Stable Inclusion Research Articles

Screening and inclusion of luteolin for β-cyclodextrin: molecular simulations and experiments

In this study, we first established a guest small molecule screening mechanism by molecular simulation, and then screened lignans from 10 polyphenolic compounds to identify the most suitable guest molecule for encapsulation with β-cyclodextrin (β-CD). Subsequently, the subject-guest interactions and encapsulation mechanisms of lignans with β-CD, 2-hydroxypropyl-cyclodextrin (HP-β-CD) and 2,6-dimethyl-cyclodextrin (DM-β-CD) were investigated using a combination of molecular simulation and experimental methods, respectively. Molecular simulations were performed to calculate the microstructural parameters, including solubility parameters, binding energies, and mean square displacements. The simulation results demonstrated that DM-β-CD exhibited the strongest interaction with luteolin and formed the most stable inclusion complex. The inclusion complexes of luteolin with the three cyclodextrins were prepared by freeze-drying method, and the formation of the inclusion complexes was demonstrated using infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and ultraviolet-visible spectroscopy (UV). Phase solubility studies confirmed the formation of 1:1 stoichiometric inclusion complexes of lignans with cyclodextrins. Furthermore, 2,2-diphenyl-1-pyridine hydrazine (DPPH) free radical scavenging experiments demonstrated that the inclusion complexes exhibited enhanced antioxidant capacity. In light of these findings, it can be concluded that among the three cyclodextrins, DM-β-CD was optimally encapsulated with luteolin.

Deep Eutectic Solvents for Next-generation Cyclodextrin Science

Abstract In cyclodextrin science, water has been almost exclusively employed as solvent, and this imposes non-negligible limitations to the scope of applications. Accordingly, deep eutectic solvents, constructed from hydrogen-bonding donors and acceptors, have been attracting much interest as important substitutes of water. This review comprehensively covers chemical and physicochemical features of cyclodextrins in these eco-friendly solvents. In one category, cyclodextrins or their derivatives are dissolved as solutes in conventional deep eutectic solvents. All of α-, β-, and γ-cyclodextrins efficiently form inclusion complexes with various guest molecules, exactly as observed in water. Notably, chemically modified cyclodextrins (e.g., 2-hydroxypropyl-cyclodextrins) form still more stable inclusion complexes than native cyclodextrins. Alternatively, deep eutectic solvents are prepared by combining cyclodextrins with other hydrogen-bonding components. The cyclodextrin units in these mixtures also form inclusion complexes with guest molecules. It has been proposed that enhanced flexibility of cylindrical structures of cyclodextrins allows effective induced-fit to stabilize inclusion complexes. The applications of these systems widely range from catalysis for organic synthesis to extraction, analysis, pharmaceutics, and many other fields. High solubilities of CDs and various chemicals in these solvents guarantee high productivity of target transformation, and unprecedentedly novel functions are promising for these unique systems.

Hypogene Alteration of Base–Metal Mineralization at the Václav Vein (Březové Hory Deposit, Příbram, Czech Republic): The Result of Recurrent Infiltration of Oxidized Fluids

The Václav vein (Březové Hory deposit, Příbram ore area, Czech Republic) is a base–metal vein containing minor Cu-Zn-Pb-Ag-Sb sulfidic mineralization in a usually hematitized gangue. A detailed mineralogical study using an electron microprobe revealed a complicated multistage evolution of the vein. Early siderite and Fe-rich dolomite were strongly replaced by assemblages of hematite+rhodochrosite and hematite+kutnohorite/Mn-rich dolomite, respectively. In addition, siderite also experienced strong silicification. These changes were associated with the dissolution of associated sulfides (sphalerite, galena). The following portion of the vein contains low-Mn dolomite and calcite gangue with Zn-rich chlorite, wittichenite, tetrahedrite-group minerals, chalcopyrite, bornite, and djurleite, again showing common replacement textures in case of sulfides. The latest stage was characterized by the input of Ag and Hg, giving rise to Ag-Cu sulfides, native silver (partly Hg-rich), balkanite, and (meta)cinnabar. We explain the formation of hematite-bearing oxidized assemblages at the expense of pre-existing “normal” Příbram mineralization due to repeated episodic infiltration of oxygenated surface waters during the vein evolution. Episodic mixing of ore fluids with surface waters was suggested from previous stable isotope and fluid inclusion studies in the Příbram ore area. Our mineralogical study thus strengthens this genetic scenario, illustrates the dynamics of fluid movement during the evolution of a distinct ore vein structure, and shows that the low content of ore minerals cannot be necessarily a primary feature of a vein.

