Stable Inclusion Complexes Research Articles

Investigating the Interaction of Anthracene and Phenanthrene with Cucurbit[n]urils (n=6‐8): Experimental and Molecular Dynamics Studies

AbstractThe supramolecular interaction of anthracene (ANT) and phenanthrene (PHN) with cucurbit[n]uril, CB[n] (n=6‐8) has been investigated in aqueous media for the first time. The inclusion complexes were investigated and characterized by fluorescence spectroscopy, matrix‐assisted laser desorption ionization time‐of‐flight (MALDI‐TOF) mass spectrometry, and 1HNMR. The stability of these complexes and the mode of inclusion in aqueous media at atomistic levels were monitored by molecular dynamic (MD) simulations. The results obtained from the experimental and MD studies have demonstrated the formation of stable 1 : 1 complexes between the two guests with all hosts in aqueous media. From the fluorescence study, the binding constants of PHN with CB[6], CB[7], and CB[8] were found to be 398±63, 544±128, and 655±162 M−1, respectively. Whereas, ANT‐ CB[n] formation constants are 213±37 M−1 270±35 M−1, and 356±94 M−1 for CB[6], CB[7], and CB[8], respectively. The results obtained show that the size of the cavity of the macrocycle and the polarity of the rim play an important role in the stability of the formed complex. Surprisingly, CB[6] forms an inclusion complex with ANT while it interacts by its side with PHN through dipole‐dipole interaction. The larger cavity sizes of CB[7], CB[8], were found to encapsulate the two guests forming highly stable inclusion complexes.

Combined Computational and Experimental Studies of Anabasine Encapsulation by Beta-Cyclodextrin.

The encapsulation of the famous alkaloid, anabasine, with β-CD was studied to obtain a more stable and bioavailable inclusion complex. Various in silico and experimental studies of the obtained β-CD-anabasine complex are presented. Firstly, molecular docking studies were conducted against the α, β, and γ cyclodextrins to explore which subclass is the best for encapsulation. The obtained results that pointed at β-cyclodextrin were further confirmed by five MD simulations and MM-PBSA studies. Experimentally, the spectral properties of the anabasine β-cyclodextrin complex were determined by FT-IR, 1H, and 13C-NMR spectroscopic methods. Additionally, the surface morphology of the anabasine β-cyclodextrin was investigated using a scanning electron microscope. Furthermore, the outputs of the thermographic measurements utilizing a differential scanning calorimeter were displayed. The activation energy of the reaction of thermo-oxidative destruction of the clathrate complex was calculated, and the kinetic parameters of the thermal destruction processes were decided using the Freeman–Carroll, Sharpe–Wentworth, Achar, and Coates–Redfern methods. The kinetic parameters of the thermal decomposition of the anabasine β-cyclodextrin were in agreement and verified the reliability of the obtained results. The obtained computational, spectral, morphological, and thermogravimetric results verified the successful formation of the anabasine β-cyclodextrin complex.

Facile fluorescent detection of o-nitrophenol by a cucurbit[8]uril-based supramolecular assembly in aqueous media

The efficient and selective detection of isomers is an attractive but challenging area. In this study, a supramolecular fluorescent probe based on cucurbit[8]uril (Q[8]) and a pyrene-based derivative (G) was prepared, which effectively recognized and removed o-nitrophenol (o-NP) from a mixture of nitrophenol isomers. The newly designed probe G@Q[8] was characterized by NMR spectroscopy, fluorescence emission and UV–Vis spectroscopy, and its host-guest properties in aqueous solution were investigated. The results revealed that the system forms a stable inclusion complex with a stoichiometric ratio of 1:1, which was accompanied by a distinct fluorescence enhancement of G. Moreover, it was employed for the rapid detection of nitrophenol isomers where o-NP showed a dramatical quenching efficiency with a detection limit of 1.53 × 10−7 mol·L-1. This highly efficient supramolecular fluorescent probe offers a new strategy for the convenient detection and removal of o-NP from mixtures in aqueous medium.

