Host–Guest Interaction Study of Resveratrol With Natural and Modified Cyclodextrins

The aim of this work is to increase the stability and water solubility of resveratrol by complexation with different cyclodextrins. Furthermore, physical–chemical properties of each inclusion compound were investigated. Complexes of resveratrol with cyclodextrins both native (α, β, γ) and modified (2-hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin) were obtained by using the suspension method. An inclusion complex with β-cyclodextrin was also prepared by using the microwave. Solid state characterization of the products was carried out using Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (DRX); solution studies were performed by UV–Vis spectrophotometry and ¹H-NMR spectroscopy. Phase solubility profiles with all cyclodextrins employed were classified as A_N type, indicating the formation of 1:1 stoichiometric inclusion complexes. Stability constants (K _c) from the phase solubility diagrams were calculated. Stability studies in the solid state and in solution were performed; the photodegradation by UV–Vis spectrophotometry was monitored. The isomerization rate trans to cis, in ethanol solution, decreased with inclusion. The dissolution studies revealed that resveratrol dissolution rate was improved by the formation of inclusion complexes.     

Preparation and physicochemical characterization of omeprazole:methyl-beta-cyclodextrin inclusion complex in solid state

In this work, we illustrate the usefulness of cyclodextrins, namely, methyl-β-cyclodextrin (MβCD), an amorphous, methylated derivative of the natural β-cyclodextrin (βCD), as a tool to form an inclusion complex with omeprazole (OME), a poorly water soluble drug. Solid binary systems between OME and MβCD were prepared experimentally in a stoichiometry 1:1 by different techniques (physical mixing, kneading, spray-drying and freeze-drying). Afterward these products were characterized by Fourier transformation-infrared spectroscopy (FTIR); X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The results obtained suggest that spray-drying and freeze-drying methods yield a higher degree of amorphous entities suggesting the formation of inclusion complexes between OME and MβCD.     

Inclusion Complexation and Dissolution Properties of Nimesulide and Meloxicam–hydroxypropyl-β-cyclodextrin Binary Systems

The purpose of the work is physicochemical characterization of nimesulide (NI) and meloxicam (ME)–hydroxypropyl-β-cyclodextrin (HP-β-CD) binary systems both in solution and solid states and to improve the pharmaceutical properties of NI and ME via inclusion complexation with HP-β-CD. Binary systems of NI and ME with HP-β-CD have been characterized both in solution and solid state by different physicochemical methods. Three types of drug–HP-β-CD binary systems, namely physical mixtures (PM), kneaded systems (KS) and co evaporated systems (CS) in 1:1 and 1:2 molar ratios (1:1 and 1:2 M) were prepared. Phase solubility and ¹H-NMR spectroscopic studies in solution state revealed 1:1 M complexation of NI and ME with HP-β-CD. A partial inclusion of NI with HP-β-CD at both molar ratios of kneaded and co evaporated systems and a true inclusion of ME with HP-β-CD at both molar ratios of co evaporated systems in solid state was confirmed by differential scanning calorimetry (DSC), powder X-ray diffractometry (powder X-RD) and scanning electron microscopy (SEM) studies. Dissolution properties of NI and ME–HP-β-CD binary systems were superior when compared to corresponding pure drugs. The aqueous solubility and dissolution properties of NI and ME can be improved by inclusion complexation with HP-β-CD. Author for correspondence: E-mail: nbnaid2@E-mail.uky.edu     

2,4-D-α-Cyclodextrin Complexes

The aqueous solubility of the pesticide 2,4-D was improved by inclusion complexation with α-CD. The formation of such inclusion compounds was studied via the phase-solubility diagram (solution state) and by DSC and HSM (solid state). 2,4-D presented a typical B_s Higuchi solubility curve, coprecipitating a 1:2 pesticide-α-CD complex. In order to obtain solid complexes, three processing methods were checked: kneading, coprecipitation and spray-drying. DSC and HSM showed that only the last two of these yielded true inclusion compounds. Chemical analysis also revealed that the stoichiometry of such solid complexes corresponds to a 2,4-D-α-CD ratio of 1:2.     

