Inclusion Complexation Behavior Research Articles

Thermoresponsive behavior of cyclodextrin inclusion complexes with weakly anionic alkyl ethoxy carboxylates.

This study investigates the temperature responsive behavior of inclusion complexes formed by weakly anionic alkyl ethoxy carboxylates and α (αCD) and β-cyclodextrins (βCD). Small-angle neutron scattering (SANS) was performed to probe the structural behaviour at the 1-100 nanometer scale of the hierarchical assemblies at different temperatures. The phase transitions and thermodynamics were systematically monitored as a function of the degree of ionization of the surfactant by differential scanning calorimetry (DSC). Herein, we investigate the effect of the surfactant degree of ionization on the thermoresponsive properties of the inclusion complex supramolecular assemblies. Inclusion complexes formed with the ionized surfactant spontaneously assemble into multilayered structures, which soften with increasing temperature. We also found that the presence of charges is not only required to impart order to the supramolecular assemblies, but also induced in-plane crystallization of the inclusion complexes. Finally, the use of a weakly anionic surfactant allows us to probe the interplay between the charge density and temperature on the assembly of surfactant-cyclodextrin inclusion complexes. This study helps to improve the design of multi-responsive supramolecular systems based on cyclodextrins.

Experimental and Computational Investigation of Clustering Behavior of Cyclodextrin-Perfluorocarbon Inclusion Complexes as Effective Histotripsy Agents.

Recently developed nanocones (NCs), which are inclusion complexes that are made up of cyclodextrins (CDs) and perfluorocarbons (PFCs), have shown promising results in nanoparticle-mediated histotripsy (NMH) applications due to stable inclusion complexation, PFC quantification, simple synthesis, and processing. FDA-approved βCD and its modified versions such as low-degree methylated βCD have been previously demonstrated as prime examples of structures capable of accommodating PFC molecules. However, the complex formation potential of different CDs with various cavity sizes in the presence of PFC molecules, and their consequent aggregation, needs to be explored. In the present study, the complexation and aggregation potential of some natural CDs and their respective derivatives either exposed to perfluoropentane (PFP) or perfluorohexane (PFH) were studied in the wet lab. Computational studies were also performed to account for the limitations faced in PFC quantification because of the low optical density of PFCs within the CD complex and to discover the best candidate for NMH applications. All results revealed that only βCD and γCD (except HMγCD) derivatives form an inclusion complex with PFCs and only LMβCD, βCD, and γCD form nanocone clusters (NCCs), which precipitate and can be collected for use. Furthermore, the data collectively show that βCD and PFCs have the best complexation due to stable complex formation, ease of production, and product recovery, especially with PFH as a more suitable candidate due to its high boiling point, which allows workability during synthesis. Although simulations suggest that highly stable inclusion complexes exist, such as HPβCD, the cluster formation resulting in precipitation is hindered due to the high solubility of CDs in water, resulting in intangible yields to work with even after employing general laboratory recovery methods. Conclusively, histotripsy cavitation experiments successfully showed a decreased cavitation threshold among optimal NCC candidates that were identified, supporting their use in NMH.

Inclusion Complexation Behaviors of Favipiravir into Cyclodextrins

This paper describes the inclusion complexation behaviors of anti-viral favipiravir (1) into native and permethylated cyclodextrins (CDs) in aqueous media. The formations of inclusion complexes are supported by UV-vis spectra, Job plots, and mass spectral measurements. The association constants between 1 and CDs are systematically estimated by titration experiments.

Host-guest inclusion complexes of sulfabenzamide with β- and methyl-β-cyclodextrins: Characterization, antioxidant activity and DFT calculation

The inclusion complexation behavior, characterization and binding ability of sulfabenzamide (SBZ) with β-cyclodextrin (β-CD) and methyl-β-cyclodextrin (Mβ-CD) have been investigated both in solution and solid state by different experimental techniques. Sulfabenzamide drug having poor water solubility and slow dissolution. In order to improve its water solubility and thus dissolution, cyclodextrin complexation technique was followed. The spectral shifts revealed that part of aniline ring of SBZ is entrapped in the CD cavity. The association constants were determined by Benesi-Hildebrand plots and spectroscopic studies. The phase solubility studies were carried using two different types of cyclodextrins viz., β, methyl-β cyclodextrins. The phase solubility profiles with all the two cyclodextrins were classified as AL-type, indicating the formation of 1:1 stoichiometric inclusion complexes. Inclusion complexes exhibited higher rates of dissolution than the corresponding physical mixtures and pure drug. Characterization of inclusion complexes was done by solubility studies, in vitro dissolution studies, FTIR, 1HNMR, XRD and SEM studies. We investigated the interaction of the host–guest Mβ-CD/SBZ complex by means of molecular dynamics simulation using a density functional based tight-binding code (DFT).

