Na with various cyclodextrins was studied using three complementary techniques: affinity capillary electrophoresis (ACE), isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). The apparent binding constants of the complexes formed between the drugs and 8 CDs (α-CD, β-CD, γ-CD, HP-α-CD, HP-β-CD, HP-γ-CD, CM-β-CD and amino-β-CD) were determined by ACE through linear Scott's plots. The apparent and averaged binding constants of the complexes formed between PG490-88 and β-CD, γ-CD, HP-α-CD, HP-β-CD or HP-γ-CD are contained in the narrow range 135-167 M(-1). For the anionic CM-β-CD and cationic amino-β-CD, these constants are 38 and 278 M(-1), respectively, which is in accordance with electrostatic repulsions or attractions with the succinate moiety. ITC and NMR investigations for the binding constants determinations were performed for 2 CDs allowing high complexation: HP-β-CD and amino-β-CD. The three techniques provided similar results. ITC and NMR, in contrast to ACE, allowed to study the complexes formed between the neutral compound PG490 and neutral cyclodextrins. A more advanced characterization of the PG 490-88Na/amino-β-CD complex, which displays the highest apparent binding constant, was undertaken using NMR spectroscopy. The 1:1 stoichiometry of the complex was established by (1)H NMR 1D and selective 1D TOCSY experiments using the continuous variation method. Moreover, the 1D and 2D ROESY experiments revealed the inclusion of the isopropyl moiety of the triptolide derivative in the hydrophobic CD cavity. Altogether, the data provide strong evidences that the two triptolide compounds can be efficiently complexed with CD.     

Non-covalent columnar cyclodextrin-based structures

Examples of the formation of ordered ensembles of α-, β-, and γ-cyclodextrins (CDs) molecules with a columnar packing of macrocycles are reported. These ensembles are formed by (1) the supramolecular dissociation of polymer inclusion complexes under the action of organic solvents that are selective with respect to a polymer guest and (2) the fixation of columnar CD aggregates self-organized in aqueous solutions at high temperatures upon the precipitation from water into organic solvents. Specific features of the organization of cyclodextrins in the thus-synthesized structures are studied by X-ray diffraction. Preliminarily oriented polymer inclusion complexes based on corresponding CDs are used as a model with the columnar arrangement of macrocycles.     

Spectral properties and supramolecular inclusion complex formation between 2-styrylbenzothiazolium dye and cyclodextrins

The effect of native and randomly methylated β-CDs on the absorption and steady-state fluorescence spectra of 2-(4-dimethylaminostyryl)-3-(2-hydroxyethyl)-benzothiazolium chloride (DHB) in aqueous buffer solutions with various pH values was studied. The inclusion with both CDs at pH 7.2 barely changed the UV spectra, whereas significant variations were produced in the emission spectra in all buffer solutions. In all cases the CDs increase guest fluorescence. The 1:1 stoichiometry of the inclusion complexes of the dye with both CDs was established according to the modified Benesi-Hildebrand method. Binding constant values were calculated using the iterative nonlinear least-squares regression approach. The pH of the solution and the type of the CD affected complex stability. The results indicate that native β-CD possesses better complexing ability towards DHB than randomly substituted β-CD and that the most stable inclusion complexes are formed in basic medium because of the structural changes in the guest molecule. In basic medium an attempt is made to interpret the proposed mechanism in terms of molecular rearrangement which take place as the dye penetrates the CD cavity.     

Effect of the ring size and asymmetry of cyclodextrins on their inclusion ability: a theoretical study

Effect of the ring size and asymmetry upon methylation of cyclodextrins (CDs) on their inclusion ability has been demonstrated for the inclusion complexes of native α-, β-, γ-CDs, dimethylated β-CD (DIMEB) and trimethylated β-CD (TRIMEB) with piperazine (PIZ) by PM3 and ONIOM calculations. In all complexes, PIZ prefers residing mostly in the central CD cavity. The complex stability in the order TRIMEB–PIZ > DIMEB–PIZ > α-CD–PIZ > γ-CD–PIZ > β-CD–PIZ indicates that the CD-ring asymmetry promotes the macrocycle deformation and inclusion ability. Our calculation results suggest that the inclusion complexes of both native and methylated CDs with PIZ in the gas phase are energetically stable, in addition to the β-CD–PIZ inclusion complex that has been evidenced thus far by X-ray crystallographic and spectroscopic analyses. Further calculations in the presence of water and adjacent CD molecules show that the increased intermolecular hydrogen bond interactions enhance the stability of β-CD–PIZ complex.     

