Guest Inclusion Complexes Research Articles

Host–Guest Complexation of Olmesartan Medoxomil by Heptakis(2,6-di-O-methyl)-β-cyclodextrin: Compatibility Study with Excipients

Background: Olmesartan medoxomil (OLM) is the prodrug of olmesartan, an angiotensin II type 1 receptor blocker that has antihypertensive and antioxidant activities and renal protective properties. It exhibits low water solubility, which leads to poor bioavailability and limits its clinical potential. To improve the solubility of OLM, a host–guest inclusion complex (IC) between heptakis(2,6-di-O-methyl)-β-cyclodextrin (DMβCD) and the drug substance was obtained. Along with active substances, excipients play a crucial role in the quality, safety, and efficacy of pharmaceutical formulations. Therefore, the compatibility of OLM/DMβCD IC with several pharmaceutical excipients was evaluated. Methods: IC was characterized in both solid and liquid states, employing thermoanalytical techniques, universal-attenuated total reflectance Fourier-transform infrared spectroscopy, powder X-ray diffractometry, UV spectroscopy, and saturation solubility studies. Compatibility studies were carried out using thermal and spectroscopic methods to assess potential physical and chemical interactions. Results: The 1:1 OLM:DMβCD stoichiometry ratio and the value of the apparent stability constant were determined by means of the phase solubility method that revealed an AL-type diagram. The binary system showed different physicochemical characteristics from those of the parent entities, supporting IC formation. The geometry of the IC was thoroughly investigated using molecular modeling. Compatibility studies revealed a lack of interaction between the IC and all studied excipients at ambient conditions and the thermally induced incompatibility of IC with magnesium stearate and α-lactose monohydrate. Conclusions: The results of this study emphasize that OLM/DMβCD IC stands out as a valuable candidate for future research in the development of new pharmaceutical formulations, in which precautions should be considered in choosing magnesium stearate and α-lactose monohydrate as excipients if the manufacture stage requires temperatures above 100 °C.

Development of a liquid crystal-based sensor utilizing EDTA-cyclodextrin polymer for real-time optical detection of methylene blue in natural water samples

The discharge of dyes in industrial wastewater poses significant environmental and health risks when released into natural water resources. In this study, we report the development of an EDTA-crosslinked cyclodextrin polymer (ECDP)-based sensor for the real-time, naked-eye detection of hazardous methylene blue (MB) dye in aqueous solutions and natural water samples. The sensor functions via a competitive host–guest inclusion mechanism involving sodium dodecyl sulphate (SDS) and ECDP, which modulates the alignment of liquid crystals (LCs). Initially, SDS induces homeotropic ordering at the fluid interface, but when complexed with ECDP, it causes a tilted LC alignment. Upon the introduction of MB, SDS is displaced from the ECDP cavity and re-adsorbs at the LC/aqueous interface, triggering an orientational transition from tilted to homeotropic. This transition is clearly observed as a distinct bright-to-dark shift under crossed polarizers. The host–guest (ECDP/MB) inclusion complexation mechanism was further confirmed by FT-IR, XRPD, and DSC analyses. The developed sensor exhibits high selectivity for MB in dye-contaminated natural water samples and sensitivity to MB concentrations upto 0.10 mM. This study demonstrates the potential of cyclodextrin-based polymers for liquid crystal sensing applications, offering promising pathways for future developments in environmental monitoring.

Probing host guest inclusion complex and its applications by biophysical approach subsequently optimized by molecular docking

Herein, we explored the construction of a supramolecular encapsulated complex between Nile blue (NB) and p-sulfonatothiacalix[4]arene (TSC4X). The developed inclusion complex (NB-TSC4X) was established by fluorescence spectroscopy, TGA, FTIR, 1H NMR, and DFT studies. Benesi-Hildebrand calculation showed a linear plot that indicated a 1:1 stoichiometric ratio having a fairly high stability constant of 2720 M−1 in the solution phase. DFT analysis helps us to find out the optimized structure of the inclusion complex. Finally, the binding interaction of the inclusion complex with bovine serum albumin (BSA) was evaluated. In brief, this work uncloses a new strategy to enhance the performance of fluorescent dye.

