Sugar esters, a class of surfactants derived from renewable resources, have attracted significant attention due to their biodegradability, low toxicity, and broad applications in food, cosmetic, and pharmaceutical formulations. Despite their widespread use, the phase behavior of these compounds in aqueous systems remains incompletely understood. In this study, we investigate the self-assembly of a nonionic sucrose ester of lauric acid in 1–40 wt% concentration range using rheological measurements, dynamic light scattering, X-ray scattering, DOSY NMR, and molecular dynamics simulations. Formation of spherical micelles with a diameter of 5.4 nm is observed at low surfactant concentrations, driven by hydrophobic interactions between the alkyl tails. These solutions exhibit Newtonian flow behavior with viscosities close to that of pure water. However, the viscosity increases from 5 mPa.s at 16 wt% to 640 mPa.s at 40 wt%, while the Newtonian character persists even at 40 wt%. This behavior is explained with the formation of interconnected, thread-like micellar structures of (almost) spherical micelles that largely preserve their distinctiveness, resembling the “pearl necklace” arrangement known for polymer systems. The main driving force for this supramolecular organization was found to be the hydrogen bonding between sucrose headgroups. The addition of 6 M urea, a known hydrogen bond disruptor, significantly reduces micelle clustering and the viscosity decreases to 150 mPa.s at 40 wt% concentration, supporting the proposed aggregation mechanism. These findings contribute to a deeper understanding of the self-assembly behavior of sucrose esters in aqueous environment and highlight their potential for controlled aggregation in practical formulations.

Hypothesis
Solubilization is a fundamental process that underpins various technologies in the pharmaceutical and chemical industry. However, knowledge of the location, orientation and interactions of solubilized molecules in the micelles is still limited. We expect all-atom molecular dynamics simulations to improve the molecular-level understanding of solubilization and to enable its in silico prediction.
Methods
The solubilization of six drugs in intestinal mixed micelles composed of taurocholate and dioleoyl phosphatidylcholine was simulated by molecular dynamics in explicit water and measured experimentally by liquid chromatography. The location and orientation of the solubilized drugs were visualized by cumulative radial distribution functions and interactions were characterized by radial distribution function ratios and hydrogen bonding.
Findings
A new simulation-derived parameter was defined, which accounts for drug-micelle and drug-water interactions and correlates (R2 = 0.83) with the experimentally measured solubilization. Lipophilicity was found to govern the location of all drugs in the micelle (hydrophobic core, palisade layer or on the surface), while hydrogen bonding was crucial for orientation and solubilization of two of the molecules. The study demonstrates that explicit, hydrogen bond-forming water molecules are vital for accurate prediction of solubilization and provides a comprehensive framework for quantitative studies of drug location and orientation within the micelles.

Micelles formed by bile salts in aqueous solution are important for the solubilization of hydrophobic molecules in the gastrointestinal tract. The molecular level information about the mechanism and driving forces for primary-to-secondary micelle transition is still missing. In the current study, the micelle formation of 50 mM solutions of taurodeoxycholate (TDC) is studied by atomistic molecular dynamics simulations. It is shown that primary micelles with an aggregation number of 8-10 emerge and persist within the first 50 ns. Then, they coalesce to form secondary micelles with an aggregation number of 19 molecules. This transition is governed by hydrophobic interactions, which significantly decrease the solvent-accessible surface area per molecule in the secondary micelles. The addition of monomers of the sodium salt of fatty acids (FAs), as agents aiding hydrophobic drug delivery, to secondary TDC micelles results in the co-existence of mixed FA-TDC and pure FA micelles. The studied saturated FAs, with chain lengths of C14:0 and C18:0, are incorporated into the micelle core, whereas TDC molecules position themselves around the FAs, forming a shell on the micelle surface. In contrast, the tails of the C18:1 unsaturated fatty acid mix homogeneously with TDC molecules throughout the entire micelle volume. The latter creates a very suitable medium for hosting hydrophobic molecules in the micelles containing unsaturated fatty acids.

In our previous study (Mustan et al. 2021) we showed that foams formed from two oil-soluble nonionic surfactants (Span 60 and Brij 72) can remain stable for more than 10 days at room temperature at high sugar concentration. The major aim of the current study is to reveal the interrelation between the surfactant structure and foam stability by investigating 6 polyoxyethelene alkyl ethers and 12 fatty acid esters with a wide variety of hydrophobic chain lengths (C12; C16; C18 and C18:1) and hydrophilic head-groups (sorbitol, glycerol, sucrose). Foams stable for more than 100 days at room temperature are obtained when sucrose palmitate or stearate (P1670 or S1670) are used as surfactants. This exceptional foam stability is related to the gelation of the aqueous phase and to the formation of solid adsorption layer with zero surface tension upon compression, thus preventing water drainage and decelerating the bubble Ostwald ripening. The foam stability decreases with (i) increasing the number of EO groups in polyoxyethylene alkyl ethers and in fatty acid sorbitan esters; (ii) decreasing the number of C-atoms in the surfactant tail for all studied surfactants; (iii) addition of double bond in the surfactant tail. The lower foam stability in all three cases is related to the worse packing of the surfactant molecules within the adsorption layer, leading to faster Ostwald ripening and subsequent bubble coalescence. The diesters present as admixture in the fatty acid esters play an important role in the foam stabilization by further compacting the adsorption layers and lowering the rate of Ostwald ripening. These conclusions can be used as a predictive tool for surfactant selection in the development of food or pharmaceutical foam concentrates that can be diluted before final use.

The surface and foam properties of two oil-soluble surfactants, Span 60 and Brij 72, and two water-soluble surfactants, Tween 60 and Brij S20, are compared. Aqueous surfactant solutions containing sugar at high concentration (63 wt%) are also studied in the context of sweet food-related foams. The experimental results show that foams with very small bubbles of ca. 5 µm are formed and remain stable for more than 10 days at room temperature when oil-soluble surfactants are dispersed in the sugar-rich solutions. The excellent stability of these foams is related to (1) The multilamellar vesicles present in the respective surfactant dispersions which increase the viscosity and decrease the rate of water drainage from the foam; (2) The very slow exchange of surfactant molecules between the interface and the adjacent aqueous solution that leads to very significant difference in the surface tension of shrinking and expanding bubbles, which in turn decreases the rate of bubble Ostwald ripening. The foams formed from Span 60 are more stable as compared to the foams formed from Brij 72, due to the higher viscosity and the slower interface-solution exchange. The foams formed from Brij S20 solutions are least stable – they are completely destroyed after 1 day at room temperature, even in the presence of sugar. The main conclusion of this study is that oil soluble surfactants can form condense adsorption layers on the bubble surfaces after adsorption from aqueous solutions with and without sugar in it. The formed layers, which present a better molecular packing, reduce the gas permeability and decelerate the Ostwald ripening disproportionation of the foam This is obtained by a relatively low interfacial tension imparted by continuous shrinkage and expansion of bubbles during foam generation, ultimately ensuring long-term stabilization of formed foams.