Computational Procedure for Analysis of Crystallites in Polycrystalline Solids of Quasilinear Molecules.

In the current work, a comprehensive procedure for structural analysis of quasilinear organic molecules arranged in a polycrystalline sample generated by molecular dynamics is developed. A linear alkane, hexadecane, is used as a test case because of its interesting behavior upon cooling. Instead of a direct transition from isotropic liquid to the solid crystalline phase, this compound forms first a short-lived intermediate state known as a "rotator phase". The rotator phase and the crystalline one are distinguished by a set of structural parameters. We propose a robust methodology to evaluate the type of ordered phase obtained after a liquid-to-solid phase transition in a polycrystalline assembly. The analysis starts with the identification and separation of the individual crystallites. Then, the eigenplane of each of them is fit and the tilt angle of the molecules relative to it is computed. The average area per molecule and the distance to the nearest neighbors are estimated by a 2D Voronoi tessellation. The orientation of the molecules with respect to each other is quantified by visualization of the second molecular principal axis. The suggested procedure may be applied to different quasilinear organic compounds in the solid state and to various data compiled in a trajectory.

Computational assessment of hexadecane freezing by equilibrium atomistic molecular dynamics simulations.

HYPOTHESIS: Upon cooling, alkanes can form intermediate phases between liquid and crystal. They are called "rotator" or "plastic" phases and have long-range positional order with rotational freedom around the long molecular axis which gives them non-trivial and useful visco-plastic properties. We expect that the formation and structure of rotator phases formed in freezing alkanes can be understood much deeper by tracking the process at molecular level with atomistic molecular dynamics. SIMULATIONS: We defined an appropriate CHARMM36-based computational protocol for simulating the freezing of hexadecane, which contained a sufficiently long (500 ns) equilibrium sampling of the frozen states. We employed it to simulate successfully the freezing of bulk and interface-contacting hexadecane and to provide a pioneering clarification of the effect of surfactant on the crystallization mechanism and on the type of intermolecular ordering in the crystallites. FINDINGS: The devised computational protocol was able to reproduce the experimentally observed polycrystalline structure formed upon cooling. However, different crystallization mechanisms were established for the two types of models. Crystallites nucleate at random locations in the bulk and start growing rapidly within tens of nanoseconds. In contrast, the surfactants freeze first during the fast cooling (<1 ns), followed by rapid hexadecane freezing, with nucleation starting along the entire surfactant adsorption layer. Thereby, the hexadecane molecules form rotator phases which transition into a more stable ordered phase. This collective transition is first-time visualized directly. The developed robust computational protocol creates a foundation for future in-depth modelling and analysis of solid-state alkane-containing, incl. lipid, structures.

Structure and Undulations of Escin Adsorption Layer at Water Surface Studied by Molecular Dynamics.

The saponin escin, extracted from horse chestnut seeds, forms adsorption layers with high viscoelasticity and low gas permeability. Upon deformation, escin adsorption layers often feature surface wrinkles with characteristic wavelength. In previous studies, we investigated the origin of this behavior and found that the substantial surface elasticity of escin layers may be related to a specific combination of short-, medium-, and long-range attractive forces, leading to tight molecular packing in the layers. In the current study, we performed atomistic molecular dynamics simulations of 441 escin molecules in a dense adsorption layer with an area per molecule of 0.49 nm2. We found that the surfactant molecules are less submerged in water and adopt a more upright position when compared to the characteristics determined in our previous simulations with much smaller molecular models. The number of neighbouring molecules and their local orientation, however, remain similar in the different-size models. To maintain their preferred mutual orientation, the escin molecules segregate into well-ordered domains and spontaneously form wrinkled layers. The same specific interactions (H-bonds, dipole-dipole attraction, and intermediate strong attraction) define the complex internal structure and the undulations of the layers. The analysis of the layer properties reveals a characteristic wrinkle wavelength related to the surface lateral dimensions, in qualitative agreement with the phenomenological description of thin elastic sheets.

Development and evaluation of doxycycline niosomal thermoresponsive in situ gel for ophthalmic delivery.

The present study was focused on the development of doxycycline niosomal thermosensitive in situ gel for ophthalmic application. For this purpose, in situ gel formulations based on Poloxamer 407 alone and in combination with hydroxypropyl methylcellulose were prepared by cold method and evaluated in terms of sol-gel transition temperature, gelling time and capacity. The addition of hydroxypropyl methylcellulose to the composition led to decrease in the phase transition temperature of the systems. Conversely, the inclusion of doxycycline niosomes to the formulations didn''t have a significant influence on their gelling and rheological properties. Doxycycline niosomal in situ gel based on 15%w/w Poloxamer and 1.5% w/w hydroxypropyl methylcellulose was characterized with gelation temperature of 34 °C, appropriate for ophthalmic application, pseudoplastic flow behavior and very good physical stability. In vitro release studies indicated slower and sustained doxycycline release from the developed in situ gel as compared to niosomes. The conducted microbiological studies revealed its enhanced antibacterial activity with respect to doxycycline solution and doxycycline in situ gel. The obtained results indicate that the elaborated niosomal in situ gel may serve as a promising system for ophthalmic delivery of doxycycline, ensuring sufficient therapeutic concentration and sustained drug release.