X-ray structures, thermal stabilities and kinetics of guest desolvation of complexes of three fluorenone-derived host compounds with the polar aprotic guest solvent, tetramethylurea

The wheel-and-axle host compounds 9,9′-(1,4-phenylene)bis(fluoren-9-ol) (H1), 9,9′-(ethyne-1,2-diyl)bis(fluoren-9-ol) (H2) and 9,9′-(biphenyl-4,4′-diyl)bis(fluoren-9-ol) (H3) each formed complexes with tetramethylurea (TMU), a polar aprotic organic solvent, with host: guest ratios of 1:2. Single crystal X-ray diffraction revealed that these complexes crystallized in the monoclinic space group P21/c, their analyses being performed in P21/c for H1⋅2(TMU) and in the alternative setting P21/n for both H2·2(TMU) and H3·2(TMU). Furthermore, these inclusion compounds are stabilized by both classical and non-classical hydrogen bonds between the host and guest molecules. Hirshfeld surface analyses demonstrated that the percentage of interatomic (host)H···O(guest) interactions ranged between 7.8 and 10.3%, while thermal analyses showed that the relative thermal stabilities of these complexes were high, with the onset temperatures for the guest release event, Ton, being 83.1 (H1·2(TMU)), 81.1 (H2·2(TMU)) and 90.3 °C (H3·2(TMU)). Moreover, the calculated mass loss percentages, after heating each complex in a controlled manner to release the guest species, correlated closely with those expected for these 1:2 host: guest inclusion complexes. Finally, determination of the activation energies for complex desolvation yielded 148.7 ± 5.4, 128.6 ± 10.8 and 149.4 ± 0.8 kJ·mol‒1 for H1·2(TMU), H2·2(TMU) and H3·2(TMU) respectively. A single guest desolvation mechanism was at work in the first and last of these complexes, while this mechanism in H2·2(TMU) changed during this process. The H1·2(TMU) inclusion complex has been reported previously, and the results obtained in that work are also compared with those from the present investigation.

Viscoelastic behaviors for optimizing self-healing of gels with host–guest inclusion complexes

Viscoelastic behaviors for optimizing self-healing of gels with host–guest inclusion complexes

Molecular recognition of dicyanoalkane guest in a cyclic dimeric silver(I) complex based on pillar[5]-bis-crown

We herein report the formation of the cyclic dimeric silver(I) complexes and the selective organic guest recognition. The reaction of pillar[5]-bis-crown with AgPF6 afforded a cyclic dimeric supramolecular complex [Ag4(L)2(H2O)2(CH3CN)2](PF6)4 in which the silver(I) atoms exist inside the crown ether cavities. The cyclic dimeric silver(I) complex reacts with 1,2-dicyanoethane (C2) to form a guest-inclusion complex [Ag4(C2@L)2(CH3CN)2](PF6)4, exhibiting its formation being controlled by the length of the guest molecules used. Additionally, the silver(I) supramolecular complex demonstrated molecular recognition for C2 in both solution and solid states.

Supramolecular Nano‐Grid Platform to Load and Deliver Liposomes and Exosomes

In general, carriers are designed to deliver pharmaceutical (featuring small drug‐molecules) and biopharmaceutical (featuring large‐molecule drugs, e.g., antibodies, proteins, etc.) active ingredients and platform that is capable of transporting nanoparticles is rare. Herein, the fabrication of a supramolecular carrier with a nano‐grid structure for the entrapment of liposomes and exosomes is reported. The nano‐grid particles (NGP) are made of cyclodextrins as elementary units which are widely used to load drugs through host–guest inclusion complexes, whilst its secondary structure further formed the NGP tertiary architectures, enabling the entrapment of nanoparticles. The NGP features stimuli responsiveness, tunable surface charge, and good biocompatibility. The entrapped liposomes in NGP present enhanced distribution in lungs and extended duration of action in mice. And elongated release profiles for over 14 days is obtained for exosomes—making one‐of‐its‐kind unique platform to load and deliver nanoparticles.