METALLOGRAPHIC ANALYSIS OF NON-METALLIC INCLUSIONS IN SEMI-KILLED STEEL (GRADE 25G2S) DEOXIDIZED WITH A COMPLEX ALLOY Fe-Si-Mn-Al

This study presents a metallographic analysis of non-metallic inclusions in steel samples obtained from six different heats of the oxygen converter shop at JSC «Qarmet» and under laboratory conditions at the Karaganda Industrial University. The investigation focused on semi-killed steel samples deoxidized using traditional technology under industrial conditions and with a complex alloy containing Fe-Si-Mn-Al under laboratory conditions, aiming to identify the types and assess the level of contamination by non-metallic inclusions. The results revealed the presence of various types of non-metallic inclusions, such as corundum, chromite spinel, chromium oxides, as well as titanium nitrides and carbonitrides. The degree of contamination by non-metallic inclusions ranged from 2 to 3 points. The analysis showed that the use of a complex Fe-Si-Mn-Al alloy instead of traditional deoxidizers can affect the quantitative and qualitative composition of non-metallic inclusions. It was established that the complex alloy promotes the formation of more stable inclusion phases, which can positively impact the mechanical properties of the steel. It was also found that different production technologies and the use of deoxidizers can significantly influence the quantity and types of non-metallic inclusions, requiring further study and optimization of technological processes. Therefore, the results of this study can be valuable for metallurgical enterprises in selecting optimal steel deoxidation methods and improving steel quality, as well as for further scientific research in the fields of metallurgy and materials science.

Functionalized composite nanofiber membranes for selective steroid hormone micropollutants uptake from water: Role of cyclodextrin type

Cyclodextrins (CD) entrapped in nanofiber composite membranes are potential selective adsorbing materials to remove steroid hormone (SHs) micropollutants from water. This study aims to elucidate the role of CD macrocyclic host type on the SHs inclusion complexation and uptake in filtration. Three CD types (α, β, and γ) are cross-linked with epichlorohydrin to form polymers (αCDP, βCDP and γCDP) and entrapped into a nanofiber composite membrane by electrospinning. TGA analysis confirmed the CD entrapment into the nanofiber without loss of CD molecules during filtration.The CD type plays a dominant role in controlling the removal of different SHs. A similar removal (range 33 to 50 %) was observed with αCDP, irrespective of the SH type. In contrast, removal and uptake dependent on SH type were observed for β and γCDP, with the highest removal of 74 % for progesterone, followed by estradiol (46 %) and estrone (27 %) and the lowest removal of 3 % for testosterone.Molecular dynamic (MD) simulation revealed a stronger and more stable complex formed with βCDP, as demonstrated by: i) the closer spatial distribution of SH molecules from the βCDP cavity and, ii) the quantum chemistry calculations of the lower de-solvation energy (+6.0 kcal/mol), which facilitates the release of water molecules from interacting interface of CD molecule and hormone. Regarding γCDP, the highest de-solvation energy (+8.3 kcal/mol) poses an energetic barrier, which hinders the formation of the inclusion complex. In the case of αCDP, a higher interaction energy (-8.9 kcal/mol) compared to βCDP (-4.9 kcal/mol) was obtained, despite the broader spatial distribution observed from the MD simulation attributed to a dominant hydrogen bonding interaction with the OH primary groups on the external surface cavity.The findings highlight the relevance of the CD type in designing selective adsorbing membranes for steroid hormone micropollutant uptake. Experimental results and MD simulation suggest that βCD is the most suitable CD type for steroid hormone uptake, due to a more stable and stronger inclusion complexation than α and γCD.

Structure-Activity Relationship Studies Leading to the Discovery of Highly Water-Soluble and Biocompatible Acyclic Cucurbit[n]uril FY-3451 as a Universal Antagonist That Rapidly Reverses Neuromuscular Blocking Agents In Vivo.