Interaction of Valdecoxib with β-cyclodextrin: Experimental and Molecular Modeling Studies

This study aimed to investigate the effect of β-cyclodextrin on aqueous solubility and dissolution rate of valdecoxib and also to get an insight of molecular interactions involved in formation of valdecoxib‐β-cyclodextrin inclusion complex. Phase solubility analysis indicated complex with possible stoichiometry of 1:1 and a stability constant of 234.01 M⁻¹. Thermodynamic studies in water indicated exothermic nature of inclusion complexation.␣Valdecoxib‐β-cyclodextrin complexes (1:1 M) were prepared by kneading method, solution method and␣freeze–drying method. The complex was characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (P-XRD), Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance␣(¹H-NMR) spectroscopy. Molecular modeling was used to help establish the mode of interaction of β-cyclodextrin with valdecoxib. ¹H-NMR analysis suggested that the unsubstituted phenyl ring of valdecoxib display favorable interaction with the hydrophobic cavity of β-cyclodextrin, which was confirmed by molecular dynamic simulations. An inclusion complex model has been established for explaining the observed enhancement of solubility of valdecoxib in water by β-cyclodextrin. Dissolution studies in water showed that the valdecoxib in freeze-dried complex dissolved much faster than the uncomplexed drug and physical mixture. This improvement in dissolution rate is attributed to the increased solubility and wettability due to encapsulation along with decreased crystallanity caused by complex formation, which is evident by DSC and P-XRD studies.     

Inter-molecular physiochemical characterization for etodolac-hydroxypropyl-β-cyclodextrin polymeric systems in solid and liquid state

The purpose of this study was to explore the utility of hydroxypropyl-β-cyclodextrin (HP-β-CD) systems in forming inclusion complexes with the anti-rheumatic or anti-arthritic drug, etodolac (EDC), in order to overcome the limitation of its poor aqueous solubility. This inclusion system achieved high solubility for the hydrophobic molecule. The physical and chemical properties of each inclusion compound were investigated. Complexes of EDC with HP-β-CD were obtained using the kneading and co-evaporation techniques. Solid state characterization of the products was carried out using Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and Scanning electron microscopy (SEM). Studies in the solution state were performed using UV-Vis spectrophotometry and ¹H-NMR spectroscopy. Phase solubility profiles with HP-β-CD employed was found to be A_L type. Stability constants (K_c) from the phase solubility diagrams were calculated indicating the formation of 1:1 inclusion complex. Stability studies in the solid state and in liquid state were performed; the possible degradation by RP-HPLC was monitored. The dissolution studies revealed that EDC dissolution rate was improved by the formation of inclusion complexes.      

Complexation of nevirapine with β-cyclodextrins in the presence and absence of Tween 80: characterization,thermodynamic parameters,and permeability flux

The work is undertaken to evaluate the effect of Tween 80 on the complexing ability of β-cyclodextrins to encapsulate the poorly soluble antiretroviral agent, nevirapine. The phase solubility diagram indicates 1:1 stoichiometry and is supported by electronspray ionization mass spectrometry. The complexes were characterized by DSC, FT-IR, and XRD in the solid state. The ternary systems were autoclaved before being lyophilized for the best results. Proton NMR suggests that the methyl pyridine ring of the drug is involved in inclusion and enters from the wider side of the cavity which was confirmed by COESY NMR. Solution calorimetry, a direct method to determine the thermodynamic parameters, was used to determine the complexation constant (K) and other thermodynamic properties. The process is associated with negative ∆H and positive ∆S indicating a stable inclusion complex. The value of K follows the order β-CD < HP-β-CD < M-β-CD. The molar enthalpy of solution in autoclaved solid formulation is less endothermic as compared to additive molar enthalpy of solution obtained by summation of enthalpy of solution of individual components suggesting synergistic interaction between the drug and its constituents. A threefold increase of the in vitro permeability flux was observed for binary systems which was elevated to fourfold for autoclaved ternary complexes.     