A comparative study of green solid contact ion selective electrodes for the potentiometric determination of Letrozole in dosage form and human plasma

Analysis of drugs clinically and their identification in biological samples are of utmost importance in the process of therapeutic drug monitoring, also in pharmacokinetic investigations and tracking of illicit medications. These investigations are carried out using a variety of analytical methods, including potentiometric electrodes. Potentiometric electrodes are a wonderful solution for researchers because they outperform other methods in terms of sustainability, greenness, and cost effectiveness. In the current study, ion-selective potentiometric sensors were assembled for the aim of quantification of the anticancer drug Letrozole (LTZ). The first step was fabrication of a conventional sensor based on the formation of stable host–guest inclusion complex between the cationic drug and 4-tert-butylcalix-8-arene (TBCAX-8). Two additional sensors were prepared through membrane modification with graphene nanocomposite (GNC) and polyaniline (PANI) nanoparticles. Linear responses of 1.00 × 10–5–1.00 × 10–2, 1.00 × 10–6–1.00 × 10–2 and 1.00 × 10–8–1.00 × 10–3 with sub-Nernstian slopes of 19.90, 20.10 and 20.30 mV/decade were obtained for TBCAX-8, GNC, and PANI sensors; respectively. The developed sensors were successful in determining the drug LTZ in bulk powder and dosage form. PANI modified sensor was used to determine LTZ in human plasma with recoveries ranging from 88.00 to 96.30%. IUPAC recommendations were followed during the evaluation of the electrical performance of the developed sensors. Experimental conditions as temperature and pH were studied and optimized. Analytical Eco-scale and Analytical GREEness metric were adopted as the method greenness assessment tools.

Electrochemical sensor for simultaneous determination of antiviral favipiravir drug, paracetamol and vitamin C based on host–guest inclusion complex of β-CD/CNTs nanocomposite

Favipiravir (FVI) is extensively used as an effective medication against several diverse infectious RNA viruses. It is widely administered as an anti-influenza drug. Combination therapy formed from FVI, paracetamol (PAR) and vitamin C (VC) is needed for treating patients diseased by RNA viruses. Thus, an efficient electrochemical sensor is developed for detecting FVI in human serum samples. The sensor is fabricated by casting a thin layer of carbon nanotubes (CNTs) over a glassy carbon (GC) electrode surface followed by electrodeposition of another layer of β-cyclodextrin (β-CD). Under optimized conditions, the sensor shows excellent catalytic effect for FVI, PAR and VC oxidation in the concentration ranges (0.08 µM → 80 µM), (0.08 µM → 50 µM) and (0.8 µM → 80 µM) with low detection limits of 0.011 μM, 0.042 μM and 0.21 μM, respectively. The combined effect of host–guest interaction ability of β-CD for the drugs, and a large conductive surface area of CNTs improves the sensing performance of the electrode. The sensor exhibits stable response over 4 weeks, good reproducibility, and insignificant interference from common species present in serum samples. The reliability of using the sensor in serum samples shows good recovery of FVI, PAR and VC.

Different Conformational Properties and Frequencies of Periodic Motion in the β‐ and γ‐Cyclodextrin

AbstractCyclodextrins (CDs) are cyclic oligosaccharides with application in different fields. These systems can encapsulate hydrophobic molecules and allow their solubilization in water. CDs and CD complexes can self‐associate forming aggregate or micelle‐like structures. Theoretical studies based on molecular mechanics (MM) and molecular dynamics (MD) simulations are demonstrated to be a useful tool for understanding the conformational properties, the stability, their host–guest inclusion complexes in the solid state or in aqueous solution in a good agreement with experimental data. The aim of this work is to compare at atomistic level the conformational properties, the flexibility of the native β‐ and γ‐CD. The β‐CD shows very slightly deviation from C7 symmetry, and its glycosidic oxygens are on a flat plane, while in the γ‐CD they are in different arrangement on a curved plane. From the variation of the distance between opposite glycosidic oxygens in these CDs, the frequencies of motion due to periodic motions are calculated during MD run. These frequencies indicate faster periodic motion for the β‐CD and slower for the γ‐CD having larger dimension and less symmetrical structure. MD simulations are an interesting tool for investigating the flexibility of these systems, their possible periodic motion, and their frequencies of motion.