The development of a reversal agent that can rapidly reverse clinically used nondepolarizing neuromuscular blocking agents (NMBAs) has long been a challenge. Here, we report the synthesis of a series of highly water-soluble acyclic cucurbit[n]urils (acCBs). Systematic structure-activity relationship studies reveal that introducing two propylidene units on the peripheral benzene rings not only remarkably improves the activity of the corresponding derivative acCB6 (FY 3451) in reversing the neuromuscular block of rocuronium, cisatracurium, vecuronium, and pancuronium, the four clinically used NMBAs, through stable inclusion, but also allows for high water-solubility as well as a maximum tolerated dose (2000 mg/kg on rats). In vivo experiments with rats show that, at the identical dose of 25 mg/kg, for rocuronium, vecuronium, and pancuronium, acCB6 can achieve a recovery time shorter than that of sugammadex for rocuronium and, at the dose of 100 mg/kg, realize comparably rapid reversal for cisatracurium.

Inclusion Complexation of Flavonoids with Cyclodextrin: Molecular Docking and Experimental Study

AbstractIn our work, the inclusion ability and binding pattern of flavonoids (catechin, iso‐liquiritigenin, luteolin, puerarin, rutin, and curcumin) with β‐cyclodextrin (β‐CD) and curcumin (CUR) with CDs (α‐CD, β‐CD, γ‐CD, dimethyl‐β‐CD, Hydroxypropyl‐β‐CD, and glucosyl‐β‐CD) were studied by molecular docking. The results showed that CUR among the six flavonoids was more likely to form stable inclusion complexes with β‐CD, and the HP‐β‐CD is the most suitable for CUR inclusion among the 6 types of CD. Phase solubility studies showed that CUR with β‐CD or HP‐β‐CD, respectively, could form stable inclusion complexes in a stoichiometric ratio of 1 : 1. The CUR/β‐CD and CUR/HP‐β‐CD inclusion complexes (ICs) were prepared by freeze‐drying method. The successful preparation of IC was confirmed by SEM images, FT‐IR spectra, and TG‐DSC. The results of in vitro release showed that the release of CUR from IC prepared with β‐CD or HP‐β‐CD could be improved significantly, and the release effect of HP‐β‐CD was better than that of β‐CD. The inclusion with CD could be used to improve the solubility and bioavailability of CUR.

Unique Organic Crystal Skeleton Based on N-Phenyl-Carbazole Derivatives with Adjustable Room Temperature Phosphorescence and Highly Stable Inclusion Ability to Dichloromethane.

Monosubstituted 9-(2-bromophenyl)-carbazole (1Br1CZ) and disubstituted 9,9'-(2,4-dibromo-1,3-phenylene) bis(9H-carbazole) (2Br2CZ) are synthesized by introducing bromine into ortho-phenyl position of 9-phenyl-carbazole (PhCZ). The decomposition temperature with 5% mass loss and melting point of 2Br2CZ crystal are 360 and 230°C. The highest occupied molecular orbital energy level of PhCZ is the highest, and that of 2Br2CZ is the lowest. The crystals of PhCZ, 1Br1CZ, and 2Br2CZ are monoclinic, orthorhombic, and triclinic system, which exhibit room temperature phosphorescence with lifetimes of 171.81, 37.15, and 28.77ms, and their corresponding phosphorescence quantum yields are 0.83%, 0.16%, and 4.58%. It theoretically reveals that six triplet energy levels (T1-T6) exist under S1 in 2Br2CZ crystal, and the spin orbit coupling constants between S1 and Tn in 2Br2CZ are also greater than those in PhCZ and 1Br1CZ, which promotes the intersystem crossing. Meanwhile, through crystal structure and Hirshfeld surface analysis, the torsion angles between the carbazole unit of 2Br2CZ and the central phenyl group reached 85.28°. The 2Br2CZ crystal exhibits the richest intermolecular interactions. A cavity of 4.498Å is formed within the crystal skeleton of 2Br2CZ, which can precisely fixe dichloromethane with a record-high desorption temperature over 145°C.

Sustained-Release Microspheres of Cyclodextrin-Resveratrol Complex Using Fenugreek Galactomannan Hydrogels: A Green Approach to Phytonutrient Delivery.