Water soluble complexes of methyl β-cyclodextrin and sulconazole nitrate

Complexation between methyl β-cyclodextrin (Me βCD) and sulconazole nitrate (SULC) was realized both under freeze drying and ultrasonication conditions. The process was carried out in solution and in solid state. In solution, the complexation was evaluated using solubility studies, nuclear magnetic resonance spectroscopy (¹H-NMR) and UV–Vis absorption studies. In the solid state, differential scanning calorimetry (DSC), and X-ray diffraction studies were used. Solubility studies indicate the existence of inclusion complexes between SULC and Me βCD. ¹H-NMR data showed that the inclusion complexes have different structures, according with the method we used for synthesis: for the freeze dried method the complex is obtained by complexation of dichlorobenzene ring of SULC into inner cavity of CD while for ultrasonication method the complex is obtained by complexation of imidazole graph of SULC into the CD molecule. DSC and X-ray studies bring supplementary information concerning the formation of complex Me βCD–SULC. As a result of the inclusion process into Me βCD, the solubility of SULC increase significant, being 10 times more comparative with the pure drug. We anticipate that these modifications will have a significant impact on the biological effects of the drug, making the SULC–Me βCD complex an appropriate candidate for a new drug delivery system.     

Bifonazole-β-cyclodextrin Inclusion Complexes. Thermal analysis and X-ray powder diffraction study

The complexation of bifonazole, an antimycotic hydrophobic imidazole derivative, with β-cyclodextrin (β-CD) was investigated in solid phase, using the following complementary techniques: differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and X-ray powder diffractometry. The β-CD-bifonazole samples were prepared in both aqueous medium by coprecipitation and in solid state by kneading method and the β-CD-bifonazole binary diagrams were drawn. The experimental results demonstrate the formation of two binary compounds, β-CD-bifonazole and (β-CD)_x bifonazole (x =2 or 4). The first compound may be an inclusion compound and the second a crystallized compound, in which the bifonazole is not necessarily included in the cyclodextrin internal cavity. This revised version was published online in July 2006 with corrections to the Cover Date.     

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 A_L 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.     

Effect of Buffer Species on the Complexation of Basic Drug Terfenadine with β-Cyclodextrin

The complexation of terfenadine (Terf) with β-cyclodextrin (β-CD) in solution and solid state has been investigated by phase solubility diagram (PSD), differential scanning calorimetry (DSC), powder X-ray diffractometry (PXD) and proton nuclear magnetic resonance (¹H-NMR). The PSD results indicated that the salt saturation with the buffer counter ion (citrate⁻², H₂PO₄⁻¹ and Cl⁻¹ ions) of Terf (pK _a = 9.5) and the hydrophobic effect play in tandem to increase the value of the complex formation constant (K₁₁) measured at different conditions of pH, ionic strength, buffer type and buffer concentration. The correlation of the free energy of complex formation (ΔG₁₁) with the free energy of inherent solubility of Terf (ΔG_So) obtained by changing the pH, ionic strength and buffer concentration was used to measure the contribution of the hydrophobic effect (desolvation) to complex formation. The hydrophobic effect was found to constitute 57.8% of the driving force for complex stability, while other factors including specific interactions contribute −13.4 kJ/mol. ¹H-NMR spectra of Terf–citrate and Terf–HCl salts gave identical chemical shift displacements (ΔΔ) upon complexation, thus indicating that the counter anions are positioned somewhere outside of the β-CD cavity. DSC, XRPD and ¹H-NMR proved the formation of solid Terf/acid/β-CD ternary complexes.     