Synergistic Effect of Acetazolamide-(2-hydroxy)propyl β-Cyclodextrin in Timolol Liposomes for Decreasing and Prolonging Intraocular Pressure Levels.

The purpose of this study was to design, for the first time, a co-loaded liposomal formulation (CLL) for treatment of glaucoma including timolol maleate (TM) in the lipid bilayer and acetazolamide (Acz)-(2-hydroxy)propyl β-cyclodextrin (HPβCD) complexes (AczHP) solubilized in the aqueous core of liposomes. Formulations with TM (TM-L) and AczHP (AczHP-L), separately, were also prepared and characterized. A preliminary study comprising the Acz/HPβCD complexes and their interaction with cholesterol (a component of the lipid bilayer) was realized. Then, a screening study on formulation factors affecting the quality of the product was carried out following the design of the experiment methodology. In addition, in vitro release and permeation studies and in vivo lowering intraocular pressure (IOP) studies were performed. The results of the inclusion complexation behavior, characterization, and binding ability of Acz with HPβCD showed that HPβCD could enhance the water solubility of Acz despite the weak binding ability of the complex. Ch disturbed the stability and solubility parameters of Acz due to the fact of its competence by CD; thus, Chems (steroid derivative) was selected for further liposome formulation studies. The optimization of the lipid bilayer composition (DDAB, 0.0173 mmol and no double loading) and the extrusion as methods to reduce vesicle size were crucial for improving the physico-chemical properties and encapsulation efficiency of both drugs. In vitro release and permeation studies demonstrated that the CLL formulation showed improvement in in vitro drug release and permeation compared to the liposomal formulations with a single drug (TM-L and AczHP-L) and the standard solutions (TM-S and AczHP-S). CLL showed high efficacy in reducing and prolonging IOP, suggesting that the synergistic effect of TM and Acz on aqueous humor retention and the presence of this cyclodextrin and liposomes as permeation enhancers are responsible for the success of this strategy of co-loading for glaucoma therapy.

The complexes of cannabidiol mediated by bridged cyclodextrins dimers with high solubilization, in vitro antioxidant activity and cytotoxicity

The poor water-solubility of Cannabidiol (CBD) seriously hinders its pharmacological activities such as anti-anxiety, anti-epilepsy, anti-oxidation and anti-cancer, etc. In this paper, we successfully designed and synthesized two bridged cyclodextrins (CDs) dimers with different length of bridged chains (succinic acid (SACDD) and 3,3′-thiodipropionic acid (TPACDD)) to encapsulate CBD, a reported DMCD (2,6-Di-O-methyl-β-cyclodextrin) with single cavity was used as a control complex. Their characteristics and inclusion complexation behaviors were investigated via XRD, SEM, NMR and TGA, the obtained data suggests CBD is successfully encapsulated into two cavity of bridged CD dimers with stronger stability constants, compared with DMCD. Water solubility of CBD is significantly promoted by 6.76 × 105 and 4.52 × 105 folds after formation of inclusion complexes, as well as the antioxidant activity in vitro (5.26-fold enhanced). MTT assays shows they remained effective anti-tumor activity, while they barely show cytotoxicity to normal cell. Our work might provide a strategy for development and application of water-solubility CBD.

Advanced chemical–mechanical planarization for 4H-SiC substrate by water-soluble inclusion complexes of fullerene

This study investigated the behavior of water-soluble inclusion complexes (fullerene/β-cyclodextrin, C60/β-CD) as solid-state reacted abrasive particles for chemical–mechanical planarization (CMP) of 4H-SiC substrates. The size of C60/β-CD was measured by dynamic light scattering. The material removal rate with the aid of C60/β-CD was increased by 49%. Also, the indentation hardness and wettability were examined for the transition area by mechanochemical reaction. According to the decreasing hardness and contact angle, an adlayer consisting of C60/β-CD was indented by a Berkovich indenter against the substrate. Thus, the removal mechanism of advanced CMP among SiC substrates, C60/β-CD, and SiO2 abrasives is theoretically proposed.