Food matrices are becoming increasingly complex with the impregnation of phytonutrients with health-beneficial pharmacological effects. Herein, we report the preparation, characterization, and functional application of soluble and stable microspheres of trans-resveratrol (t-RES) developed through a water-based green process involving cyclodextrin (CD) and fenugreek galactomannan (FG). Spectroscopic and thermodynamic calculations identified γ-CD as the best CD to form a stable cyclodextrin-resveratrol inclusion complex (CD-R, 49-fold enhanced solubility); however, it exhibited a burst release profile. The sustained release of resveratrol was achieved by further encapsulating the inclusion complex within the fenugreek galactomannan hydrogel scaffold by a gel-phase dispersion process, resulting in an amorphous powder (FG-CD-R) as evident from powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) studies. Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) studies confirmed the formation of the inclusion complex with no chemical alterations. When dissolved in water, FG-CD-R swelled and released stable cuboid structures with an average particle size of 500 ± 53 nm with a zeta potential of -52 ± 5.3 mV. FG-CD-R demonstrated a sustained-release profile upon in vitro release studies. Accelerated study demonstrated its stability for a shelf-life of two years. Further it was shown to be suitable for the preparation of transparent gummies with improved sensory attributes compared to unformulated t-RES. In summary, FG-CD-R is simple to prepare and easily scalable, providing a sustained-release t-RES with a natural, food-grade, and clean label status (non-genetically modified, allergen-free, vegan, and free from residual solvents) for nutritional applications.

Antibacterial, Anti-Inflammatory, and Antioxidant Cotton-Based Wound Dressing Coated with Chitosan/Cyclodextrin-Quercetin Inclusion Complex Nanofibers.

Quercetin, recognized for its antioxidant, anti-inflammatory, and antibacterial properties, faces limited biomedical application due to its low solubility. Cotton, a preferred wound dressing material over synthetic ones, lacks inherent antibacterial and wound-healing attributes and can benefit from quercetin features. This study explores the potential of overcoming these challenges through the inclusion complexation of quercetin with cyclodextrins (CDs) and the development of a nanofibrous coating on a cotton nonwoven textile. Hydroxypropyl-beta-cyclodextrin (HP-β-CD) and hydroxypropyl-gamma-cyclodextrin (HP-γ-CD) formed inclusion complexes of quercetin, with chitosan added to enhance antibacterial properties. Phase solubility results showed that inclusion complexation can enhance quercetin solubility up to 20 times, with HP-γ-CD forming a more stable inclusion complexation compared with HP-β-CD. Electrospinning of the nanofibers from HP-β-CD/Quercetin and HP-γ-CD/Quercetin aqueous solutions without the use of a polymeric matrix yielded a uniform, smooth fiber morphology. The structural and thermal analyses of the HP-β-CD/Quercetin and HP-γ-CD/Quercetin nanofibers confirmed the presence of inclusion complexes between quercetin and each of the CDs (HP-β-CD and HP-γ-CD). Moreover, HP-β-CD/Quercetin and HP-γ-CD/Quercetin nanofibers showed a near-complete loading efficiency of quercetin and followed a fast-releasing profile of quercetin. Both HP-β-CD/Quercetin and HP-γ-CD/Quercetin nanofibers showed significantly higher antioxidant activity compared to pristine quercetin. The HP-β-CD/Quercetin and HP-γ-CD/Quercetin nanofibers also showed antibacterial activity, and with the addition of chitosan in the HP-γ-CD/Quercetin system, the Chitosan/HP-γ-CD/Quercetin nanofibers completely eliminated the investigated bacteria species. The nanofibers were nontoxic and well-tolerated by cells, and exploiting the quercetin and chitosan anti-inflammatory activities resulted in the downregulation of IL-6 and NO secretion in both immune as well as regenerative cells. Overall, CD inclusion complexation markedly enhances quercetin solubility, resulting in a biofunctional antioxidant, antibacterial, and anti-inflammatory wound dressing through a nanofibrous coating on cotton textiles.

Recognition of monoamine neurotransmitters by cucurbiturils

Neurological disorders are linked to deficiencies in monoamine neurotransmitters (NTs) in the brain, and their inability to cross the blood–brain barrier (BBB) prevents their use as treatments. Encapsulating them within an appropriate host could present a potential remedy. Molecular dynamics (MD) simulations are employed to investigate the molecular recognition of protonated and neutral forms of five NTs and two dopamine (DP) analogs by cucurbit[n]urils (CBn). Binding free energies (ΔG), computed with the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, reveal CB7 forms stable inclusion complexes with all studied NTs, driven by ion–dipole/dipole–dipole interactions between and the ammonium/amine in the NT with the carbonyl portal of CB7, as well as van der Waals interactions of the included catechol/heterocyclic ring. ΔG was more favorable (by ∼2–3 kcal.mol−1) for the DP analogs. MD simulations performed to study complexation between DP and CB6 and CB8 revealed 1:1 and 2:1 stoichiometries, respectively.

