Cyclodextrin Inclusion Complexes Research Articles

Preparation and characterization of benzoyl‐hydrazide‐derivatized poly(lactic acid) and γ‐cyclodextrin inclusion complex and its effect on the performance of poly(lactic acid)

A nucleating agent, benzyl‐hydrazide‐derivatized poly(lactic acid) (PLA) and γ‐cyclodextrin inclusion complex (PLA‐IC‐BH), was synthesized through a series of reactions. Poly(lactic acid) and γ‐cyclodextrin inclusion complex (PLA‐IC) was first obtained by ultrasonic co‐precipitation, which was then subjected to carboxylation, acylation, and amidation using benzoyl hydrazine and thionyl chloride. The composition and structure of PLA‐IC‐BH was confirmed by 1H nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, and X‐ray diffraction. PLA/PLA‐IC‐BH composites were prepared by melt blending and a hot‐press forming process. Mechanical properties, thermal stabilities, and crystallization behaviors of PLA/PLA‐IC‐BH samples were investigated by thermogravimetric analysis, differential scanning calorimetry (DSC), polarized optical microscopy (POM), rheological analysis, and so on. Mechanical testing and thermogravimetric analysis showed that the tensile strengths, impact properties, and thermal stabilities of PLA/PLA‐IC‐BH composites were improved significantly compared to pure PLA and PLA/PLA‐IC. DSC results showed that crystallinity of PLA was increased from 5.17% to 38.93% after introduction of PLA‐IC‐BH. POM results showed that PLA‐IC‐BH acted as a nucleating agent for PLA and enhanced its crystallization rate. Rotational rheological behaviors of PLA/PLA‐IC‐BH demonstrated that incorporation of PLA‐IC‐BH increased the rigidity of the network structure of the PLA matrix. Compared to those of PLA, the maximum torque and apparent viscosity of PLA/PLA‐IC‐BH composites were increased by 55.56% and 25.59%, respectively. Copyright © 2017 John Wiley & Sons, Ltd.

Ultrasound processed nanoemulsion: A comparative approach between resveratrol and resveratrol cyclodextrin inclusion complex to study its binding interactions, antioxidant activity and UV light stability

Resveratrol is a naturally occurring therapeutic molecule used for treatment of diseases caused by oxidative stress. This investigation elucidates the advantages of fabrication of size controlled resveratrol inclusion complex. This has been done by encapsulating resveratrol-cyclodextrin inclusion complex in a phospholipid stabilized nanoemulsion formulated by ultrasonication emulsification method. The prepared nanoemulsion has been compared with resveratrol encapsulated nanoemulsion system. The morphology of the resveratrol nanoemulsion and inclusion complex nanoemulsion have been observed using transmission electron microscopy with average size 20.41±3.41 and 24.48±5.70nm respectively. The nanoemulsion showed good loading and release efficiency. The radical diminishing potential of resveratrol and its inclusion complex has been compared in nanoemulsion. The effect of UV irradiation (365nm) on resveratrol in different solvent systems (ethanol, water and nanoemulsion) indicated that nanoemulsion prevents degradation of resveratrol. Efforts have also been made to explore the interactions between bovine serum albumin and resveratrol in nanoemulsion.

Antioxidant α‐tocopherol/γ‐cyclodextrin–inclusion complex encapsulated poly(lactic acid) electrospun nanofibrous web for food packaging

ABSTRACTα‐Tocopherol (α‐TC) and α‐TC/cyclodextrin (CD)–inclusion complex (IC) incorporated electrospun poly(lactic acid) (PLA) nanofibers (NF) were developed via electrospinning (PLA/α‐TC–NF and PLA/α‐TC/γ‐CD–IC–NF). The release of α‐TC into 95% ethanol (fatty food simulant) was much greater from PLA/α‐TC/γ‐CD–IC–NF than from PLA/α‐TC–NF because of the solubility increase in α‐TC; this was confirmed by a phase‐solubility diagram. 2,2‐Diphenyl‐1‐picrylhydrazyl radical‐scavenging assay shows that PLA/α‐TC–NF and PLA/α‐TC/γ‐CD–IC–NF had 97% antioxidant activities; this value was expected to be high enough to inhibit lipid oxidation. PLA/α‐TC–NF and PLA/α‐TC/γ‐CD–IC–NF were tested directly on beef with the thiobarbituric acid reactive substance (TBARS) method, and the nanofibers displayed a lower TBARS content than the unpackaged meat sample. Thus, active packaging significantly enhanced the oxidative stability of the meat samples at 4 °C. In conclusion, PLA/α‐TC/γ‐CD–IC–NF was shown to be promising as an active food‐packaging material for prolonging the shelf life of foods. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 44858.