Host-guest complexation of (pyridinyltriazolylthio) acetic acid with cucurbit[n]urils (n=6,7,8): Molecular calculations and thermogravimetric analysis

Cucurbiturils are cage-like macrocyclic molecules that can form strong host–guest inclusion complexes, offering remarkably higher selectivity over conventional macrocycles towards guests with particular sizes and shapes. Here we use a combination of molecular docking, semiempirical quantum-chemical (PM6, PM7) and high-level DFT calculations along with all-atom molecular dynamics (MD) simulations to characterize 1:1 host-guest complexation between the cucurbit[n]urils (CB[n], where n = 6–8) and biologically active 2-[[5-(4-pyridinyl)-4H-1,2,4-triazol-3-yl]thio]acetic acid (PTTA). While the molecular docking and the semiempirical calculations suggest that PTTA favors inserting into larger size cavities of CB[7] and CB[8], the classical OPLS-AA MD simulations of the potential of the mean force (PMF) in an aqueous solution demonstrate the favorable free binding energy of PTTA with all three studied CB[n]s (n = 6–8). These findings were further examined by refining the binding energy of the MD-derived PTTA-CB[n] structures by the high-level dispersion-corrected DFT calculations. Our combined MD/DFT approach provides the detailed host-guest complexation mechanism and suggests that the stability of the host-guest inclusion complex of PTTA with CB[n]s decreases in the order CB[6]>CB[7]>CB[8]. Finally, the formation of the stable inclusion complex of PTTA with CB[6] was validated by thermogravimetric analysis and differential scanning calorimetry measurements, pointing out that low-level quantum-chemical methods might be unable to capture the correct thermodynamics of host-guest supramolecular structures based on cucurbituril macrocycles.

Inclusion complexes of capsanthin with acyclic cucurbit[n]urils to improve its stability and antioxidant capacity

Capsanthin is a natural red pigment widely used in the food industry, but its pigment is severely lost during use and storage. Supramolecular chemistry-based macrocyclic hosts can encapsulate small molecule pigments to improve their stability and solubility. Herein, we synthesized two acyclic cucurbit[n]urils (ACBs, M1 and M2) as carriers for encapsulating capsanthin, and we expect this strategy to generate some positive improvements on the properties of capsanthin, extending its use by the food industry. Successful host–guest inclusion complexes (IC) formation was confirmed via 1H NMR, 2D-ROESY NMR, 13C NMR, XRD, and FT-IR. After encapsulation, the solubility of capsanthin was increased by 75.8 times and 62.3 times, respectively. Furthermore, the storage and utility of capsanthin was enhanced due to the phase transition from oil to solid powder. IC exhibited enhanced stability for capsanthin in challenging environments, such as high temperature, light exposure, acidity, metal ions, food additives, and extreme oxidation.

Computational study of inclusion complexes of V-type nerve agents (VE, VG, VM, VR and VX) with β-cyclodextrin

The effective detoxification of organophosphate (OP) nerve agents (OPNAs) is a challenging issue for scientists. The host–guest inclusion complexes of five V-type nerve agents (VE, VG, VM, VR and VX) with β-cyclodextrin (β-CD) have been studied by combining quantum mechanical (QM) calculations and molecular dynamics (MD) simulations. The frontier molecular orbital (FMO) and molecular electrostatic potential (MEP) have been analyzed to describe the reactivity parameters and electronic properties. The obtained results clearly reveal that stable complexes were formed in both vacuum and water media, and the complexation process occurred spontaneously. To understand non-covalent interactions, natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) have been used. IR and Raman spectra have been calculated to confirm the formation of complexes and also thermodynamic parameters have been investigated. It was demonstrated that in addition to van der Waals interactions, the presence of intermolecular hydrogen bonds enhances the stability of these complexes. Furthermore, MD simulations were carried out to get a better insight into the inclusion process of the above complexes. From MD simulations, all simulated systems reached full equilibration at 1000 ps and the V-agent molecules consistently remained in the β-CD cavity and only had vibrational motion inside the cavity. More importantly, MD simulations support the findings of QM calculations and indicate that hydrogen bonding can help the leaving groups of V-agents to be released and them to be hydrolyzed. All results have shown that the VR agent formed the most stable complex with β-CD molecule than that of other agents. Communicated by Ramaswamy H. Sarma

17-β-Estradiol-β-Cyclodextrin Complex as Solid: Synthesis, Structural and Physicochemical Characterization.