Design of silk fibroin-based supramolecular hydrogels through host-guest interactions: Influence of the crosslinking type

Due to their pivotal role in non-textile utilization of silk, silk fibroin (SF)-based hydrogels continue to receive a lot of attention, in order to discover new crosslinking methods. SF may form stable inclusion complexes with β-cyclodextrins (β−CD) driven by host-guest interactions between β−CD and amino acid side chains (such as tyrosine, tryptophan, phenylalanine and histidine). This favorable feature makes supramolecular assembly a promising crosslinking method for construction of SF-based hydrogels. However, different β−CD conjugation methods lead to variations in hydrogel properties; influence of the crosslinking types and the related underlying mechanisms remain to be elucidated. In this study, new types of SF-based hydrogels were designed based on host-guest interactions between β−CD and the amino acids, showing that the hydrogel properties could be adjusted by employing either different solvation methods for regenerating SF or diverse conjugation methods for β−CD. This study not only provides a new generation of SF-based hydrogels, but also greatly expands the supramolecular assembly strategy for design of protein-based hydrogels.

Encapsulationof the Haloalkane 4‐Chloromethylpyridine Hydrochloride by Cucurbit[8]uril

AbstractComplexation of 4‐chloromethylpyridine hydrochloride (G) with cucurbit[8]uril (Q[8]) has been investigated using NMR spectroscopy, UV‐visible spectroscopy, isothermal titration calorimetry (ITC), Quantum calculation, and X‐ray crystallography. The data indicated that the guest 4‐chloromethylpyridine hydrochloride is completely encapsulated by the cavity of the Q[8] host in both aqueous solution and the solid state, generating a highly stable inclusion complex, namely G2@Q[8]. Interestingly, ion–dipole interactions and hydrogen‐bonding interactions play a central role in the formation of the inclusion complex G2@Q[8], which provides a reliable basis for the encapsulation of small organic guests by the hydrophobic microenvironment of the cavity.

Affinity and putative entrance mechanisms of alkyl sulfates into the β-CD cavity

Cyclodextrins (CDs) are novel pharmaceutical excipients and are widely used in the pharmaceutical industry and drug delivery due to their ability to form host–guest complexes. There are countless structural features of guest molecules responsible for the efficiency of guest–CD interactions. Among these factors, the hydrophobic moieties of a guest and their size are commonly considered to govern its binding affinity to CD molecules. Experimentally, it is often challenging to extract structural and dynamic information at the atomic scale about CD inclusion complexes, especially in the aqueous phase. Therefore, this study consisted of experimental (isothermal titration calorimetry and conductometric titration) and in silico analysis to rigorously characterize the interactions of β -CD with three alkyl sulfates of different hydrophobic chain lengths: sodium dodecyl sulfate (S12S), sodium decyl sulfate (S10S) and sodium octyl sulfate (S8S) in aqueous solutions. We find that the hydrophobic interactions are not always a key factor leading to the formation of stable inclusion complexes. Our results demonstrate that van der Waals interactions contribute more to complexation efficiency for sulfates with a longer hydrophobic tail, whereas electrostatic interactions are more pronounced for sulfates with shorter ones. Furthermore, we propose and discuss for the first time the putative mechanisms of the guest entering the host cavity conditioned by the lengths of hydrocarbon chains of alkyl sulfates. Finally, we prove that different types of inclusion complexes can exist in a conformational equilibrium depending on the size of a guest tail.

Inclusion Complexes Between β‐cyclodextrin and the Anticancer Drug 5‐Fluorouracil for its Solubilization: a Molecular Dynamics Study at Different Stoichiometries

AbstractCyclodextrins (CDs) are natural macrocyclic oligosaccharides able to solubilize hydrophobic drugs in water improving their bioavailability, thanks to favorable noncovalent interactions particularly in their hydrophobic cavity. Using a simulation protocol proposed in previous work, in this theoretical study based on Molecular Mechanics (MM) and Molecular Dynamics (MD) methods, inclusion complexes between β‐cyclodextrin and 5‐Fluorouracil (5‐FU) are investigated. 5‐FU is an anticancer drug hardly soluble in water used for more than 50 years. This drug is mainly administered by intravenous injection for the treatment of inner cancers or as a cream in the case of skin‐related cancers. For drug delivery applications, it is important to characterize stable inclusion complexes at different drug concentrations in order to enhance the anticancer activity by maintaining lower dose, thus reducing cytotoxic effects on the normal cells, causing several negative impacts in the course of treatment. In this work, the structure and stability of the host–guest complexes β‐CD:5‐FU in a 1:1 and 1:2 stoichiometries are investigated because this drug is relatively small compared to the size of the hydrophobic β‐CD cavity. The 5‐FU complexes with CDs allow its solubilization, thanks to favorable van der Waals interactions. Interestingly, these intermolecular interactions in inclusion complexes may also affect the release profile. MD simulations are a powerful tool to evaluate interactions between hydrophobic anticancer drugs and hydrophilic carriers with an inner hydrophobic cavity such as CDs and oligosaccharides in general.