Inclusion complexation of diclofenac with natural and modified cyclodextrins explored through phase solubility, 1H-NMR and molecular modeling studies

Guest–host interactions were examined for neutral diclofenac (Diclo) and Diclofenac sodium (Diclo sodium) with each of the cyclodextrin (CD) derivatives: α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), all in 0.05 M aqueous phosphate buffer solution adjusted to 0.2 M ionic strength with NaCl at 20 °C, and with β-CD at different pHs and temperatures. The pH solubility profiles were measured to obtain the acid–base ionization constants (pK _as) for Diclo in the presence and absence of β-CD. Phase solubility diagrams (PSDs) were also measured and analyzed through rigorous procedures to obtain estimates of the complex formation constants for Diclo/CD and Diclo sodium/CD complexation in aqueous solutions. The results indicate that both Diclo and Diclo sodium form soluble 1:1 complexes with α-, β-, and HP-β-CD. In contrast, Diclo forms soluble 1:1 Diclo/γ-CD complexes, while Diclo sodium forms 1:1 and 2:1 Diclo/γ-CD, but the 1:1 complex saturates at 5.8 mM γ-CD with a solubility product constant (pK _sp = 5.5). Therefore, though overall complex stabilities were found to follow the decreasing order: γ-CD > HP-β-CD > β-CD > α-CD, some complex precipitation problems may be faced with aqueous formulations of Diclo sodium with γ-CD, where the overall concentration of the latter exceeds 5.8 mM γ-CD. Both ¹H-NMR spectroscopic and molecular mechanical modeling (MM⁺) studies of Diclo/β-CD indicate the possible formation of soluble isomeric 1:1 complexes in water.     

Prednisone/Cyclodextrin Inclusion Complexation: Phase Solubility,Thermodynamic, Physicochemical and Computational Analysis

Guest–host interaction of prednisone (PN) with cyclodextrins (CDs) have been investigated using phase solubility diagrams (PSD), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), scanning electron microscopy (SEM) and molecular mechanical modeling (MM). Estimates of the complex formation constant (K ₁₁) show that the tendency of PN to complex with CDs follows the order: β-CD>γ-CD>HP-β-CD>α-CD. At the same pH of 7.0, β-CD forms soluble 1:1 and insoluble 1:2 PN/CD complexes (B_S-type PSDs). The thermodynamic functions for 1:1 PN/β-CD estimated at pH = 7.0 (ΔG ₁₁^o=−20.8 kJ⋅mol⁻¹) show that complexation is driven by enthalpy (−30.7 kJ⋅mol⁻¹) but retarded by entropy (ΔS ₁₁^o=−33.1 J⋅mol⁻¹⋅K⁻¹) changes. The MM modeling study indicates the formation of different isomeric 1:1 complexes with CDs. PSD, DSC, XRPD, SEM and MM studies established the formation of inclusion complexes in solution and the solid state.     

Enhancement of cyclosporine aqueous solubility using α- and hydroxypropyl β-cyclodextrin mixtures

Cyclodextrins (CDs) are cyclic oligosaccharides that form inclusion complexes with lipophilic molecules through their hydrophobic central cavity. In this study, the effect of α-CD, hydroxylpropyl-β-CD (HP-β-CD) and mixtures of these two CDs on the aqueous solubility of cyclosporine A (CyA) was investigated. Infrared spectroscopy and thermal analysis were used to confirm CyA-CD complex formation. CyA aqueous solubility was increased by 10 and 80 fold in the presence of α-CD and HP β-CD, respectively. The phase-solubility profile for HP-β-CD was linear while that for α-CD had positive deviation from linearity. In the presence of constant concentration of α-CD (15% w/v), aqueous solubility of CyA was further increased upon addition of HP-β-CD up to a concentration of 20% w/v. At higher HP-β-CD concentrations, aqueous solubility of CyA was observed to decrease. Addition of sodium acetate (up to 5% w/v) to aqueous solutions containing 20% w/v HP-β-CD and increasing concentrations of α-CD resulted in a significant reduction in CyA solubility. Complex formation between CyA and both α-CD and HP-β-CD was confirmed by differential scanning calorimetry (DSC). No significant changes were observed in the IR spectra of either CyA or CD following complex formation suggesting chemical interaction between CyA and the CD was unlikely. Phase-solubility studies showed that α-CD had a much greater effect on the solubility of CyA than HP-β-CD. Addition of HP-β-CD to aqueous solutions of α-CD affected the solubility of CyA in these systems. A mixture of 15% w/v α-CD and 20% w/v HP-β-CD was optimal for increasing aqueous solubility of CyA.     