Physicochemical characterization of terbinafine-cyclodextrin complexes in solution and in the solid state

Terbinafine (TB) is an allylamine derivative used as oral and topical antifungal agent. The physicochemical properties of the complexes between TB and different cyclodextrins (CDs): α-CD, β-CD, hydroxypropylβ-CD, methylβ-CD and γ-CD, have been studied in pH 12 aqueous solutions at 25 °C and in the solid state. Different phase solubility profiles of TB in the presence of CDs have been obtained: A_L type for TB with hydroxypropylβ-CD and γ-CD, A_P type for the complexes with methylβ-CD and α-CD, while a B_S profile was found for TB-β-CD. The apparent stability constants of the complexes were calculated at 25 °C from the phase solubility diagrams. The higher increase of TB solubility, up to 200-fold, together with the higher value of the stability constant were found for the complex with methylβ-CD. Solid systems of 1:1 drug:CD molar ratio were prepared and characterised using X-ray diffraction patterns, thermal analysis and FTIR spectroscopy. The coevaporation method can be considered the best method in preparing these solid complexes. The complexes of TB with natural CDs, except with α-CD, were crystalline, whereas the methyl and hydroxypropyl derivatives gave rise to amorphous phases. Dissolution rate studies have been performed with TB-β-CD and TB-HPβ-CD complexes, showing a positive influence of complexation on the drug dissolution.     

Cyclodextrin effects on physical–chemical properties of novocaine

The UV-vis absorption and the fluorescence emission spectra of novocaine were analysed in aqueous cyclodextrin (CD) solutions. Either the absorbance read at λ_max 290 nm or the fluorescence emission intensity at λ_ems 346 nm increase in the presence of both α- and β-CD due to the formation of 1:1 inclusion complexes. The lower polarity of the CD-cavity sensed by the included drug enhances the emitted fluorescence; in fact, the same effect was observed in aqueous mixtures of acetonitrile, dioxane, or dimethylsulfoxide. The inclusion complex formation between the monocation of novocaine and CDs diminishes the electrical conductance of aqueous solutions of novocaine hydrochloride (NoHCl). Both the nitrosation reaction in aqueous acid medium and the ester hydrolysis in alkaline medium are retarded in the presence of CDs. The strongest effect was observed with β-CD as a consequence of the higher stability inclusion complex.     

Spectroscopic study and antioxidant activity of the inclusion complexes of cyclodextrins and amlodipine besylate drug

The aim of the study was to synthesize and characterization the inclusion complexes of amlodipine besylate (AML) drug with β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) which has antioxidating activity property. The guest/host interaction of AML with β-CD and γ-CD in order to complexation drug in β-CD and γ-CD were investigated. The interaction inclusion complexes was characterized by fourier transform infrared and ultraviolet–visible spectroscopies. The formation constant was calculated by using a modified Benesi–Hildebrand equation at 25 °C. The stoichiometry of inclusion complexes was found to be 1:1 for β-CD and γ-CD with AML drug. The antioxidant activity of AML drug and its inclusion complexes were determined by the scavenging of stable radical 2,2′-diphenyl-1-picrylhydrazyl (DPPH^·). Kinetic studies of DPPH^· with AML and CDs complexes were done. The experimental results confirmed the forming of AML complexes with CDs also these indicated that the AML/β-CD and AML/γ-CD inclusion complexes was the most reactive than its free form into antioxidant activity.     

Preparation and characterization of cyclodextrin complexes of doxycycline hyclate for improved photostability in aqueous solution

Doxycycline hyclate is Biopharmaceutical Classification System, class I drug (high solubility and high permeability), but it is associated with poor photostability. It is in the class of tetracycline antibiotic, which is used to treat various infections, but its bioavailability is compromised due to its sensitivity to light and aqueous instability. In this paper, the influence of inclusion complexation with different cyclodextrins, i.e., αCD, γCD, HPβCD and RMβCD, on the photostability of doxycycline hyclate in aqueous media was investigated. Host–guest inclusion complexes were prepared by freeze- drying method. The prepared complexes were characterized for drug content, SEM, XRPD, in vitro permeation studies and photostability studies. XRPD showed diffused peaks for most of the complexes, while SEM showed irregularly shaped particles. The formulation D20 (Drug: γCD in 1:20 molar ratio) showed the highest % drug content (83.72?±?1.2%), and the formulations D1 (Drug: αCD in 1: 2 molar ratio) showed the lowest % drug content among all the CD complexes. It was found that the photodegradation of the drug was reduced significantly upon complexation. For Drug: CD complexes, the photostability of the aqueous solution of drug/CD complexes was found to be in the order of γCD?>?RMβCD?>?HPβCD?>?αCD with maximum photostability shown by Drug: γCD (1:20 molar ratio) complex. The obtained results suggested that cyclodextrin complexation can be used as an alternative approach for increasing the photostability of doxycycline hyclate.