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.

Cucurbit[8]uril-controlled [2 + 2] photodimerization of styrylpyridinium molecule

Complexation of ( E )-4-(4-(1-methyl-pyridinium)styryl)-1-methyl-pyridinium chloride (SMP) guest and cucurbit[8]uril (CB[8]) host depending on the host-guest interactions which was characterized by 1 H NMR spectroscopy, electronic absorption, isothermal titration calorimetry, high-resolution electrospray mass spectrum and fluorescence spectroscopy. What’s more interesting is that the styryl units in supramolecular complexes can more easily undergo [2 + 2] photodimerization under the promotion of macrocyclic CB[8] when irradiated with visible light. • Complexation of SMP and CB[8] depending on the host-guest interaction. • The styryl group of SMP is located in the cavity of CB[8], resulting in a highly stable inclusion complex SMP@CB[8] with a host-guest binding ratio of 2:1. • The styryl units of supramolecular complexes can more easily undergo [2 + 2] photodimerization under the promotion of CB[8] when irradiated with visible light. he interaction of ( E )-4-(4-(1-methyl-pyridinium)styryl)-1-methyl-pyridinium chloride (SMP) guest, with cucurbit[8]uril (CB[8]) host was characterized by 1 H NMR spectroscopy, electronic absorption, isothermal titration calorimetry (ITC), high-resolution electrospray mass spectrum and fluorescence spectroscopy. Experimental data indicated that the styryl group of SMP resides within the cavity of CB[8] in aqueous solution, generating a highly stable inclusion complex SMP@CB[8] with a host-guest binding ratio of 1:2. Isothermal titration calorimetry experiments showed that the complexation of the SMP guest with CB[8] were enthalpy and entropy driven, which benefits from ion dipole interactions between the guest SMP and the host CB[8]. What’s more interesting is that the styryl units of supramolecular complexes can more easily undergo [2 + 2] photodimerization under the promotion of macrocyclic CB[8] when irradiated with visible light.

Composition-selective full inclusion host-guest interaction of azobenzene-containing photoresponsive nanoring with fullerene C60.

By means of density functional theory calculations, the encapsulation capabilities of a series of azobenzen-containing photoresponsive nanoring hosts (labeled as host 1, 2, 3, 4, 5 and 6 according to the number of the azo unit, respectively) for fullerene C60 were surveyed. Interestingly and abnormally, it is found that the host 5, of which the diameter is only 1.218 nm, can form stable full inclusion complex with C60 . However, irrespective of their cavity sizes (11.98 ~ 12.94 Å) of the hosts, the structures 1~ 4 and 6 were all disable to form inclusion complex with C60 . In this paper, the group-number-composition-selective full inclusion host-guest interaction of the azobenzene-containing nanorings with fullerene C60 is firstly presented. The calculated interaction energies, together with the detection and visualization of the weak interaction regions, provided evidences for the host-guest binding based on relative strong repulsion interaction in the full inclusion complex. Analysis on the frontier orbital feature of the host-guest systems suggests that under the electron excited condition, the chemical activity may be transferred from host 5 to guest C60 by formation of the floating host-guest complex, and the chemical reactivity of the host 5 can be passivated via formation of the full inclusion host-guest complex. Additionally, UV-vis-NIR and 1 H NMR spectra of the hosts before and after the formations of the complexes have been simulated and discussed qualitatively, which may be helpful for further experimental investigations in future.

Chiral separation of catechin and epicatechin by reversed phase high-performance liquid chromatography with β-cyclodextrin stepwise and linear gradient elution modes