The modes of complexation of benzimidazole with aqueous β-cyclodextrin explored by phase solubility, potentiometric titration, 1H-NMR and molecular modeling studies

The results of rigorous modeling of phase solubility diagrams, pH solubility profiles and potentiometric titrations revealed the following for benzimidazole (BZ) and BZ/β-CD complexation in aqueous solution: (a) the pK _a value of BZ estimated at 5.66 ± 0.08 was reduced to 5.33 ± 0.06 in the presence of 15 mM β-CD at 25 °C, thus indicating inclusion complex formation; (b) BZ forms soluble 1:1 and 2:1 BZ/β-CD complexes with complex formation constants K ₁₁ = 104 ± 8 M⁻¹ and K ₂₁ = 16 ± 6 M⁻¹; (c) protonated BZ forms only 1:1 complex with K ₁₁ = 42 ± 12 M⁻¹; (d) ¹H-NMR studies in D₂O showed significant upfield chemical shift displacements for inner cavity β-CD protons indicating inclusion complex formation, while (e) Molecular modeling of BZ-β-CD interactions in water clearly indicated complete inclusion of one BZ molecule into the β-CD cavity.     

Preparation and characterization of inclusion complexes containing fixolide, a synthetic musk fragrance and cyclodextrins

AHTN (7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene), commercially known as fixolide or tonalide, is a synthetic fragrance widely used in replace of natural musk odor which is more expensive. It is a popular fragrance material added in the manufacturing of personal care and household products, such as perfumes, soaps, shampoos, detergents, and fabric softeners. AHTN is semivolatile and is degraded under light exposure and high temperature. This work focuses on the complexation of AHTN with cyclodextrins in the effort to stabilize the fragrance material. AHTN was complexed with β-cyclodextrin, methyl (MβCD), and hydroxypropyl (HPβCD) derivatives in the mole ratio 1:1, 1:2, and 1:3 guest:host, and the complexes formed by physical mixing, co-precipitation, kneading, and freeze-drying were analyzed by DSC and FTIR. Percent AHTN included in the complex was also determined by hexane extraction and GC analysis. It was found that no inclusion complex was formed in the physical mixture. When co-precipitation method was performed, only βCD could form inclusion complex with AHTN, while the other two derivatives could not. Using 1:2 AHTN:βCD, no free AHTN was left in the complex as evidenced by DSC and FTIR spectrum. In kneading and freeze-drying methods, complexes could be formed with all CDs tested. However, co-precipitation method with 1:2 AHTN:βCD and kneading method with 1:2 AHTN:MβCD provided the highest complex yield with highest amount of AHTN included in the complex. AHTN in the complex form was more stable against high temperature and UV exposure than its free form.     

Solubility-dependent complexation of active pharmaceutical ingredients with trimethyl-β-cyclodextrin under supercritical fluid condition

The effect of the solubility of active pharmaceutical ingredients (APIs) in supercritical carbon dioxide (SC-CO₂) on their complexation behavior with trimethyl-β-cyclodextrin (TM-β-CD) has been investigated. Flurbiprofen or naproxen, the solubility of which is lower than that of ibuprofen, was mixed with TM-β-CD and the complexation phenomena on SC-CO₂ processing was evaluated using powder X-ray diffraction, differential scanning calorimetry and IR measurement. Drug complexation depended both on SC-CO₂ treatment time and on drug solubility in CO₂. The inclusion complex formation of flurbiprofen with TM-β-CD proceeded slowly compared with the case of ibuprofen. The slower complexation behavior was also observed when naproxen was used as the guest molecule. These results indicate that dissolution of drug molecules in SC-CO₂ is a rate-determining step for the inclusion complex formation with TM-β-CD and that complexation proceeds after dissolving the both components in SC-CO₂.     