     

Study of inclusion complex formation between a cationic surfactant, two cyclodextrins and a drug

In this study inclusion of hexadecyltrimethylammonium bromide (HTAB) with α-, and β-cyclodextrin (CD) in the presence and the absence of bromhexine (BH) was investigated using ion-selective electrode method. The association constants of HTAB with CDs were determined by potentiometry and were close to literature values. The obtained results indicated that α-CD formed 1:1 and 1:2 inclusion complexes, but β-CD formed only a 1:1 inclusion complex. In the presence of drug, the interaction between CDs and HTAB decreased, because both drug and HTAB could interact with CDs. The results showed that the interaction between drug and CDs are greater than HTAB and CDs. The stoichiometry of the inclusion complexes, the critical aggregation concentration (CAC), the monomer surfactant concentration of HTAB, [HTAB]_f, and also the effect of the inclusion complex on the micellization process of the HTAB were determined by conductivity measurements.     

1H NMR study of the inclusion of Costa-type organocobalt(III) complexes in cyclodextrins

The inclusion behavior between Costa-type complexes and cyclodextrins (CDs) was studied by 1H NMR in aqueous solution. The results indicated that 1:1 inclusion complex was formed, in which the alkyl group of the guest was included in the cavity of CDs. The stability constants of the inclusion complexes were determined by the quantitative 1H NMR method. The effects on stability constants were discussed when various host and guest compounds were used.     

Understanding the interactions between artemisinin and cyclodextrins: spectroscopic studies and molecular modeling

Artemisinin extracted from Artemisia annua L. proved to be currently, with its derivatives, the most effective drugs against simple and severe malaria, and is also effective on the chloroquine-resistant forms. The advantageous effect of some cyclodextrins (CDs) on artemisinin solubilization was demonstrated by different authors. The present work aims to confirm the effect of several CDs on artemisinin solubilization and to analyse the complexes formed between these CDs and artemisinin in order to understand their solubilization capacities. In this context, solubility studies, liquid-state NMR spectroscopy (¹H NMR studies and ROESY experiments) as well as theoretical studies (molecular modeling) have been performed. Randomly methylated-βCD, Crysmeb^? and hydroxypropylated-γCD were also found to improve the aqueous solubilization of artemisinin as well as βCD, γCD and hydroxypropylated-βCD whose effects were already demonstrated. The best solubilization ability was found with Crysmeb^?. The spectroscopic studies showed a lot of interactions between artemisinin and all the CDs studied, but mainly outside the cavity. Molecular modeling confirmed that artemisinin and CDs formed non-inclusion complexes.     

Complexation of tauro- and glyco-conjugated bile salts with three neutral beta-CDs studied by ACE

Complexation of the bile salts (BS) taurocholate, tauro-beta-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate, and glycochenodeoxycholate common in rat, dog, and man with natural beta-CD and the chemically modified beta-CDs 2-hydroxypropyl-beta-CD and 2-O-methyl-beta-CD was studied using mobility shift ACE. The CDs were selected due to their frequent use in preformulation and drug formulation as oral excipients for the solubilization of drug substances with low aqueous solubility. ACE was demonstrated to be a feasible and efficient technique for investigation of the interactions between BS and beta-CDs. All the investigated BS possessed affinity for the three CDs with stability constants ranging from 2x10(3) to 4x10(5) M(-) (1). The requirements and assumptions related to the use of ACE for estimating high affinity stability constants were discussed. The extent and pattern of hydroxylation significantly influenced the affinity of the glyco- and tauro-conjugated BS toward the beta-CDs (chenodeoxycholates > deoxycholates > cholates) whereas the nature of the beta-CD derivatization and BS conjugation played a minor role only. The results indicate that displacement of drug substances from beta-CD inclusion complexes is likely to occur in the small intestine where BS are present potentially influencing drug bioavailability.     