Catechin and epicatechin were enantioseparated by high-performance liquid chromatography (HPLC) with a phenyl column and aqueous mobile phases containing 0.05% (w/v) and 0.6% (w/v) of β-cyclodextrin for catechin and epicatechin, respectively. β-Cyclodextrin was found to be scarcely retained on a phenyl column. Consequently, it was suggested that catechin, which was eluted earlier than epicatechin, formed more stable inclusion complex with β-cyclodextrin than epicatechin and earlier eluted enantiomers, (−)-catechin and (+)-epicatechin, formed more stable diastereomer complexes with β-cyclodextrin than the respective enantiomers. This was confirmed by β-cyclodextrin-modified micellar electrokinetic chromatography and Benesi−Hildebrand plots by fluorescence spectrophotometry. Effect of sugars (D-sucrose, D-glucose, and D-fructose) on the epimerization of (+)-catechin and (+)-epicatechin by heating was investigated by HPLC with a β-cyclodextrin stepwise elution mode, in which two kinds of aqueous eluents containing different concentrations of β-cyclodextrin were used by turns. The epimerization of the two enantiomers was suppressed only when D-fructose was added. Separation of ten kinds of catechins including catechin and epicatechin enantiomers was investigated by a β-cyclodextrin linear gradient HPLC elution mode without using organic solvents, where two kinds of aqueous eluents containing different concentrations of β-cyclodextrin were used with changing their ratio gradually. These catechins in a green tea infusion could be separated successfully by this method.

Supramolecular Complexes of Plant Neurotoxin Veratridine with Cyclodextrins and Their Antidote-like Effect on Neuro-2a Cell Viability.

Veratridine (VTD) is a plant neurotoxin that acts by blocking the voltage-gated sodium channels (VGSC) of cell membranes. Symptoms of VTD intoxication include intense nausea, hypotension, arrhythmia, and loss of consciousness. The treatment for the intoxication is mainly focused on treating the symptoms, meaning there is no specific antidote against VTD. In this pursuit, we were interested in studying the molecular interactions of VTD with cyclodextrins (CDs). CDs are supramolecular macrocycles with the ability to form host–guest inclusion complexes (ICs) inside their hydrophobic cavity. Since VTD is a lipid-soluble alkaloid, we hypothesized that it could form stable inclusion complexes with different types of CDs, resulting in changes to its physicochemical properties. In this investigation, we studied the interaction of VTD with β-CD, γ-CD and sulfobutyl ether β-CD (SBCD) by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) spectroscopy. Docking and molecular dynamics studies confirmed the most stable configuration for the inclusion complexes. Finally, with an interest in understanding the effects of the VTD/CD molecular interactions, we performed cell-based assays (CBAs) on Neuro-2a cells. Our findings reveal that the use of different amounts of CDs has an antidote-like concentration-dependent effect on the cells, significantly increasing cell viability and thus opening opportunities for novel research on applications of CDs and VTD.

Controlled release and antibacterial properties of PEO/casein nanofibers loaded with Thymol/β-cyclodextrin inclusion complexes in beef preservation

There are still many limitations in the application of natural active compounds in meat preservation. Herein, thymol was first inserted into the cavity of β-cyclodextrin (β-CD) to form a stable inclusion complex (THY/β-CD-IC). The computational investigation showed that the optimized complexation energy for THY/β-CD-IC was −12.95 kcal mol−1. It contributed to the improvement of the thermal stability of thymol in the inclusion compound. Furthermore, the functionalized nanofibers (THY/β-CD-IC-NFs) loaded with THY/β-CD-IC were successfully fabricated by electrospinning of the mixture of casein and polyethylene oxide. When dealing with protease-producing bacteria, controllable release of thymol from THY/β-CD-IC-NFs was achieved through the response of casein to the hydrolysis of bacterial protease. The application results indicated that the prepared THY/β-CD-IC-NFs had a long-term antimicrobial activity for chilled beef preservation during 7-days storage. The information from this study presents a feasible strategy for the development of natural extracts for use in meat preservation.

Molecular encapsulation and bioactivity of gnetol, a resveratrol analogue, for use in foods.

BACKGROUNDGnetol is a stilbene whose characterization and bioactivity have been poorly studied. It shares some bioactivities with its analogue resveratrol, such as anti‐inflammatory, anti‐thrombotic, cardioprotective and anti‐cancer activities. However, the low solubility of stilbenes may limit their potential applications in functional foods. Encapsulation in cyclodextrins could be a solution.RESULTSThe antioxidant activity of gnetol was evaluated by 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid) radical cation and ferric reducing antioxidant power methods (Trolox equivalents 13.48 μmol L−1 and 37.08 μmol L−1 respectively at the highest concentration) and it was higher than that of resveratrol, and depending on the method, similar or higher to that of oxyresveratrol. Spectrophotometric and spectrofluorimetric characterization of gnetol is published for the first time. Moreover, its water solubility was determined and improved almost threefold after its molecular encapsulation in cyclodextrins, as well as its stability after storage for a week. A physicochemical and computational study revealed that cyclodextrins complex gnetol in a 1:1 stoichiometry, with better affinity for like 2‐hydroxypropyl‐β‐cyclodextrin (K F = 4542.90 ± 227.15 mol−1 L). Temperature and pH affected the encapsulation constants.CONCLUSIONThese results could increase interest of gnetol as an alternative to the most studied stilbene, resveratrol, as well as aid in the development of more stable inclusion complexes that improve its aqueous solubility and stability so that it can be incorporated into functional foods. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Enhanced Solubility of Albendazole in Cyclodextrin Inclusion Complex: A Molecular Modeling Approach and Physicochemical Evaluation.