Enzymatic digestion of amylose and high amylose maize starch inclusion complexes with alkyl gallates

The interactions between starch and phenolic compounds have a great impact on the physicochemical and nutritional properties of starch-containing foods. One particular form of the interaction is starch-guest inclusion complexation, which is a specific non-covalent interaction formed between starch and guest molecules. This study investigates complexation ability and enzymatic digestibility profiles of amylose and high amylose maize starch (HAMS) inclusion complexes with gallic acid (GA) and alkyl gallates of various chain lengths, including butyl (BG), octyl (OG), dodecyl (DG), hexadecyl (HG), and octadecyl (SG) gallates. The formation of inclusion complex was examined by complementary techniques including differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectroscopy. The digestibility profiles, represented as rapidly digestible starch (RDS), slowly digestible starch (SDS), and resistant starch (RS) contents, were obtained through simulated in vitro enzymatic digestion assays. The results showed that while GA, BG, and OG were not capable of forming inclusion complex with either amylose or HAMS, gallates with longer alkyl chains were able to form more stable inclusion complexes. Precipitated amylose and HAMS samples without inclusion complex formation contained the lowest RDS and highest SDS + RS, probably due to starch retrogradation. Amylose and HAMS inclusion complexes with long alkyl chain, particularly HG and SG, also possessed the lowest RDS and highest SDS + RS, but higher SDS proportions than the non-complexed starch samples. It was suggested that the inclusion complexes, especially amylose-HG and SG, and HAMS-DG, HG, and SG, might have contributed to the increase in SDS content. The water insusceptibility and high thermal stability of these inclusion complexes helped retard the starch digestion. The resistant yet steady digestion behavior of the starch-gallate inclusion complexes has significant implications in modulating glycemic response, as well as enabling a slow and sustained release of bioactive guest compounds into the gastrointestinal tract.

Inclusion complexation of imidazolium-based ionic liquid and β-cyclodextrin: A detailed spectroscopic investigation

Host-guest inclusion complexation (IC) behavior of ionic liquid (IL) 1-decyl-3-methylimidazolium tetrafluoroborate [Dmim][BF4] within β-cyclodextrin (β-CD) and the nature of complexation as well as binding affinity were studied in aqueous solution with the help of different spectroscopic methods i.e., fluorescence, dynamic light scattering (DLS), UV–vis, FTIR, and 1H NMR spectroscopy. The nature of complexation has been established from the results obtained for critical micelle concentration (cmc), aggregation number (Nagg), Stern-Volmer constant, particle size. Fluorescence and UV–vis studies revealed that 1:1 M stoichiometry of the ICs, while FTIR and DLS studies show the formation of H-bonding, electrostatic, hydrophobic interactions within the system and size of ICs formed. IL [Dmim][BF4] imparts distinctive properties of the ICs along with the instantaneous presence of vesicle and micelle which is well supported by DLS results. Binding constants for β-CD and [Dmim][BF4] complexes have been derived using Benesi-Hildebrand method and the thermodynamic properties have been evaluated with the help of van't Hoff equation. 1H NMR results are significant to show the changes for chemical shift of the β-CD and [Dmim][BF4] complexes which reveals that alkyl part of the IL is inserted into the hydrophobic cavity of β-CD. The obtained results on the ICs of [Dmim][BF4]/β-CD in this article can find potential application in soft matter construction, sensing and drug delively.

Host-Guest Inclusion Systems of Morin Hydrate and Quercetin with Two Bis(β-cyclodextrin)s: Preparation, Characterization, and Antioxidant Activity

The inclusion complexation behaviour of morin hydrate (MH) and quercetin (QCT) with the two amide-bridged bis(β-cyclodextrin (β-CD))s, 1 and 2, was investigated in both solution and the solid state. The inclusion complexations were characterised by proton nuclear magnetic resonance, 2D rotating-frame Overhauser effect spectroscopy, X-ray powder diffraction, infrared spectroscopy and scanning electron microscopy. Ultraviolet titration analysis indicated that 1 and 2 form 1:1 molar stoichiometry inclusion complexes with MH and QCT, and the data obtained showed that 2 with two guests has a higher complex stability constant (KS) when compared with that of 1. Moreover, 1 and 2 were able to solubilize MH and QCT to high levels, up to ~200-fold. Furthermore, the antioxidant activity of MH, QCT and their inclusion compounds were determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging. Together, these results showed that the inclusion complexes exhibited a more effective antioxidant activity when compared with free MH. The satisfactory antioxidant activity and high water solubility of the bis(β-CD)s/flavonoid complexes may have potential use as healthcare products and herbal medicine.

