Cyclodextrin and its derivatives as effective excipients for amorphous ulipristal acetate systems.

Many efforts have been devoted to screening new solid-state forms of poorly soluble drugs in the pharmaceutical industry, thus modulating the drug properties without changing the pharmacological nature. It is a wise strategy to prepare amorphous series with cyclodextrin (CD) and its derivatives as excipients to enhance the aqueous solubility, dissolution, and bioavailability of water-insoluble drugs. In this study, four binary amorphous mixtures of ulipristal acetate (UPA) with CDs (ß-CD, γ-CD, dimethyl-ß-CD, hydroxypropyl-ß-CD) were prepared by the co-milling method and characterized in the solid-state. According to powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC), UPA existed in the noncrystalline form in the four binary amorphous mixtures. Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR) indicated that UPA interacted with the four CDs, which was also verified by molecular docking. Compared with the crystalline and amorphous UPA, the solubility, dissolution, and stability of the drug in the four amorphous UPA systems were significantly improved, so they were considered potentially advantageous solid forms. Our research shows that CDs can be used as new effective excipients in amorphous systems for active pharmaceutical ingredients (API).

Molecular recognition patterns between vitamin B12 and human serum albumin explored through STD-NMR and spectroscopic methods.

Ligand-receptor molecular recognitionis the basis of biological process. The Saturation Transfer Difference-NMR (STD-NMR) technique has been recently used to gain qualitative and quantitative information about physiological interactions at atomic-resolution. The molecular recognition patterns between Vitamin B12 (VB12) and human serum albumin (HSA) were investigated by STD-NMR supplemented by other spectroscopies and molecular docking. STD-NMR delivered a complete picture that the substituent groups on the tetrapyrrole ring of VB12 interacted with site III of HSA through binding epitope mapping and competitive probe experiments. STD-NMR and fluorescence results proved the moderate binding capability of VB12 and clarified a static, spontaneous, and temperature-sensitive binding mechanism. 3D-fluorencence, FT-IR and circular dichroism spectra showed a compact protein structure by interacting with VB12. Size distribution and surface hydrophobicity showed the surface properties changes of HSA caused by the binding of VB12. Computer simulation confirmed the recognition mode in theory and was compared with experiments. This work is beneficial for understanding the safety and biological action of VB12, and will attract researchers interested in NMR technology.

Supramolecular Self-Assembly of Perylene Bisimide-Based Rigid Giant Tetrahedra.

Recently, ordered structures constructed from rigid three-dimensional (3D) shaped polyhedra have been drawing general interest, with the tetrahedron being the simplest one but showing complicated assembly behaviors. Rigid tetrahedron building blocks have been shown to form quasicrystalline and crystalline phases with high packing fractions by both simulation and experiments. Nevertheless, the study of 3D tetrahedral building blocks is limited, especially in the field of supramolecular self-assembly. Here, we present an experimental study of rigid giant tetrahedral molecules constructed by attaching four bulky polyhedral oligomeric silsesquioxane (POSS) cages to a tetrahedral perylene bisimide (PBI) scaffold. Self-assembly of these giant tetrahedra is mediated by π-π interaction between the tetrahedral PBI-based scaffolds and their overall tetrahedral symmetry. A monolithic nearly centimeter-sized hexagonal supramolecular structure was observed in the giant tetrahedron with short flexible linkers between PBI and POSS cages, while a micrometer-sized crystalline helical structure formed in that with completely rigid aromatic linkers. Their significant difference in electrical conductivity could be explained by two completely different packing models of the giant tetrahedra.

Characterizing the interaction between methyl ferulate and human serum albumin by saturation transfer difference NMR.

Methyl ferulate (MF) is an alkyl ferulate ester that widely exists in edible plants and has application value in the food and medicine industries. Thus, its effect on biological macromolecules should be considered. In this study, we exploit saturation transfer difference NMR (STD-NMR) to characterize the interaction of all protons of MF with human serum albumin (HSA) at the molecular level. STD-NMR and K a (1.298 × 103 M-1) revealed that protons H1-6 and H8 bound to HSA with a medium affinity. Binding epitope mapping further showed that the aromatic ring played a key role in the HSA-MF interaction. STD-NMR site-marker-displacement experiments and circular dichroism spectroscopy revealed that MF prefered to bind to site II of HSA without changing the basic skeleton of HSA. Computer simulations confirmed these experimental results. Overall, this work elucidates the molecular level interaction of MF with HSA and provides new insights into the possibility of the potential applications of MF in the food and medicine industries.

Preparation of a carboxymethyl ß-cyclodextrin polymer and its rapid adsorption performance for basic fuchsin.