Origin of the extremely high elasticity of bulk emulsions, stabilized by Yucca Schidigera saponins.

We found experimentally that the elasticity of sunflower oil-in-water emulsions (SFO-in-W) stabilized by Yucca Schidigera Roezl saponin extract, is by >50 times higher as compared to the elasticity of common emulsions. We revealed that strong specific interactions between the phytosterols from the non-purified oil and the saponins from the Yucca extract lead to the formation of nanostructured adsorption layers which are responsible for the very high elasticity of the oil-water interface and of the respective bulk emulsions. Remarkably, this extra high emulsion elasticity inhibits the emulsion syneresis even at 65 vol% of the oil drops - these emulsions remain homogeneous and stable even after 30 days of shelf-storage. These results demonstrate that the combination of saponin and phytosterols is a powerful new approach to structure oil-in-water emulsions with potential applications for formulating healthier functional food.

Role of interfacial elasticity for the rheological properties of saponin-stabilized emulsions.

HYPOTHESIS: Saponins are natural surfactants which can provide highly viscoelastic interfaces. This property can be used to quantify precisely the effect of interfacial dilatational elasticity on the various rheological properties of bulk emulsions. EXPERIMENTS: We measured the interfacial dilatational elasticity of adsorption layers from four saponins (Quillaja, Escin, Berry, Tea) adsorbed on hexadecane-water and sunflower oil-water interfaces. In parallel, the rheological properties under steady and oscillatory shear deformations were measured for bulk emulsions, stabilized by the same saponins (oil volume fraction between 75 and 85%). FINDINGS: Quillaja saponin and Berry saponin formed solid adsorption layers (shells) on the SFO-water interface. As a consequence, the respective emulsions contained non-spherical drops. For the other systems, the interfacial elasticities varied between 2 mN/m and 500 mN/m. We found that this interfacial elasticity has very significant impact on the emulsion shear elasticity, moderate effect on the dynamic yield stress, and no effect on the viscous stress of the respective steadily sheared emulsions. The last conclusion is not trivial, because the dilatational surface viscoelasticity is known to have strong impact on the viscous stress of steadily sheared foams. Mechanistic explanations of all observed effects are described.

Structure of Dense Adsorption Layers of Escin at the Air-Water Interface Studied by Molecular Dynamics Simulations.

Saponins are natural surfactants with high surface activity and unique surface properties. Escin is a triterpenoid saponin which has unusually high surface viscoelasticity [Golemanov et al. Soft Matter 2013, 9, 5738] and low permittivity to molecular gas diffusion of its adsorption layers. In our previous study [Tsibranska et al. Langmuir 2017, 33, 8330], we investigated the molecular origin of this unconventional behavior and found that escin molecules rapidly assemble in a compact and stable surface cluster. This behavior was explained with long-range attraction between the hydrophobic aglycones combined with intermediate dipole-dipole attraction and strong short-range hydrogen bonds between the sugar residues in the adsorbed escin molecules. In this study, we performed atomistic molecular simulations of escin molecules in dense adsorption layers with two different areas per molecule. The results show that the surfactant molecules in these systems are much less submerged in water and adopt a more upright position compared to the dilute layers studied previously. A significant number of trapped water molecules are located around the hydrophilic groups placed above the water equimolecular surface to solvate them in the dense layer. To maintain the preferred orientation of the escin molecules with respect to the interface, the most compact adsorption layer acquires a significant spontaneous curvature. The substantial elasticity of the neutral escin layers, as in our previous study, is explained with the presence of a specific interaction, which is intermediate between hydrogen bonding and dipole-dipole attraction (populated lengths in the range 0.16 to >0.35 nm), supplemented by substantial flexibility of the surfactant heads, optimal curvature of the interface, and significant normal displacement of the molecules to allow their tight surface packing. The simulations reveal long-range order within the layers, which signifies the role of the collective behavior of the saponin molecules in such dense adsorption layers.

Self-Assembly of Escin Molecules at the Air-Water Interface as Studied by Molecular Dynamics.

Escin belongs to a large class of natural biosurfactants, called saponins, that are present in more than 500 plant species. Saponins are applied in the pharmaceutical, cosmetics, and food and beverage industries due to their variously expressed bioactivity and surface activity. In particular, escin adsorption layers at the air-water interface exhibit an unusually high surface elastic modulus (>1100 mN/m) and a high surface viscosity (ca. 130 N·s/m). The molecular origin of these unusual surface rheological properties is still unclear. We performed classical atomistic dynamics simulations of adsorbed neutral and ionized escin molecules to clarify their orientation and interactions on the water surface. The orientation and position of the escin molecules with respect to the interface, the intermolecular interactions, and the kinetics of molecular aggregation into surface clusters are characterized in detail. Significant differences in the behavior of the neutral and the charged escin molecules are observed. The neutral escin rapidly assembles in a compact and stable surface cluster. This process is explained by the action of long-range attraction between the hydrophobic aglycones, combined with intermediate dipole-dipole attraction and short-range hydrogen bonds between the sugar residues in escin molecules. The same interactions are expected to control the viscoelastic properties of escin adsorption layers.