Construction of a water-soluble and photostable rubropunctatin/β-cyclodextrin drug carrier.

The purpose of the current study was to construct a β-cyclodextrin drug carrier for rubropunctatin to improve its water solubility and light stability for future cytotoxicity studies. The inclusion complexation behavior of rubropunctatin with β-cyclodextrin was investigated using FESEM, FT-IR and XRD. A molecular docking study was performed to elucidate the most probable inclusion structure. The inclusion complex could be completely dispersed in water and had a small size of 121.87 ± 2.13 nm (n = 3), a good PDI (0.320 ± 0.017), and an acceptable potential value of −27.7 ± 0.32 mV (n = 3). Furthermore, the stability of the rubropunctatin in water under light irradiation was found to be greatly enhanced after being encapsulated in cyclodextrin, and it exhibited a retention rate of over 70% vs. 10.17%. In addition, the cytotoxicity of the inclusion complex was evaluated by MTT assay and Annexin V-FITC/PI detection using cervical adenocarcinoma HeLa cells. The results showed that the inclusion complex had comparable toxicity compared to rubropunctatin solubilized with 0.4% DMSO. More importantly, the formation of the inclusion complex contributed greatly to the intensification of the bioavailability of rubropunctatin because the use of organic solvent was avoided.

Acid-controlled release complexes of podophyllotoxin and etoposide with acyclic cucurbit[n]urils for low cytotoxicity.

The targeted or responsive systems are appealing therapeutic platforms for the development of next-generation precision medications. So, we design and prepare acid-controlled release complexes of podophyllotoxin (POD) and etoposide (VP-16) with pH-labile acyclic cucurbit[n]urils, and their characteristics and inclusion complexation behaviors were investigated via fluorescence spectroscopy, nuclear magnetic resonance and X-ray power diffraction. Cells incubated with complexes have been analyzed by high-content analysis (HCA), and cytotoxicity tests have been completed by MTT assay. The results showed that complexes with different binding constants can release the drug substance in the physiological pH environment of cancer cells, maintain good anticancer activity, and have low cytotoxicity. This provides a strategy about targeted and responsive systems of POD and VP-16 for clinical application.

Supramolecular assembly between adenocard and native beta-cyclodextrin: Preparation, characterization and in-vitro cytotoxic evaluation

The inclusion complexation behavior, characterization and binding ability of adenocard with beta-cyclodextrin were investigated in both solution and the solid state. Absorbance and fluorescence intensities of adenocard were enhanced due to the formation of a 1:1 inclusion complex with beta-cyclodextrin. The inclusion complexed product in solid state was further characterized by Fourier-transform infrared spectroscopy, Scanning electron microscopic images, powder X-ray diffraction pattern, thermo gravimetric/differential scanning calorimetric and rotating-frame overhauser effect spectroscopic techniques. The implementation of molecular docking study confirmed the complexation could reduce the energy of the system. A mechanism was proposed to explain the mode of inclusion in the inclusion process. The cell viability analysis demonstrate that all the inclusion complex are nontoxic against Breast Adenocarcinoma-7 cell lines up to the concentrations 500 µg/mL with contact time of up to 72 hr, whereas beta-cyclodextrin showed the half maximal inhibitory concentration at the concentration of 300 µg/mL.