Host-Guest Complexes of Flavanone and 4'-Chloroflavanone with Naturals and Modified Cyclodextrin: A Calorimetric and Spectroscopy Investigations.

The aim of the research was to investigate and compare the interaction between flavanones (flavanone, 4-chloro-flavanone) with potential anticancer activity and selected cyclodextrins. Measurements were made using calorimetric (ITC, DSC) and spectrophotometric (UV-Vis spectroscopy, FT-IR, 1H NMR) methods. The increase in the solubility in aqueous medium caused by the complexation process was determined by the Higuchi-Connors method. As a result of the study, the stoichiometry and thermodynamics of the complexation reaction were determined. The formation of stable inclusion complexes at a 1:1 M ratio between flavanone and 4-chloroflavanone and the cyclodextrins selected for research was also confirmed.

Integrative approach for improved dofetilide solubility using β-cyclodextrin and two its substituted derivatives: Solutions and solid dispersions

The complexation an anti-arrhythmia drug dofetilide (DFT) with β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD) were studied using two main approaches: phase solubility diagrams and solid dispersions technique. The phase solubility diagrams were constructed in buffer solutions with physiological values рН 2.0 и 7.4. In accordance with the protolytic properties of the drug, the solubilizing effect of cyclodextrins turned out to be more effective in a neutral environment (buffer pH 7.4): the solubility improvement of DFT in the presence of β-CD, HP-β-CD and SBE-β-CD was 3.6, 11.8 and 18.1 times, respectively. In buffer pH 2.0, the tendency for an increase in the solubilizing effect, depending on the chemical nature of the CDs used, is maintained, but the solubility of the drug almost does not grow. The binding constants for the DFT/HP-β-CD and DFT/SBE-β-CD complexes equal to 344 L·mol−1 and 429 L·mol−1 in buffer pH 7.4 indicate the formation of stable inclusion complexes and belong to the optimal range for refinement bioavailability and stability of hydrophobic drugs. Amorphous solid dispersions DFT/β-CD, DFT/HP-β-CD and DFT/SBE-β-CD with stoichiometry 1:1 were obtained by grinding method. The combination FTIR, PXRD, DSC, TGA and SEM methods confirmed the inclusion complexes formation of the drug with cyclodextrins used. Dissolution profiles of solid dispersions DFT/β-CD, DFT/HP-β-CD and DFT/SBE-β-CD were graphing in buffer solutions рН 2.0 and 7.4. Enlargement factor of DFT solubility in the composition of solid dispersions DFT/β-CD, DFT/HP-β-CD and DFT/SBE-β-CD in the neutral medium are 3.4, 4.1 and 5.2, respectively. Whereas the formation of solid inclusion complexes DFT/CDs in an acidic buffer has virtually no effect on the increase in the equilibrium concentration of the active substance in the solution. Findings have demonstrated that the use of SBE-β-CD shows the best solubilization potential for DFT both in solution and as a solid dispersion.

Formation of Inclusion Complexes of 2-Hydroxypropyl β-Cyclodextrin with 2-Hydroxychalcone: Experimental and Theoretical Study

The formation of inclusion complexes of 2-hydroxypropyl-β-cyclodextrin (HP β-CD) with 2-hydroxychalcone (2HOCH) in solution and solid state was investigated using UV–Visible, fluorescence, Fourier transform-infrared (FT-IR) spectroscopy, powder X-ray diffraction (PXRD), scanning electron microscope (SEM) techniques. The results obtained confirmed that 2HOCH formed the stable inclusion complex with HP β-CD. Moreover, the spectral data and Benesi–Hildebrand plots results indicated that the stoichiometry of the inclusion complex was 1:1. Theoretically, the structure of the inclusion complexes and the physical parameters such as complexation energy, highest occupied molecular orbital–lowest unoccupied molecular orbital, and energy gap were obtained using the DFT/B3LYP/6-311G method. It was found that the complexation energy for orientation B was lower than that for orientation A as evidenced by the theoretical calculations. Moreover, the carbonyl group of molecules was located outside of the cyclodextrin cavity while the hydroxyl group was located inside the cavity. The antioxidant capacity and antibacterial responses of the inclusion complexes and, for comparison, the parent compounds were also carried out.