Effect of Drug Particle Size on Complexation, Physicochemical Properties and Dissolution of Cyclodextrin Inclusion Complexes

The main purpose of this study was to investigate the role of drug particle size on the complexation, physicochemical properties and dissolution of β-cyclodextrin inclusion complexes. In this work, ibuprofen in size of 3 μm and 45 μm (ibuprofen 3 and ibuprofen 45) were employed as the poorly water-soluble drug model. Complexation kinetics and complexation efficiency studies were conducted to investigate the complexation of ibuprofen with β-cyclodextrin in water. The solid cyclodextrins inclusion complexes were prepared with kneading method and characterized by Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray powder difractometry, optical microscopy analyses and dissolution test. Ibuprofen with smaller particle size showed higher complexation rate with β-cyclodextrin in complexation kinetics study. By comparing the apparent stability constant, Kc and complexation efficiency of complexes, it also indicated that smaller drug particles are more efficient to interact with β-cyclodextrin than larger particles. The phase solubility diagram could be classified as Bs type, which denotes complexes with limited solubility. The Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray powder difractometry and optical microscopy analyses confirmed the formation of β-cyclodextrin inclusion complexes with ibuprofen 3 or ibuprofen 45. In the dissolution study, the inclusion complexes presented faster dissolution rate on contrast with the physical mixtures and pure drugs. What is more, the inclusion complexes prepared with ibuprofen in small particle size showed improving dissolution rate than in large particle size.

Interfacial rheological behaviors of inclusion complexes of cyclodextrin and alkanes.

The transformation of cyclodextrins (CDs) and alkanes from separated monomers to inclusion complexes at the interface is illustrated by analyzing the evolution of interfacial tension along with the variation of interfacial area for an oscillating drop. Amphiphilic intermediates are formed by threading one CD molecule on one alkane molecule at the oil/aqueous interface. After that, the amphiphilic intermediates transform into non-amphiphilic supramolecules which further assemble through hydrogen bonding at the oil/aqueous interface to generate a rigid network. With the accumulation of supramolecules at the interface, microcrystals are formed at the interface. The supramolecules of dodecane@2α-CD grow into microrods which form an unconsolidated shell and gradually cover the drop. However, the microcrystals of dodecane@2β-CD are significantly smaller which fabricate into skin-like films at the interface. The amphiphilic intermediates during the transformation increase the feasibility of self-emulsification and the skin-like films enhance the stability of the emulsion. With these unique properties, CDs can be promising for application in hydrophobic drug delivery, food industry and enhanced oil recovery.

Study on Preparation and Migration Behavior of Polyvinyl Alcohol Active Packaging Film Based on Clove Essential Oil/β-Cyclodextrin Inclusion Complex

Study on Preparation and Migration Behavior of Polyvinyl Alcohol Active Packaging Film Based on Clove Essential Oil/<i>β</i>-Cyclodextrin Inclusion Complex

Pharmacodynamic and pharmacokinetic investigation of cyclodextrin-mediated asenapine maleate in situ nasal gel for improved bioavailability