17-β-estradiol (EST) is the most potent form of naturally occurring estrogens; therefore, it has found a wide pharmaceutical application. The major problem associated with the use of EST is its very low water solubility, resulting in poor oral bioavailability. To overcome this drawback, a complexation with cyclodextrins (CD) has been suggested as a solution. In this work, the host-guest inclusion complex between the ß-CD and EST has been prepared using four different methods. The obtained samples have been deeply characterized using 13C CP MAS solid state NMR, PXRD, FT-IR, TGA, DSC, and SEM. Using SCXRD, the crystal structure of the complex has been determined, being to the best of our knowledge the first solved crystal structure of an estrogen/CD complex. The periodic DFT calculations of NMR properties using GIPAW were found to be particularly helpful in the analysis of disorder in the solid state and interpretation of experimental NMR results. This work highlights the importance of a combined ssNMR/SCXRD approach to studying the structure of the inclusion complexes formed by cyclodextrins.

Encapsulation of vortioxetine with cyclodextrins via host–guest inclusion complex: Synthesis, characterization, solubility, and in vitro dissolution studies

AbstractDrug solubility plays a significant role in the development of drug formulation. The objectives of this work are to improve the solubility and dissolution rate of vortioxetine (VT) by preparing its inclusion complexes (ICs) with β‐Cyclodextrin (β‐CD) and γ‐Cyclodextrin (γ‐CD). The ICs were prepared in 1:1 M ratio via recrystallization method and characterized by P‐XRD, FT‐IR, 1H NMR, 2D NOESY, and DSC. Further, the crystal structure of VT‐β‐CD was analyzed by SC‐XRD. P‐XRD data obtained for ICs describe the crystalline pattern. The DSC analysis shows change in the thermal behavior of VT, CDs and ICs. FT‐IR analysis shows shifting of frequencies in ICs when compared with the pristine VT drug and CDs. The 2D NOESY in DMSO‐d6 indicates weak interaction between the VT and CD molecules. The crystal structure of VT‐β‐CD consists of one guest VT, one host CD, and nine water molecules in the crystal lattice. The solubility of ICs was significantly improved in distilled water, pH 1.2 acidic, and phosphate buffer pH 6.8 medium, as compared with the solubility of the pristine VT drug. The in vitro dissolution rate of ICs in different dissolution media was investigated, which was higher than that of the commercial product of VT.

Formation of Supramolecular Gels from Host–Guest Interactions between PEGylated Chitosan andα‐Cyclodextrin

AbstractChitosan‐based hydrogels are prepared via the formation of polypseudorotaxanes (PPR), by selectively threadingα‐cyclodextrin (α‐CD) macrocycles onto polymeric chains, which, through the formation of microcrystalline domains, act as junction points for the network. Specifically, host–guest inclusion complexes are formed betweenα‐CD and PEGylated chitosan (PEG‐Ch), resulting in the formation of supramolecular gels. PEG‐grafted chitosan is obtained with a reaction yield of 79.8%, a high degree of grafting (50.9% GW) and water solubility (≈16 mg mL−1), as assessed by turbidimetry. A range of compositions for mixtures of PEG‐Ch solutions (0.2–0.8% w/w) andα‐CD solutions (2−12% w/w, or 0.04–0.2% mol) are studied. Regardless of PEG content, gels are not formed at lowα‐CD concentrations (<4%). Dynamic rheology measurements reveal stiff gels (G’ above 15k) and a narrow linear viscoelastic region, reflecting their brittleness. The highest elastic modulus is obtained for a hydrogel composition of 0.4% PEG‐Ch and 6%α‐CD. Steady‐state measurements, cycling between low and high shear rates, confirm the thixotropic nature of the gels, demonstrating their capacity to fully recover their mechanical properties after being exposed to high stress, making them good candidates to use as in‐situ gel‐forming materials for drug delivery to topical or parenteral sites.