Polyaromatic Hydrocarbon Inclusion Complexes with 2-Hydroxylpropyl-β/γ-Cyclodextrin: Molecular Dynamic Simulation and Spectroscopic Studies.

In aqueous and solid media, 2-HP-β/γ-CD inclusion complexes with poly aromatic hydrocarbon (PAH) Phenanthrene (PHN), Anthracene (ANT), Benz(a)pyrene (BaP), and Fluoranthene (FLT) were investigated for the first time. The inclusion complexes were characterized and investigated using fluorescence and 1HNMR spectroscopy. The most prevalent complexes consisting of both guests and hosts were those with a 1:1 guest-to-host ratio. The stability constants for the complexes of PHN with 2-HP-β-CD and 2-HP-γ-CD were 85 ± 12 M-1 and 49 ± 29 M-1, respectively. Moreover, the stability constants were found to be 502 ± 46 M-1 and 289 ± 44 M-1 for the complexes of ANT with both hosts. The stability constants for the complexes of BaP with 2-HP-β-CD and 2-HP-γ-CD were (1.5 ± 0.02) × 103 M-1 and (9.41 ± 0.03) × 103 M-1, respectively. The stability constant for the complexes of FLT with 2-HP-β-CD was (1.06 ± 0.06) × 103 M-1. However, FLT was observed to form a weak complex with 2-HP-γ-CD. Molecular dynamic (MD) simulations were used to investigate the mechanism and mode of inclusion processes, and to monitor the atomic-level stability of these complexes. The analysis of MD trajectories demonstrated that all guests formed stable inclusion complexes with both hosts throughout the duration of the simulation time, confirming the experimental findings. However, the flexible Hydroxypropyl arms prevented the PAHs from being encapsulated within the cavity; however, a stable exclusion complex was observed. The main forces that influenced the complexation included van der Waals interactions, hydrophobic forces, and C-H⋯π interaction, which contribute to the stability of these complexes.

Room-temperature stable Perillaldehyde—Natural cyclodextrin inclusion complexes: Preparation, characterization, thermal stability, water solubility, antioxidant activity and slow–release performance

The compound Perillaldehyde (PA) is a bioactive constituent found in natural Perilla oil, exhibiting remarkable antibacterial and antioxidant activity. However, the instability of this compound caused by the easy oxidation of its aldehyde and olefin groups imposes limitations on its extensive applications. Therefore, it is crucial to develop effective strategies for enhancing the stability of PA. This study focuses on utilizing a series of natural cyclodextrins (CDs) to synthesize inclusion complexes (ICs) with PA, aiming to improve water solubility and achieve exceptional stability at room temperature, which is essential for their potential applications in biomedicine or food industries. The hydrophobic cavity of CDs can accommodate the hexatomic ring and hydrophobic chains of PA based on the well-known size-matching effect and hydrophobic interaction, thereby forming stable ICs. Additionally, the hydrophilic outer wall of CDs imparts excellent water solubility to ICs. Phase solubility investigations demonstrate successful construction of α-CD-PA IC and β-CD-PA IC with an inclusion ratio of 1:1. Their respective stability constant (KC) are determined as 342 L/mol and 180 L/mol, indicating superior stability for α-CD-PA IC compared to β-CD-PA IC. Conversely, γ-CD with a larger cavity fails to form a stable inclusion complex with PA due to inadequate size matching. Nuclear Magnetic Resonance Hydrogen Spectroscopy (1H and 2D NMR) studies reveal that PA enters the CDs cavity (α-CD or β-CD) from its wide rim with almost the entire molecule being obliquely embedded within it. Thermogravimetry Analysis (TGA) confirm that after inclusion with CDs, PA exhibits expected stability at 25 ℃. Furthermore, CDs-PA ICs demonstrate significantly improved water solubility compared to pure PA along with enhanced antioxidant activity and slow-release performance, rendering them highly favorable for various applications.