Asenapine maleate (AM) is used in the treatment of schizophrenia. Its oral and sublingual bioavailability is <2% and 35%, respectively, due to first pass metabolism and poor solubility. To avoid first pass metabolism and to enhance solubility at all nasal pH conditions, thermo-responsive in situ nasal gel containing asenapine maleate-hydroxyl propyl β cyclodextrin inclusion complex (AM-HPβCD) was prepared in the present study. Inclusion complex (1:1 molar ratio) was characterized using UV spectroscopy, FITR and XRD techniques. Selected formulation (F8b) contained a thermo-sensitive polymer poloxamer 407 which formed gel at 23%w/v concentration and a mucoadhesive polymer PVP K 30 (0.3%w/v) in temperature range of 29–34 °c. It was analyzed for pH, clarity, gelation temperature, mucoadhesive strength, gel strength and rheological parameters using Anton paar compact rheometer. This formulation was subjected to in vitro drug diffusion study using the Franz diffusion cell. Maximum % drug diffusion was obtained at the end of 120 min (99.1 ± 0.44%w/v). Dissolution in simulated nasal fluid was 92.33 ± 0.15%w/v at the end of 120 min. Locomotor activity was improved with nasal gel containing AM-HPβCD as compared to AM and AM-HPβCD oral solution in rats. Cmax for nasal gel was found to be more (9 ng/ml) as compared to AM-HPβCD (5.5 ng/mL) and oral standard solution (2 ng/ml). Tmax was found to be 1.5 h. AUC and thus bioavailability in rats by nasal route was increased by 2.5 fold.

Identification of a cyclodextrin inclusion complex of antimicrobial peptide CM4 and its antimicrobial activity.

Antibacterial peptide CM4 (ABP-CM4) is a natural product isolated from the silkworm Bombyx mori. It is a small cationic peptide with broad-spectrum activities against harmful microorganisms and may be used as a novel food preservative. However, ABP-CM4 lacks tertiary structure in water-like solutions, which makes it more susceptible to proteases and labile when exposed to air. In this study, β-cyclodextrin (β-CD) was chosen to form an inclusion complex with ABP-CM4, which enhanced the physical and chemical properties of ABP-CM4 but did not decrease its antibacterial activity. The storage stability and susceptibility to proteinases of ABP-CM4 were apparently improved under the protection of β-CD. This technology could also be widely applied to other AMPs as an antimicrobial system to be used in the food industry.

Ionic liquids and cyclodextrin inclusion complexes: limitation of the affinity capillary electrophoresis technique.

The state of the art of inclusion complex formation between cyclodextrins and ionic liquids is reported. Mechanisms, stoichiometries, and binding constants are summarized and classified by anion. We investigated the supramolecular interactions between the β-cyclodextrin cavity and six ionic liquids based on 1-dodecyl-3-methylimidazolium by affinity capillary electrophoresis and compared the results with those obtained by isothermal titration calorimetry. We show that the presence of basic or acidic buffers leads to a metathesis reaction, underlining the limitation of the affinity capillary electrophoresis technique.

Hot-melt extrusion as a continuous manufacturing process to form ternary cyclodextrin inclusion complexes

The aim of this study was to evaluate hot-melt extrusion (HME) as a continuous process to form cyclodextrin (CD) inclusion complexes in order to increase the solubility and dissolution rate of itraconazole (ITZ), a class II model drug molecule of the Biopharmaceutics Classification System. Different CD derivatives were tested in a 1:1 (CD:ITZ) molar ratio to obtain CD ternary inclusion complexes in the presence of a polymer, namely Soluplus® (SOL). The CD used in this series of experiments were β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD) with degrees of substitution of 0.63 and 0.87, randomly methylated β-cyclodextrin (Rameb®), sulfobutylether-β-cyclodextrin (Captisol®) and methyl-β-cyclodextrin (Crysmeb®).Rheology testing and mini extrusion using a conical twin screw mini extruder were performed to test the processability of the different CD mixtures since CD are not thermoplastic. This allowed Captisol® and Crysmeb® to be discarded from the study due to their high impact on the viscosity of the SOL/ITZ mixture. The remaining CD were processed by HME in an 18mm twin screw extruder. Saturation concentration measurements confirmed the enhancement of solubility of ITZ for the four CD formulations. Biphasic dissolution tests indicated that all four formulations had faster release profiles compared to the SOL/ITZ solid dispersion. Formulations of HPβCD 0.63 and Rameb® even reached 95% of ITZ released in both phases after 1h.The formulations were characterized using thermal differential scanning calorimetry and attenuated total reflectance infra-red analysis. These analyses confirmed that the increased release profile was due to the formation of ternary inclusion complexes.