The presence of dyes in a water system has potential adverse effects on the ecological environment. The conventional cyclodextrin (CD) polymer only has CD cavities as adsorption sites and exhibits slow adsorption for dye removal. In this study, we designed a novel carboxymethyl ß-CD polymer (ß-CDP-COOH). The structural properties of ß-CDP-COOH were characterized as an irregular cross-linked polymer with negative surface charge, and the introduction of carboxymethyl groups greatly enhanced the adsorption ability of the ß-CD polymer to basic fuchsin (BF). The maximum removal efficiency of ß-CDP-COOH (96%) could be achieved within 1 min, whereas that of conventional ß-CD polymer (70%) was achieved after 50 min. The adsorption mechanism revealed that the adsorption behavior of ß-CDP-COOH could be effectively fitted with the pseudo-second-order kinetic model and Langmuir isotherm. Both CD cavities and carboxymethyl groups were effective adsorption sites, so ß-CDP-COOH had an advantage in adsorption capacity over the conventional ß-CD polymer. This study indicated that ß-CDP-COOH is a potential highly efficient adsorbent for the removal of cationic dye contaminants.

Insights into protein recognition for γ-lactone essences and the effect of side chains on interaction via microscopic, spectroscopic, and simulative technologies.

The binding properties between γ-lactone essences and HSA were investigated to explore interactional mechanism and influence of ligand side chains on binding via computer simulations, microscopy, and multiple-spectroscopies. Docking and molecular dynamics presented protein recognition mode with low fluctuations. NMR analysis revealed that the lactone ring of ligands was the main group bound to HSA. UV-vis and lifetime results revealed that the combination was static quenching mechanism with binding constants of 102-103 L/mol. FTIR and CD spectra showed conformational changes in the protein secondary structure induced by ligands. Side chains affect the binding process through steric hindrance and hydrophobicity. AFM images showed the four compounds caused different effects on molecular size of HSA. In conclusion, the binding ability and the protein secondary structure changes had a positive correlation with the length of side chain. These studies are beneficial for understanding the safety and biological action of γ-lactone essences.

Mechanism and structure studies of cinnamaldehyde/cyclodextrins inclusions by computer simulation and NMR technology.

This work aims to explore the inclusion mechanism and structure of cinnamaldehyde (CNMA) and cyclodextrins (CDs), and to provide some theoretical information for the application of CNMA and its inclusion. In this study, we prepared three kinds of inclusion and investigated the mechanism and structure by theory and experiment. Molecular docking and dynamical simulations presented a stable 1:1 inclusion complex and the visual structure model. The structural features indicated that the benzene ring of CNMA was enclosed in the hydrophobic cavity of CDs, which were consistent with the results of 1H NMR, 2D-ROESY, Fourier transform infrared spectroscopy. The inclusion mechanism studies showed that the inclusion process was driven mainly by enthalpy with the binding constant following the order of DM (dimethyl) > HP (hydroxypropyl) > ß-CD. Moreover, the inclusion complex showed an advantageous water solubility and dissolution rate compared with CNMA.

Studies of the binding properties of the food preservative thiabendazole to DNA by computer simulations and NMR relaxation.

Thiabendazole (TBZ) is a commonly used food preservative and has a wide range of anthelmintic properties. In this study, computer simulations and experiments were conducted to investigate the interaction mechanism of TBZ and herring sperm DNA (hsDNA) at the molecular level. Molecular docking showed that TBZ interacted with DNA in groove mode and bound in A-T and C-G base pair regions. Molecular dynamics (MD) was used to evaluate the stability of the TBZ-DNA complex and found that the three phases in MD and the hydrogen bonds helped maintain the combination. NMR relaxation indicated that TBZ had a certain affinity to hsDNA with a binding constant of 462.43 L mol-1, and the thiazole ring was the main group bound with DNA. Results obtained from fluorescence experiments showed that the binding of TBZ and hsDNA was predominantly driven by enthalpy through a static quenching mechanism. Circular dichroism and viscosity measurements proved the groove binding mode. The FTIR results clarified the conformational changes of DNA, that the DNA helix became shorter and compact, and the DNA structure transformed from B-form to A-form.

Interaction mechanism of olaparib binding to human serum albumin investigated with NMR relaxation data and computational methods.

The interaction mechanism between olaparib (OLA) and human serum albumin (HSA) has been investigated using experimental and computational techniques. An NMR relaxation approach based on the analysis of proton selective and non-selective spin-lattice relaxation rates at different temperatures can provide quantitative information about the affinity index and the thermodynamic equilibrium constant of the OLA-HSA system. The affinity index and the thermodynamic equilibrium constant decreased as temperature increased, indicating that the interactions between OLA and HSA could be weakened as temperature increased. Molecular docking and dynamics simulations revealed that OLA stably bound to subdomain II (site 1), and OLA could induce the conformational and micro-environmental changes in HSA. CD results suggested that α-helix content decreased after OLA was added, demonstrating that OLA affected the secondary structure of HSA.