Microencapsulation of caffeic acid phenethyl ester and caffeic acid phenethyl amide by inclusion in hydroxypropyl-β-cyclodextrin

Caffeic acid phenethyl ester (CAPE) is a bioactive polyphenolic compound obtained from propolis extract. Although it has a broad therapeutic potential, the bioavailability of CAPE is limited, due to reduced solubility and poor plasmatic stability. Efforts to reduce these pharmacokinetic drawbacks resulted in the synthesis of caffeic acid phenethyl amide (CAPA). Cyclodextrins have been proved as promising excipients for the formulation of active ingredients. Herein, we report the inclusion complexation behavior and binding ability of CAPE and CAPA with hydroxypropyl-β-cyclodextrin (HP-β-CD). The supramolecular interactions were examined through UV and FTIR spectroscopy, DSC, 1H NMR and 2D ROESY. The CAPE/HP-β-CD and CAPA/HP-β-CD inclusion complexes stability constants were determined to be, respectively, 2911.6 and 584.6 M−1 in water and 2866.2 and 700.1 M−1 at physiological pH. The aqueous solubility increased notably, proving that HP-β-CD can be potentially useful to improve the biological, chemical and physical properties of CAPE and CAPA.

Investigation of the thermal behavior of inclusion complexes with antifungal activity

The indiscriminate use of antifungal agents has led to the advancement of microorganisms tolerant to the various drugs known in the market. Therefore, the search for new compounds and new technologies capable of giving more stable formulations and better pharmacological activities is of paramount importance as an alternative for the development of new therapeutics. However, its effectiveness is directly related to the knowledge of its characteristics in the solid state. Thus, the objective of this work was evaluating the thermal behavior, physicochemical aspects and microbiological of the complexes of inclusion of β-cyclodextrin (BCD) and biphenyl-4-methyl carboxylate (B4CMET). Therefore, differential scanning calorimetry, thermogravimetry, Fourier-transformed infrared spectroscopy, X-ray diffraction and microbiological assay were used to generate robust fingerprint of the inclusion complexes. The results showed the formation of inclusion complexes of B4CMET with βCD, thereby stressing its greater stability and potential use as an antifungal agent against Candida spp. Thus, with thermoanalytical techniques it was possible to observe the increased thermal stability, with FTIR changes of characteristic bands were verified, with XRD the disappearance of diffraction peaks of the B4CMET was verified, and with the microbiological assay it was possible to visualize increased antifungal activity.

Study on preparation and inclusion behavior of inclusion complexes between β-cyclodextrin derivatives with benzophenone

In the paper, the two chemically modified β-cyclodextrin derivatives of 4,4´-diaminodiphenyl ether-bridged-bis-β-cyclodextrins (ODA-bis-β-CD) and p-aminobenzenesulfonic acid-β-cyclodextrin (ABS-β-CD) were synthesized, and then these two β-cyclodextrin derivatives were respectively formed into inclusion complexes with benzophenone (BP) by co-precipitation method. The structure of the inclusion complexes were characterized by UV/vis spectroscopy, FT-IR spectroscopy, elemental analysis, 1H NMR spectroscopy and XRD. Spectral titration was performed to study the inclusion behavior of the inclusion complexes. These experiments indicated that two inclusion complexes were formed at a stoichiometric ratio of 1:1 and the inclusion stability constants at different temperatures were calculated using the Benesi–Hildebrand (B–H) equation. The thermodynamic parameters (ΔG°, ΔH°, ΔS°) were obtained. As a result, it was found that the two chemically modified β-cyclodextrins containing BP were exothermic and spontaneous process (ΔG° < 0), and the processes of inclusion complexation were mainly enthalpy driven with negative or minor negative entropic contribution.

Interfacial activity and emulsifying behaviour of inclusion complexes between helical polysaccharides and flavouring molecules resulting from non-covalent interactions

This study deals with the fabrication of inclusion complexes starting from a cross coupling of seven helical polysaccharides (host) and six flavouring agents (guest). Neither of the substrates is considered as an emulsifier when studied alone. Due to a complexation mechanism, the presence of intermolecular hydrogen bonds between substrates was highlighted by infra-red spectroscopy and 13C NMR. In addition, depending on the polysaccharide used, the guest molecule could be preferentially located either inside or in the interstitial spaces of the helix. In a comparison between raw substrates, the inclusion complexes obtained presented the unique interfacial activity of decreasing surface tension values (γ) and, in some cases, their behaviour in water was similar to that of regular emulsifiers due to the presence of a critical aggregation concentration (CAC). Substrate concentrations and the ratios between them were the main parameters investigated in this study, which focused on the two inclusion complexes: vanillin/amylose and vanillin/ι-carrageenan. The first decreased γ values by as much as 53mN/m with a double transition, whereas the second could cause γ fall to 36mN/m with a regular break. In addition, these systems were able to stabilize foams for up to 60min, which confirmed their unique emulsifying properties.