Formulation and Evaluation of Cyclodextrin Inclusion Complex Tablets of Carvedilol

Objective: The aim of this series of experiments was to improve the solubility of a poorly soluble drug. Materials and Methods: Binary inclusion complexes of carvedilol and cyclodextrins derivatives were prepared by kneading method. Their solubility and dissolution behavior were compared with that of the pure drug and the marketed formulation of carvedilol. Results: Saturation solubility studies indicate that the solubility of the drug was increased and X-ray diffraction, differential scanning calorimetry, scanning electron microscopy showed that the crystalline nature of drug was lost or decreased significantly in the inclusion complex, indicating the drug was present in a solubilized form in the formulation. All inclusion complex tablets showed increase in dissolution rate than tablet prepared with pure drug. Formulation FT8 showed faster drug release in comparison to other formulations and data were fitted to various kinetic models. The mechanism of drug release from tablets was found to be Supercase 2 Transport. Stability studies suggested that there was no significant degradation or changes taking place in the tablets during the study period. Conclusion: It can be concluded that the inclusion complexation technique is an effective approach for the dissolution rate improvement of water insoluble drugs such as carvedilol.

α-Cyclodextrin – Water binary system. New data on dehydration of α-cyclodextrin hexahydrate

Cyclodextrins (CDs) are torous-like macrocycles composed of glucopyranose units. Due to their shapes, they are capable to include a wide variety of organic and inorganic guest molecules with formation of inclusion complexes in solid and liquid state. CDs crystallize from aqueous solution as hydrates (water molecules are located in the cavities and fill intermolecular space). The process of inclusion complex formation is, in fact, a replacement reaction of water molecules by hydrophobic guest molecules. Given the important role of water in the formation of CDs inclusion complexes, and the fact that the main commercial forms of cyclodextrins are the hydrated ones, the study of temperature (T) – composition (x) phase diagram of cyclodextrin – water binary system is of scientific and practical interest. This article reports an experimental study of the T, x – phase diagram of α-cyclodextrin – water binary system under isochoric conditions by differential thermal analysis (DTA) and differential scanning calorimetry (DSC). Powder X-ray diffraction was used to identify the structures of different α-CD hydrates and to follow their phase transformations. It was shown that dehydration processes in isochoric and isobaric (open air) conditions differ significantly. In the temperature range of approximately 351K–359K the α-CD hexahydrate of known Form I structure transforms into the α-CD·5.3H2O of unknown structural type. It is found that the solid solution on the base of the structure α-CD hexahydrate Form I is formed within the limits of α-CD·6.1H2O – α-CD·2.1H2O. The above findings give new insight on dehydration processes in the α-CD – water binary system. Thermodynamic parameters of the dehydration process are derived from DSC data and tensimetric measurements of vapor pressure over α-CD·6.1H2O by static method. The data obtained represent new and valuable information which can be very helpful when choosing conditions of the gas-phase synthesis of α-CD complexes.

Study to explore host-guest inclusion complexes of cyclodextrins with biologically active molecules in aqueous environment

Molecular inclusion of two natural amino acids, viz., L-asparagine and L-aspartic acid as guest into the host cavity of α and β-cylodextrins in aqueous solution have been studied which have various applications in the field of present bio-medical science for controlled delivery of necessary amount of the guest at the targeted site for a period of time efficiently and precisely. Surface tension and conductivity studies establish the formation of inclusion complexes with 1:1 stoichiometry. The inclusion complexes have been characterized by various thermodynamic factors basing upon density and viscosity studies. Contributions of various groups of the guest amino acid molecules toward the limiting apparent molar volume and viscosity B-coefficient have been calculated, as well as the solvation and hydration numbers are determined to support the inclusion phenomenon. Formations of the inclusion complexes have been explained with the help of hydrophobic effect, H-bonding, electrostatic forces and structural effects.