Geochemistry of hydrothermal illitizations in Eocene Kösedağ magmatic rocks, Zara-Suşehri area, NE Sivas, East-Central Anatolia: Origin and age of alteration

The study area located at the periphery of the collision zone between the Eurasian plate (i.e. Pontides) and Tauride-Anatolide platform, NE of Sivas in the east-central Turkey, which is part of the Tethyan Metallogenic Belt. Mixed-layer illite-smectite (IS) and illite minerals are derived within the hydrothermal alteration zones with a few km2 surface areas (up to 30 km2) in Eocene volcanic and plutonic rocks. The representative IS and illite samples taken from plutonic- and volcanic-hosted alteration zones are investigated by optical and scanning electron microscopy (SEM), X-ray diffraction (XRD), major and trace elements and OH isotope geochemistry and KAr dating methods. Different types of hydrothermal alterations, such as propylitic and phyllic alteration in the plutonic rocks and argillic alteration in the volcanic rocks were developed as a result of intrusion of Kösedağ Pluton (syenite) into Karataş Volcanics (basaltic trachy-andesite and trachyte) with relations of hot-hot contact. The main phyllosilicate/clay minerals are characterized by kaolinite and IS in volcanic-hosted argillic alteration zones, whereas IS and illite in plutonic-hosted phyllic zones. The ordering types (Reichweite) of IS and illites are represented by R1 IS (I = 65–80 % in IS) + R3 IS (I = 90 % in IS) in the volcanic-hosted rocks, and R3 IS (I = 90 % in IS) and illite (S = 3–5 %). Dioctahedral (d060 ≤ 1.500 Å) R3 IS and illites have 1 Md + 1 M and 1 Md + 1 M + 2 M1 polytypes, respectively. The major and trace elements such as TiO2, Fe2O3, MgO, Na2O, P2O5, Sc, V, Cu, Ge, Sr, Hf, Zr and Y increase in the volcanic-hosted IS, whereas SiO2, Al2O3, K2O, Pb, W, Mo, As, Sb, Rb and U in the plutonic-hosted IS and illites. The chondrite-normalized distributions of IS and illites present a great similarity to those of host rocks. The chondrite-normalized rare earth element (REE) concentrations are more enriched in the volcanic-hosted IS in comparison with the plutonic-hosted IS and illites having distinctive Eu negative anomaly, which indicate deriving from volcanic matrix and K-feldspar, respectively. Oxygen and hydrogen isotope data of illitic clays indicate that the hydrothermal fluids are originated from magmatic water. According to stable isotopes and fluid inclusion data, IS and illites were formed at the temperature conditions ~150 °C in volcanic-hosted argillic zone, whereas ~250 °C in plutonic-hosted phyllic zones. KAr dating of alunite, IS and illite minerals indicate that the hydrothermal alteration was started at 40.45 ± 1.28 Ma, almost 2 Ma after the Q-syenite intrusion, within the plutonic body as phyllic alteration stage, and continued up to 35.27 ± 2.81 Ma, with a duration of ~5 Ma, and finalized before the exhumation of the Kösedağ Pluton (28–30 Ma). The geochemical characteristics of IS and illites were controlled by host-rock, condition, origin, and ages of alterations and they can be used as an important tool for magmatic-hydrothermal systems.

Influences of burial process on diagenesis and high-quality reservoir development of deep–ultra-deep clastic rocks: A case study of Lower Cretaceous Qingshuihe Formation in southern margin of Junggar Basin, NW China

Taking the Lower Cretaceous Qingshuihe Formation in the southern margin of Junggar Basin as an example, the influences of the burial process in a foreland basin on the diagenesis and the development of high-quality reservoirs of deep and ultra-deep clastic rocks were investigated using thin section, scanning electron microscope, electron probe, stable isotopic composition and fluid inclusion data. The Qingshuihe Formation went through four burial stages of slow shallow burial, tectonic uplift, progressive deep burial and rapid deep burial successively. The stages of slow shallow burial and tectonic uplift not only can alleviate the mechanical compaction of grains, but also can maintain an open diagenetic system in the reservoirs for a long time, which promotes the dissolution of soluble components by meteoric freshwater and inhibits the precipitation of dissolution products in the reservoirs. The late rapid deep burial process contributed to the development of fluid overpressure, which effectively inhibits the destruction of primary pores by compaction and cementation. The fluid overpressure promotes the development of microfractures in the reservoir, which enhances the dissolution effect of organic acids. Based on the quantitative reconstruction of porosity evolution history, it is found that the long-term slow shallow burial and tectonic uplift processes make the greatest contribution to the development of deep–ultra-deep high-quality clastic rock reservoirs, followed by the late rapid deep burial process, and the progressive deep burial process has little contribution.