Novel controlled ionic gelation strategy for chitosan nanoparticles preparation using TPP-β-CD inclusion complex

The aim of this study was to develop a novel controlled ionic gelation strategy for chitosan nanoparticle preparation to avoid particle aggregation tendency associated with conventional ionic gelation process. In this study inclusion complexation behaviour of sodium tripolyphosphate (TPP) with beta cyclodextrin (β-CD) has been investigated. The TPP-β-CD inclusion complex was characterized by FT-IR, XRD and DSC techniques. The complexation behaviour was also investigated by molecular docking study. The results showed that the TPP molecule formed inclusion complex with β-CD. Further, TPP-β-CD inclusion complex was used to prepare chitosan nanoparticles. The chitosan nanoparticles based on TPP-β-CD inclusion complex had smaller size of 104.2nm±0.608, good PDI value of 0.346±0.016 and acceptable zeta potential of +27.33mV±0.416. The surface characteristics of chitosan nanoparticles were also observed with transmission electron microscopy. Results indicates that TPP-β-CD inclusion complex can be used for the formation of chitosan nanoparticles with smaller and more uniform particle size in comparison to conventional TPP based chitosan nanoparticles.

Host-guest complexes of 2-hydroxypropyl-β-cyclodextrin/β-cyclodextrin and nifedipine: 1H NMR, molecular modeling, and dissolution studies

Nifedipine (NIF) is a hydrophobic drug widely used for treating cardiovascular diseases. This calcium channel blocker can present a higher apparent solubility by its inclusion into different cyclodextrins (CDs) as host-guest complexes. This paper focused on the structural investigation and dissolution behavior of inclusion complexes prepared with 2-hydroxypropyl-β-cyclodextrin (HPβCD) or β-cyclodextrin (βCD) and NIF. Drug amorphization was observed for HPβCD/NIF and βCD/NIF inclusion complexes by X-ray diffractometry (XRD). The sharp endothermic peak of NIF was not observed for these both host-guest complexes by differential scanning calorimetry (DSC). These results of XRD and DSC provide evidences of complexation between drug and the investigated CDs. 1H and saturation transfer difference nuclear magnetic resonance studies revealed the enhancement in the signal at 2.27 ppm for HPβCD/NIF and βCD/NIF inclusion complexes that corresponded to the methyl groups of NIF from the non-aromatic ring. This result suggested that non-aromatic ring of NIF was inserted into HPβCD and βCD cavities. Considering the mathematical simulations, it was observed that the inclusion process can occur in the both NH-in or NH-out forms. However, since it was used aqueous medium, it is possible to indicate that the obtained host-guest complexes HPβCD/NIF and βCD/NIF are in NH-in form which corresponded to the previous results obtained by 1H NMR experiments. Dissolution assays demonstrated that NIF inclusion complexes improved the drug release nevertheless without changing its biexponential release behavior. These host-guest complexes can be further used as feasible NIF carriers in solid dosage forms.

Supramolecular structure of glibenclamide and β-cyclodextrins complexes

Glibenclamide is an antidiabetic drug showing low bioavailability as consequence of its low solubility. To solve this drawback, the interaction with cyclodextrins has been proposed. The formation of GB-βCDs inclusion complexes was carried out using different methods, βCD derivatives and drug-to-cyclodextrin ratios. The structures of the corresponding complexes have been studied by molecular modelling, X-ray diffraction and differential thermal analysis. The dissolution behavior of inclusion complexes has been compared to that of pure GB. Dimeric inclusion complexes were obtained with different CD disposals, head-to-head for βCD and head-to-tail for HPβCD and RMβCD. Amorphous inclusion complexes were obtained by employing methods of freeze-drying or coevaporation in ammonia-water. However, crystalline structures were formed by kneading and coevaporation in ethanol/water in the case of GB-βCD complexes. The arrangement of these structures depended on the GB:βCD ratio, yielding cage type structures for 1:3 and 1:5 ratios and channel-type structures for higher GB contents. The amount of GB released and its dissolution rate was considerably increased by the use of amorphous inclusion complexes; whereas, slower GB release rates were found from crystalline inclusion complexes formed by kneading or coevaporation in ethanol/water. In addition, it was found that the porous structure strongly conditioned the GB dissolution rate from crystalline products.