Probing inclusion complexes of cyclodextrins with amino acids by physicochemical approach

Formations of host-guest inclusion complexes of two natural amino acids, viz., l-Leucine and l-Isoleucine as guests with α and β-cyclodextrins have been investigated which include diverse applications in modern science such as controlled delivery in the field of pharmaceuticals, food processing etc. Surface tension and conductivity studies establish the formation of inclusion complexes with 1:1 stoichiometry. The interactions of cyclodextrins with amino acids have been supported by density, viscosity, refractive index, hydration and solvation number measurements indicating higher degree of inclusion in case of α-cyclodextrin. l-Leucine interacts more with the hydrophobic cavity of cyclodextrin than its isomer. With the help of stability constant by NMR titration, hydrophobic effect, H-bonds and structural effects the formations of inclusion complexes have been explained.

Molecular dynamics simulations of inclusion complexation of glycyrrhizic acid and cyclodextrins (1:1) in water

By means of molecular dynamics (MD) simulations, we analyzed the formation of inclusion complex consisting of cyclodextrins and the triterpene glycoside, glycyrrhizic acid, to obtain information about the transient binding pathway and the stable complex structures in equilibrium. For each of the two possible orientations of a glycyrrhizic acid molecule, β- and γ-cyclodextrins were initially positioned on 20 different sites of the molecule at intervals of 1 A, and the MD run was performed for 0.8 nsec for the sampling conformations. The position-dependent energy contributions derived from van der Waals interactions and electrostatic interactions showed that there exist two distribution gaps responsible for the formation of β-cyclodextrin complexes, indicating that glycyrrhizic acid could not pass through the hydrophobic pocket of β-cyclodextrin, as opposed to γ-cyclodextrin. In the most stable complex structures for both β- and γ-cyclodextrins, the glucuronic acid of glycyrrhizic acid binds to the hydrophobic pocket of cyclodextrins. This is also consistent with the analysis of hydrogen bonding. These energy contributions are larger for the binding to γ-cyclodextrin than to β-cyclodextrin, which correlates well with the results of isothermal titration calorimetry experiments. We also analyzed configurational entropies based on the trajectory of the MD runs, which showed that there would be little difference in configurational entropy on the binding entropy change between β- and γ- cyclodextrins.

Antioxidant activity and photostability of α-tocopherol/β-cyclodextrin inclusion complex encapsulated electrospun polycaprolactone nanofibers

Cyclodextrin inclusion complexes (CD-ICs) can be encapsulated into electrospun nanofibers in order to achieve delivery systems having high surface area and highly porous nanofibrous structures. In this study, a well-known antioxidant molecule, α-tocopherol (α-TC) (vitamin E) was chosen as an active agent for inclusion complexation with β-cyclodextrin. Polycaprolactone (PCL) nanofibers encapsulating α-tocopherol/β-cyclodextrin inclusion complex (α-TC/β-CD-IC) which has high antioxidant activity and photostability was produced via electrospinning (PCL/α-TC/β-CD-IC-NF). The formation of α-TC/β-CD-IC was confirmed by XRD. Phase solubility studies showed An-type complex formation between α-TC and β-CD. SEM revealed that bead-free nanofibers were successfully produced from PCL/α-TC/β-CD-IC system. PCL nanofibers encapsulating α-TC without CD-IC was also produced for comparison (PCL/α-TC-NF). Antioxidant test results showed that PCL/α-TC/β-CD-IC-NF had higher antioxidant activity as compared to PCL/α-TC-NF in methanol:water (1:1) system due to the stabilization and solubility increment of α-TC in the cavity of β-CD. PCL/α-TC/β-CD-IC-NF was more stable against UV-light when compared to PCL/α-TC-NF due to the presence of inclusion complexation. In brief, PCL/α-TC/β-CD-IC-NF with the advantages of having nanofibrous structure and encapsulating CD-ICs, may serve as a novel route for administration of α-TC due to its higher antioxidant activity and better UV-light stability.