Enhancing the bioavailability of clozapine through microwave-assisted formulation of a stable β-cyclodextrin inclusion complex

The low oral bioavailability of clozapine due to its poor aqueous solubility, poor dissolution rate, and extensive hepatic first-pass metabolism poses a challenge to the effective treatment of psychiatric disorders. The objective of the current research was to address the above issues by developing a clozapine inclusion complex (CLZ-IC) using the microwave irradiation method. To optimize the formulation and processing variables, namely the molar ratio of CLZ to β-CD (X1) and the irritation reaction time (X2), a 32 factorial design was performed. The phase solubility study revealed the formation of a stable inclusion complex with a stoichiometry of 1:1, suggesting that β-cyclodextrin could effectively solubilize clozapine. The characterization data confirmed the formation of the inclusion complex of clozapine in β-cyclodextrin. The optimized inclusion complex showed a solubility of 342 ± 26 µg/ml and a percentage dissolution of 91.1 ± 3.4% after four hours. The inclusion-complex tablets exhibited excellent physical properties and showed an improved in vitro dissolution profile, with 80% of the drug being released within 100 minutes, compared to marketed tablets (80% release in 300 min). In vivo pharmacokinetic studies conducted in a rat model demonstrated an increase in Cmax, area under the curve (AUC), and relative bioavailability by a factor of 2.26 with the optimized formulation, indicating a significant improvement in drug absorption compared to the marketed tablet. The techno-economic analysis suggests a cost-benefit ratio of 25.08 after 7 years, indicating the suitability for large-scale production. Overall, using Design of Experiment, in silico, and in vivo studies proved effective in optimizing the inclusion-complex formation and enhancing the bioavailability of clozapine. In conclusion, the optimized clozapine-β-cyclodextrin inclusion complex prepared using a time-saving (90 sec) and cost-effective microwave irradiation method exhibited excellent physical properties and demonstrated significant improvements in the drug's solubility, dissolution rate, and pharmacokinetic performance.

Structure and activity of amphiphilic PEO-PPO-based polymeric micelles and gels incorporating host–guest complexes of miltefosine as novel formulations for the treatment of leishmaniasis

Hypothesis: Poloxamines are amphiphilic block copolymers that self-assemble forming polymeric micelles (PMs) and hydrogels. They have emerged as promising colloidal carriers for their potential in improving drug delivery and controlled release through their multi-responsive properties. Tetronic® 1307 (T1307) PMs and gels have been used herein as vehicles of host–guest complexes of cyclodextrins (CDs) and miltefosine (MF), an amphiphilic, anti-parasitic drug effective against leishmaniasis.Experiments: The association of MF to αCD, βCD, and HPβCD and the topology of the complexes have been fully characterized by NMR spectroscopy. Then, the structure of the complex-loaded PMs and hydrogels investigated using diffusion nuclear magnetic resonance (DOSY), small angle neutron scattering (SANS), and dynamic light scattering (DLS). The antileishmanial activity of the constructs was evaluated against Leishmania major promastigotes and amastigotes, as well as their cytotoxicity in macrophages.Findings: All the CDs investigated form highly stable inclusion complexes with MF in a 2CD:1MF stoichiometry that lead to considerable proportions of complexed drug at high dilution, the HPβCD providing the highest stability and compatibility with the poloxamine. The complex incorporates preferentially into the hydrophilic shell of the PMs, inducing the elongation of the aggregates and the dehydration of the micellar core, formed mainly by the PPO blocks. At high concentration of polymer and physiological temperature, the complex-loaded PMs pack in a BCC-type paracrystal network. The micellar formulations of the CD-complexed MF reduced the cytotoxicity of the drug, while enhancing its antileishmanial activity. This approach could improve the currently available treatments, facilitating the administration of MF at lower concentrations and achieving relevant therapeutic effects, not only through the intravenous route, but also as topical formulations through injectable thermogels for the treatment of the cutaneous and mucocutaneous forms of the disease.