A Study on Host–Guest Complexation of 5-Amino-2-Mercaptobenzimidazole with <Emphasis Type="Italic">β</Emphasis>-Cyclodextrin

Spectral characteristics of 5-amino-2-mercaptobenzimidazole (AMBZ) have been investigated in aqueous β-cyclodextrin (β-CDx) solutions. The absorbance and fluorescence intensity of the neutral and monocationic forms of AMBZ are enhanced due to the formation of an inclusion complex with β-CDx. The stoichiometry and binding constants of the complex were calculated using the Benesi–Hildebrand equation. Formation of an inclusion complex between AMBZ and β-CDx was also confirmed by steady state and time-resolved fluorescence spectroscopy. FT-IR spectral data and SEM images of the solid complex provide supporting evidence for complex formation. The effect of acidity on the ground and excited state equilibrium between neutral and monocationic forms of AMBZ was analyzed in aqueous and β-CDx environments. The ground and excited state acidity constants in β-CDx solutions were found to be different from those in aqueous solution. Based on these results, the structure of the 1:1 complex is proposed.     

Astemizole/Cyclodextrin Inclusion Complexes: Phase Solubility, Physicochemical Characterization and Molecular Modeling Studies

Guest–host interaction of astemizole (Astm) with cyclodextrins (CDs) has been investigated using phase solubility diagrams (PSD), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), proton nuclear magnetic resonance (¹H-NMR) and molecular mechanical modeling (MM⁺). Estimates of the complex formation constant, K ₁₁, show that the tendency of Astm to complex with CDs follows the order: β-CD>HP-β-CD>γ-CD, α-CD. 1:1 Astm/β-CD complex formation at pH=5.0 was largely driven by the hydrophobic effect (desolvation), which was quantitatively estimated at −16.5 kJ⋅mol⁻¹, whereas specific interactions contribute only −5.3 kJ⋅mol⁻¹ to 1:1 complex stability (ΔG ₁₁^o=−22.7 kJ⋅mol⁻¹). The percentage contributions of the hydrophobic effect and specific interactions were therefore 73 and 27%, respectively. Both enthalpic and entropic factors contribute equally well (−11 kJ⋅mol⁻¹ each) to 1:1 Astm/β-CD complex stability. ¹H-NMR and MM⁺ molecular modeling studies indicate the formation of different isomeric 1:1 and 1:2 complexes. The dominant driving force for complexation is evidently van der Waals with very little electrostatic contribution. PSD, ¹H-NMR, DSC, XRPD and MM⁺ studies proved the formation of inclusion complexes in solution and the solid state.     

Sulphamethizole-Cyclodextrin-Hydroxy Propylmethyl Cellulose Multicomponent Complexes

The effect of cyclodextrin complexation of sulphamethizole (SM) was studied. Two systems were prepared with two cyclodextrin derivatives, β-cyclodextrin (BCD) and hydroxypropyl-β-cyclodextrin (HPBCD): binary complexes and multicomponent systems (cyclodextrins and a hydroxylpropylmethyl cellulose K4M). Inclusion complexes were prepared by freeze-drying and characterized by thermal analysis (DSC) and X-ray diffractometry. The presence of the polymer in the solution increases the effect of cyclodextrins – specially BCD – on the solubility of SM. In solid state, binary inclusion complexes enhance the dissolution behaviour of SM but, from the multi-component complexes, the polymer controls the release of the drug. This revised version was published online in August 2006 with corrections to the Cover Date.