Albendazole (ABZ) is the drug of choice for the treatment of a variety of human and veterinary parasites. However, it has low aqueous solubility and low bioavailability. Cyclodextrins (CD) are pharmaceutical excipients with the ability to modulate the solubilization property of hydrophobic molecules. The aim of the study was to analyze through in vitro and in silico studies (Autodock Vina software and CycloMolder platform) the formation of inclusion complexes between ABZ, β-cyclodextrin (β-CD) and its derivatives Methyl-β-cyclodextrin (M-β-CD) and Hydroxypropyl-β-cyclodextrin (HP-β-CD). The most stable inclusion complexes were produced by the kneading method and characterized by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD), determination of the ABZ content and in vitro dissolution profile. Molecular modeling revealed that inclusion complexes between HP-β-CD:ABZ (in the proportion 1:1 and 2:1) presented the lowest formation energy and the highest number of intermolecular interactions, showing that the use of more cyclodextrins does not generate gains in the stability of the complex. On the characterization tests, the complexes experimentally obtained by the kneading method demonstrated highly suggestive parameters, including ABZ in HP-β-CD in both molar proportions, suppression of bands in the infrared spectrum, displacement of the drug's melting temperature in DSC, crystallinity halos instead of the characteristic peaks of ABZ crystals in the XRD and a release of more than 80% of ABZ in less than 5 minutes, dissolution efficiency of up to 92%. In silico studies provided a rational selection of the appropriate complexes of cyclodextrin, enabling the elaboration of more targeted complexes, decreasing time and costs for elaboration of new formulations, thereby increasing the oral biodisponibility of ABZ.

Computational studies of the encapsulation of ibuprofen and paracetamol into cucurbit[7]uril

Herein, theoretical methods were used to study the cucurbit[7]uril (CB[7]) as a possible carrier agent for the poor water soluble drugs ibuprofen (IBF) and paracetamol (PCT). These drugs form a stable inclusion complex with the CB[7] during 50 ns of molecular dynamics simulation preserving its solvation shell. Likewise CB[7], both complexes are soluble in water with calculated solvation enthalpy of –131 and –133 kcal/mol for isolated CB[7]. The binding free energy, obtained from the potential of mean force calculations, reveals that the IBF@CB[7] complex is more stable (–16.7 kcal/mol) than the PCT@CB[7] complex (–11.7 kcal/mol). Correspondingly, the binding energies obtained in DFT-D3/B3LY/6-31G(d,p) calculation are –30.07 and –24.51 kcal/mol for IBF@CB[7] and PCT@CB[7], respectively. The high energy gap of complexes implies their chemical stability. Our results indicate that the CB[7] can be a new carrier agent for IBF and PCT, improving their solubility and chemoprotection in aqueous media.

Dopamine Family Complexes With β-Cyclodextrin: Molecular Docking Studies

This study concerns the molecular docking of dopamine family compounds in the β-cyclodextrin (β-CD) to establish the most critical driving forces in complexation. Our method is called “Determination of driving forces of inclusion complexes using generated surfaces” since it is based on the contact between host and guest molecules observed on distinct generated surfaces. These surfaces allow us to examine hydrophobic interactions, hydrogen interactions, electrostatic potential and dipole moment. The results found in this article confirm the experimental results. Finally, we suggest a number of molecules that can form stable inclusion complexes.

Selective Molecular Recognition of Low Density Lipoprotein Based on β-Cyclodextrin Coated Electrochemical Biosensor.