Encapsulation of gallic acid/cyclodextrin inclusion complex in electrospun polylactic acid nanofibers: Release behavior and antioxidant activity of gallic acid

Cyclodextrin-inclusion complexes (CD-ICs) possess great prominence in food and pharmaceutical industries due to their enhanced ability for stabilization of active compounds during processing, storage and usage. Here, CD-IC of gallic acid (GA) with hydroxypropyl-beta-cyclodextrin (GA/HPβCD-IC) was prepared and then incorporated into polylactic acid (PLA) nanofibers (PLA/GA/HPβCD-IC-NF) using electrospinning technique to observe the effect of CD-ICs in the release behavior of GA into three different mediums (water, 10% ethanol and 95% ethanol). The GA incorporated PLA nanofibers (PLA/GA-NFs) were served as control. Phase solubility studies showed an enhanced solubility of GA with increasing amount of HPβCD. The detailed characterization techniques (XRD, TGA and 1H-NMR) confirmed the formation of inclusion complex between GA and HPβCD. Computational modeling studies indicated that the GA made an efficient complex with HPβCD at 1:1 either in vacuum or aqueous system. SEM images revealed the bead-free and uniform morphology of PLA/GA/HPβCD-IC-NF. The release studies of GA from PLA/GA/HPβCD-IC-NF and PLA/GA-NF were carried out in water, 10% ethanol and 95% ethanol, and the findings revealed that PLA/GA/HPβCD-IC-NF has released much more amount of GA in water and 10% ethanol system when compared to PLA/GA-NF. In addition, GA was released slowly from PLA/GA/HPβCD-IC-NF into 95% ethanol when compared to PLA/GA-NF. It was also observed that electrospinning process had no negative effect on the antioxidant activity of GA when GA was incorporated in PLA nanofibers.

Determination of formation constants and structural characterization of cyclodextrin inclusion complexes with two phenolic isomers: carvacrol and thymol.

Carvacrol and thymol have been widely studied for their ability to control food spoilage and to extend shelf-life of food products due to their antimicrobial and antioxidant activities. However, they suffer from poor aqueous solubility and pronounced flavoring ability that limit their application in food systems. These drawbacks could be surpassed by encapsulation in cyclodextrins (CDs). Applications of their inclusion complexes with CDs were reported without investigating the inclusion phenomenon in deep. In this study, inclusion complexes were characterized in terms of formation constants (Kf), complexation efficiency (CE), CD:guest molar ratio and increase in bulk formulation by using an UV–visible competitive method, phase solubility studies as well as 1H and DOSY 1H NMR titration experiments. For the first time, a new algorithmic treatment that combines the chemical shifts and diffusion coefficients variations for all guest protons was applied to calculate Kf. The position of the hydroxy group in carvacrol and thymol did not affect the stoichiometry of the inclusion complexes but led to a different binding stability with CDs. 2D ROESY NMR experiments were also performed to prove the encapsulation and illustrate the stable 3D conformation of the inclusion complexes. The structural investigation was accomplished with molecular modeling studies. Finally, the radical scavenging activity of carvacrol and thymol was evaluated by the ABTS radical scavenging assay. An improvement of this activity was observed upon encapsulation. Taken together, these results evidence that the encapsulation in CDs could be valuable for applications of carvacrol and thymol in food.

Smart stimuli-responsive fluorescent vesicular sensor based on inclusion complexation of cyclodextrins with Tyloxapol

Novel fluorescent vesicles based on inclusion complexes of β-cyclodextrins (β-CD) with Tyloxapol were constructed.

Cyclodextrin-clicked silica/CdTe fluorescent nanoparticles for enantioselective recognition of amino acids.

Fluorescent sensors based on semiconductor quantum dots (QDs) have been immensely investigated for achiral molecular recognition. For chiral discrimination of amino acids (AAs), we herein report a versatile fluorescent sensor, i.e., CdTe QDs encapsulated with cyclodextrin (CD) clicked silica via layer-by-layer modification. The as-obtained hybrid molecular recognition platform exhibited excellent chirality sensing of AAs at micromolar concentrations in water. By taking advantage of the inclusion complexation of CD and the optical properties of the QD core, chiral discrimination was realized on the basis of the different binding energies of the CD-AA enantiomer complexes, as revealed using density-functional theory calculation. The fluorescent probe exhibited linearly enhanced photoluminescence with increased concentration of d-histidine at 0-60 μM and L-histidine at 0-20 μM. These water-soluble fluorescent sensors using a chiral host with a covalently linked chromophore may find applications in the robust sensing of a wide range of achiral and chiral molecules in water.