Deciphering the interactions of genistein with β-cyclodextrin derivatives through experimental and microsecond timescale umbrella sampling simulations

Genistein (GEN), an isoflavone, exhibits wide array of biological activities such as antioxidant, anti-inflammatory, cardioprotective and neuroprotective effects. However, despite of tremendous biological activities, its incorporation into functional foods and food supplements is limited due to its low aqueous solubility and instability. The present investigation unveils the molecular mechanism of inclusion of GEN inside the cyclodextrins (CDs) cavities with special emphasis on the correlation of experimental methods with molecular dynamics (MD) simulations. Herein, host – guest inclusion complexes (ICs) of GEN with two modified forms of β-cyclodextrins [Methyl-β-cyclodextrin (M-β-CD) & Hydroxypropyl-β-cyclodextrin (HP-β-CD)] were prepared using spray-drying to improve the aqueous solubility and the apparent stability of GEN. The ICs were characterized by fourier transform infra-red (FT-IR) spectroscopy, powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM) and nuclear magnetic resonance spectroscopy (1H NMR and 2D-NOESY) providing appropriate evidences of the inclusion of GEN inside host cavities (CDs). The results of MD simulations demonstrated multiple conformations obtaining energy minimas of GEN/M-β-CD, whereas GEN/HP-β-CD only showed a single metastable structure. The results were further complemented by enhanced umbrella sampling simulations where GEN/M-β-CD demonstrated lower free energy of binding than GEN/HP-β-CD. Overall, this study presents basic mechanism behind GEN/CD inclusion complexes formation using experimental and computational approaches.

Supramolecular inclusion complexes of β-cyclodextrin with bathochromic-shifted photochromism and photomodulable fluorescence enable multiple applications

Supramolecular inclusion complexes of conjugation-extended viologens with β-CD exhibit bathochromic-shifted photochromic behavior and photomodulable fluorescence, which endow them with applications in many areas.

Thermally insulating composite aerogel with both active absorption and passive insulation functions based on azobenzene-modified chitosan/oligomeric β-cyclodextrin

Active heat absorption strategy and passive heat insulation strategy often go their separate way, and each has its own advantages and disadvantages. This study explores a new thermal insulation material design strategy that introduces thermo-sensitive host–guest inclusion complexes as active heat-absorbing components in passive thermal insulation aerogel. According to this strategy, a novel azobenzene-modified chitosan/oligomeric β-cyclodextrin (CSAZO/CD) composite aerogels were prepared by the freeze-drying method. It was found that CSAZO/CD composite aerogels showed tunable porous structure, good mechanical properties and more importantly wonderful thermal insulation properties. Since CSAZO/CD aerogels contained not only porous structure (porosity 91.03%-95.85%), but also Azo-βCD complexes in the matrix as active heat-absorbing components, these materials showed better thermal insulation capability than other aerogels with similar thermal conductivity. And unlike classic porous material-supported phase change materials which suffer the leakage of PCM after multiple thermal cycles, CSAZO/CD composite aerogels show good long-term stability since the Azo-βCD complexes absorb heat by the solid-to-solid transition. Furthermore, CSAZO/CD composite aerogels showed even better thermal insulation behavior under UV irradiation. The unique insulation properties of CSAZO/CD aerogels make them good candidates for thermal insulation materials in many fields, such as ultra-thin thermal insulation in high temperature or UV environment.

Carboxylated Pillar[6]arene Emulates Pillar[5]arene in the Host–Guest Crystal Complexes and Shows Conformational Flexibility in the Solution/Gas Phase

Despite the thriving interest in the aqueous complexation properties of carboxylated pillar[6]arene, its solid state supramolecular chemistry has remained a mystery. Here, overcoming challenging crystallogenesis, we report the first crystallographic authentication of carboxylated pillar[6]arene in the form of two host–guest inclusion complexes with methyl viologen and pentamidine. The key to the successful crystallization of carboxylated pillar[6]arene is the mixed ionization state of its 12 carboxylic substituents. The deprotonation of several but not all substituents enables intermolecular hydrogen bonding and, as a result, “gluing” and crystallization of pillar[6]arene complexes with the aid of carboxylic-carboxylate, carboxylic-carboxylic, and amidinium-carboxylate supramolecular synthons. Single crystal X-ray diffraction analysis revealed that upon guest inclusion pillar[6]arene adopts a quasi-pentagonal shape rather than the expected hexagonal shape. The squeezed quasi-pentagonal conformation of the six-membered macrocycle is stabilized by two intramolecular hydrogen bonds between pillar[6]arene substituents. Moreover, the distinctive deviation of the macrocycle from hexagonal shape stays operative in the solution/gas phase as concluded from ion mobility mass spectrometry (IM-MS) studies and theoretical calculations. These results provide the first insight into how to gain control over the conformation of flexible pillar[6]arene with a view of solid state design of more advanced supramolecular host–guest structures.