Effect of milling conditions on solid-state amorphization of glipizide, and characterization and stability of solid forms.

In this study, the amorphization of glipizide was systematically investigated through high-energy ball milling at different temperatures. The results of solid-state amorphization through milling indicated that glipizide underwent direct crystal-to-glass transformation at 15 and 25°C and crystal-to-glass-to-crystal conversion at 35°C; hence, milling time and temperature had significant effects on the amorphization of glipizide, which should be effectively controlled to obtain totally amorphous glipizide. Solid forms of glipizide were detailedly characterized through analyses of X-ray powder diffraction, morphology, thermal curves, vibrational spectra, and solid-state nuclear magnetic resonance. The physical stability of solid forms was investigated under different levels of relative humidity (RH) at 25°C. Forms I and III are kinetically stable and do not form any new solid-state forms at various RH levels. By contrast, Form II is kinetically unstable, undergoing direct glass-to-crystal transformation when RH levels higher than 32.8%. Therefore, stability investigation indicated that Form II should be stored under relatively dry conditions to prevent rapid crystallization. High temperatures can also induce the solid-state transformation of Form II; the conversion rate increased with increasing temperature.

Effect of preparation processes and structural insight into the supermolecular system: Bisacodyl and ß-cyclodextrin inclusion complex.

In this study, ß-cyclodextrin (ß-CD) and bisacodyl were chosen as model host and guest molecule to explore the effect of preparation processes on the physicochemical properties of inclusion complexes (ICs) and to gain an insight into the structure of ICs. The influence of temperature and pH on complexation was studied by multiple temperature-pH phase solubility analysis. The most favorable conformation was predicted by molecular modeling using AutoDock. (1)H nuclear magnetic resonance and rotating frame nuclear Overhauser effect spectroscopy further confirmed the structure. Moreover, bisacodyl · ß-CD ICs in solid state were successfully prepared via three different procedures (co-crystallization, co-evaporation, and co-grinding) and fully characterized by several solid-state techniques, namely, Fourier transform infrared spectroscopy, X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, solid-state NMR spectroscopy, and scanning electron microscopy. It was found that acid solution and low temperature were unfavorable for formation of bisacodyl · ß-CD. The pyridine moiety was suggested to be enclosed in the hydrophobic cavity of ß-CD. The complexes prepared using co-crystallization showed properties similar to those prepared using co-evaporation. Moreover, ICs obtained by co-evaporation and co-grinding had higher loading efficiency, water solubility, and dissolution rate than ICs obtained by co-crystallization.

Two solid forms of tauroursodeoxycholic acid and the effects of milling and storage temperature on solid-state transformations.

Two phase-pure solid forms of tauroursodeoxycholic acid (TUDCA) were prepared and characterized by thermal analysis, vibrational spectroscopy, X-ray diffraction, solid-state nuclear magnetic resonance, and morphological analysis. All solid forms can be produced from solvents and also can be obtained by mechanically and non-mechanically activated polymorph conversion. Near-infrared (NIR) spectroscopy, in combination with chemometrical techniques, was used for the quantitative monitoring of the polymorph conversion of TUDCA in milling process and at different storage temperatures. The NIR spectra in the range of 7139-5488 cm(-1) were considered for multivariate analysis. Results demonstrated that the NIR multivariate chemometric model can predict the percentage of crystal and amorphous TUDCA with the correlation coefficient of 0.9998, root mean square error of calibration of 0.740%, root mean square error of prediction of 0.698%, and root mean square error of cross-validation of 1.49%. In the milling process of crystal TUDCA (Form I), a direct transformation from crystal to glass was observed in 4h. Moreover, the impact of different storage temperatures on the stability of amorphous TUDCA was investigated, and the rate of polymorph transformation was found to be accelerated with increasing temperature.

Aggregate of nanoparticles: rheological and mechanical properties.

The understanding of the rheological and mechanical properties of nanoparticle aggregates is important for the application of nanofillers in nanocompoistes. In this work, we report a rheological study on the rheological and mechanical properties of nano-silica agglomerates in the form of gel network mainly constructed by hydrogen bonds. The elastic model for rubber is modified to analyze the elastic behavior of the agglomerates. By this modified elastic model, the size of the network mesh can be estimated by the elastic modulus of the network which can be easily obtained by rheology. The stress to destroy the aggregates, i.e., the yield stress (σy), and the elastic modulus (G') of the network are found to be depended on the concentration of nano-silica (ϕ, wt.%) with the power of 4.02 and 3.83, respectively. Via this concentration dependent behavior, we can extrapolate two important mechanical parameters for the agglomerates in a dense packing state (ϕ = 1): the shear modulus and the yield stress. Under large deformation (continuous shear flow), the network structure of the aggregates will experience destruction and reconstruction, which gives rise to fluctuations in the viscosity and a shear-thinning behavior.