The excess of low-density lipoprotein (LDL) strongly promotes the accumulation of cholesterol on the arterial wall, which can easily lead to the atherosclerotic cardiovascular diseases (ACDs). It is a challenge on how to recognize and quantify the LDL with a simple and sensitive analytical technology. Herein, β-cyclodextrins (β-CDs), acting as molecular receptors, can bind with LDL to form stable inclusion complexes via the multiple interactions, including electrostatic, van der Waals forces, hydrogen bonding and hydrophobic interactions. With the combination of gold nanoparticles (Au NPs) and β-CDs, we developed an electrochemical sensor providing an excellent molecular recognition and sensing performance towards LDL detection. The LDL dynamic adsorption behavior on the surface of the β-CD-Au electrode was explored by electrochemical impedance spectroscopy (EIS), displaying that the electron-transfer resistance (Ret) values were proportional to the LDL (positively charged apolipoprotein B-100) concentrations. The β-CD-Au modified sensor exhibited a high selectivity and sensitivity (978 kΩ·µM−1) toward LDL, especially in ultra-low concentrations compared with the common interferers HDL and HSA. Due to its excellent molecular recognition performance, β-CD-Au can be used as a sensing material to monitor LDL in human blood for preventing ACDs in the future.

Encapsulation of α-tocopherol in large-ring cyclodextrin containing 26 α-D-glucopyranose units: A molecular dynamics study

α-Tocopherol is the most biologically active form of vitamin E (VE) exhibiting various biological activities such as strong antioxidant activity, antitumor properties and antiaging effects. However, the low water solubility of α-tocopherol has limited its prospective use in food, cosmetic and pharmaceutical industry. One of the promising strategies to tackle such issue is the use of a supramolecular complex with cyclodextrins (CDs). In this study, the encapsulation of α-tocopherol with six different initial un-complexed states into the large-ring CD containing 26 α-D-glucopyranose units (CD26) was studied by means of 400-ns molecular dynamics (MD) simulations to investigate their host–guest association process and the preferential binding efficiency upon complexation at low concentration of α-tocopherol. The MD results show that α-tocopherol spontaneously interacted with CD26 within 20 ns and formed a stable inclusion complex during 150–400 ns. From all six independent simulations, the inclusion complexes can be divided into two groups, which were fully and partly encapsulated inside the cavity of CD26. The α-tocopherol of the first group was covered by 13–14 subunits of CD26, while α-tocopherol in another group was attached by 6–10 subunits of CD26. In addition, α-tocopherol was surrounded by one- or two-turn helix of one half-ring of CD26, leaving the rest of cavities for forming complexation with a larger number of α-tocopherol molecules. Therefore, CD26 can be used as a solubility and stability enhancer for α-tocopherol through inclusion complexation.

Inclusion complex of thymol and hydroxypropyl-β-cyclodextrin (HP-β-CD) in polymeric hydrogel for topical application: Physicochemical characterization, molecular docking, and stability evaluation

The current investigation aimed to prepare and characterize the inclusion complex of thymol with hydroxypropyl-β-cyclodextrin (HP-β-CD) to uniformly incorporate in hydrogel system for its topical application. An inclusion complex of thymol with HP-β-CD was formulated through different methods viz. physical mixture, kneading, and co-precipitation. Phase solubility study was carried out to find the stability constant of complex. Further, the inclusion complex of thymol with HP-β-CD was characterized by DSC, FT-IR, and 1H NMR spectroscopy. The molecular docking studies were also performed to understand the molecular interactions of stable supra-molecular host-guest inclusion complex of thymol with HP-β-CD. After that inclusion complex was incorporated in carbopol 940 hydrogel and evaluated for its drug content, pH, homogeneity, rheological behavior, and in-vitro release. The phase solubility graph demonstrated AL type correlation with apparent stability constant (K1:1) of 370 M−1. The inclusion complex formulated by the co-precipitation technique exhibited the highest dissolution rate (98.73%) of thymol as compared to kneading and physical methods. The DSC, FT-IR and 1H NMR spectroscopic analysis confirmed the formation of inclusion complex between thymol and HP-β-CD. The molecular docking study has confirmed that the binding affinity of thymol with the HP-β-CD was −9.6 kcal/mol, indicating desirable stability of the prepared inclusion complex. The diffusion flux of thymol in a form of inclusion complex was found to be approximately 4.4 folds higher as compared to that of thymol in the hydrogel system for topical administration. The in vitro release of thymol from carbopol 940 hydrogel system exhibited a sustained release profile with thixotropic behaviour. The thymol in a form of inclusion complex was found to be stable in the developed hydrogel system according to ICH guidelines. Therefore, incorporation of thymol in form of inclusion complex in hydrogel system is an effective approach to improve its biopharmaceutical performance for topical administration.