Effects of water and alcohol on the formation of inclusion complexes of d-limonene and cyclodextrins

Abstract

Systematic studies have been carried out on the role of water and alcohol in the formation of inclusion complexes between d-limonene and α-, β- and γ-cyclodextrin (CD) by a micro-aqueous method. The inclusion complex was barely formed at zero water content for all CDs. Above the specific water content for each CD, formation of the inclusion complex correlated well with an equation which was derived on the autocatalytic assumption for the inclusion phenomenon. The inclusion complex correlated well with an equation which was derived on the autocatalytic assumption for the inclusion phrnomenon. The minimum water content, which was defined as 1% of the maximum concentration of the inclusion complex formed, coincided with the number of water molecules inside the cavity of the CD. In the presence of ethanol, a significant amount of the inclusion complex was formed for β- and γ-CD/limonene systems, particularly at lower moisture content. However, for α-CD the inclusion fraction decreased significantly in the presence of ethanol. This means that ethanol inhibits the formation of the inclusion complex between x-CD and d-limonene. For other linear alcohols, the formation of the inclusion complex between d-limonene and β-CD increased with decreasing alkyl chain length. This suggests that the more hydrophilic and the smaller (in molecular size) the alcohol is, the more enhanced is the inclusion of d-limonene to β-CD.     

β-Cyclodextrin and folic acid host–guest interaction binding parameters determined by Taylor dispersion analysis and affinity capillary electrophoresis

The thermodynamic properties of molecular recognition in host–guest inclusion complexes can be studied by Taylor dispersion analysis (TDA). Host–guest inclusion complexes have modest size, and it is possible to get convergent results fast, achieving greater certainty for the obtained thermodynamic properties. Cyclodextrins (CDs) and their derivatives can be used as drug carriers that can boost stability, solubility, and bioavailability of physiologically active substances. A simple and effective approach for assessing the binding properties of CD complexes that are critical in the early stages of drug and formulation development is needed to fully understand the process of CD and guest molecules’ complex formation. In this work, TDA was successfully used to rapidly determine interaction parameters, including binding constant and stoichiometry, between β-CD and folic acid (FA) along with the diffusivities of the free FA and its complex with β-CD. Additionally, the FA diffusion coefficient obtained by TDA was compared to the results previously obtained by nuclear magnetic resonance. Affinity capillary electrophoresis (ACE) was also used to compare the binding constants obtained by different methods. The results showed that the binding constants obtained by ACE were somewhat lower than those obtained by the two TDA procedures.     

Study of the retention of aroma components by cyclodextrins by static headspace gas chromatography

The process of encapsulation is widely employed in the flavour industry to protect volatile and/or labile flavouring materials during storage. A variety of commercial practices are currently followed, but those involving the formation of flavour/cyclodextrin (CD) molecular inclusion complexes afford some of the greatest potential for increased product shelf life. The determination of the stability of inclusion complexes is of critical importance to take advantage of the complexation potential of CDs. Hence, we investigated the interactions between five CDs and thirteen aroma components. Relevant for, the retention of these compounds in presence of different CDs has been determined. The stability constants of the inclusion compounds have been calculated by static headspace gas chromatography in aqueous solution at 30 °C. The results indicate the formation of 1:1 inclusion complex for all the studied compounds. The binding between CDs and the aroma compounds depends on both hydrophobicity of the guest molecule and their geometric accommodation into the CD cavity. The results show that β-CDs are the most versatile CDs for the inclusion of the studied molecules.     

Inclusion complexes of α- andβ-cyclodextrin with α-lipoic acid

A UV spectroscopic study has been performed in neutral aqueous solution to give the complex stability constants. Data analyses assuming 1:1 stoichiometry were successfully applied to both of the host-guest combinations employed, where 1:1 host-guest complex formations were observed at lower concentration of cyclodextrins (CDs). X-ray powder diffraction and IR spectroscopy measurements also demonstrated that inclusion complexes were formed in the solid state. Furthermore, thermogravimetry and DTA were used to investigated the thermal properties of these complexes. The differential thermal analysis, as well as temperature variation experiments below 100°C, indicated that after complexing the 1,2-thiolane moiety of -lipoic acid (LP) penetrated into the cavity of the CD and the S-S linkage was protected against heat.