Solubilization of poorly water-soluble drugs in human intestinal fluids influences oral absorption and is linked to food effects. Current empirical equations for calculating intestinal solubilization via lipophilicity are built on limited data and do not adequately account for drug ionization. We aim to expand the data set and build a model to clarify the link between lipophilicity and solubilization for charged compounds. We determined the aqueous solubility, octanol–water partition coefficient, and solubilization in fed-state simulated intestinal fluids (FeSSIF) of 26 hydrophobic drugs. Combined with literature data, a good correlation (R2 = 0.74, n = 198) between intestinal solubilization and LogP/D was observed. However, data segregation showed that the solubilization of neutral compounds correlated very well with LogP (R2 = 0.89, n = 114), whereas the correlation with LogD was lost for the charged compounds (R2 = 0.40, n = 84). To better understand this behavior, the pH of FeSSIF was varied to study the solubilization of the same compounds in the neutral and charged states. While a very good correlation between solubilization and LogD was observed in the neutral state of the compounds (R2 = 0.92, n = 8), the correlation was again lost (R2 = 0.02, n = 4) in their charged state. Electrostatic interactions were suggested to play a key role in the unexpectedly low solubilization of anionic drugs and in the phase separation observed for cationic drugs. The presented insights further advance the understanding of the solubilization of hydrophobic drugs in biorelevant media and provide a foundation for broader and improved modeling approaches.

Phase behavior of lipids is of primary importance for the manufacturing and applications of foods, cosmetics and pharmaceuticals, as well as for the functions of biological membranes. Upon cooling, the molten bulk lipids crystallize into ordered domains which determine their rheological properties. While storage and loss moduli are typically used to describe these properties, their direct connection to the underlying molecular rearrangement remains poorly understood. In the current study, we performed a detailed rheological characterization of the rotator phases (intermediate phases between fully ordered crystalline and completely disordered liquid phases) formed in bulk linear alkanes. Large series of stress-relaxation and creep-recovery experiments were performed and interpreted, using generalized Kelvin-Voigt model with one spring, connected in series with three combined elements of a spring and a dashpot. We determined the elasticities and viscosities of all these rheological elements, along with the respective three relaxation times of the combined elements. These relaxation times are governed by different molecular processes in the sheared samples and differ by three orders of magnitude: t1 ≈ 0.45 s and t2 ≈ 8–9 s are related to local molecular rearrangements at the domain boundaries, while t3 ≈ 140–200 s most probably describes the rearrangement of disordered lipid molecules entrapped between the ordered domains. The storage and loss moduli, calculated from the constants of the generalized Kelvin-Voigt model, were in a very good agreement with those measured directly in amplitude sweep and temperature ramps oscillatory tests, thus supporting the self-consistency of data interpretation. The methodology presented here is applicable to other polycrystalline lipid materials with 2D or 3D domain structures, providing a valuable framework for interpreting their rheological behavior.

The behavior of a fenofibrate aggregate in water and its interaction with pure sodium taurodeoxycholate (TDC) micelles, as well as with mixed micelles of TDC and fatty acids (myristic, oleic, and stearic), was studied using atomistic molecular dynamics simulations. For each system, 500 ns trajectories were generated and analyzed in terms of the association of amphiphiles around the drug aggregate and their impact on the morphology and intermolecular interactions of the drug molecules. The results show that in the absence of fatty acids TDC covers the surface of the drug aggregate, shielding it from water without disrupting its structure. In contrast, all studied fatty acids intercalate between the drug molecules in the aggregate. However, myristic and stearic acids do not shield sufficiently the drug molecules from water, while oleic acid significantly reduces the contact between water and drug molecules. Two key requirements for effective solubilization are identified: (1) the ability of amphiphiles to disrupt the nanostructure of the drug aggregate, and (2) the flexibility and capability of amphiphiles to reduce interactions between water and hydrophobic drug molecules. These requirements were used to evaluate the efficiency of fatty acids in increasing the solubilization capacity of TDC micelles. A very good correlation was established between the efficiency determined from molecular dynamics simulations and experimental data known from the literature. The methodology developed in this study could be widely used to compare the efficiency of new lipid-based drug delivery formulations to solubilize hydrophobic drug molecules.

Escin is a triterpenoid saponin with one carboxyl group which is non-ionized at pH 4.7. The major aim of the current study is to determine how the electrolyte concentration affects the properties of concentrated escin solutions (5 wt% and 10 wt%) at pHs of 4, 6, and 8. Ionized escin molecules at pH >4.7 form charged micelles that repel one another when there is no added electrolyte and solutions remain clear and stable for more than a month. Lowering the pH to 4 leads to formation of uncharged micelles. These micelles attract each other and form inter-micellar hydrogen bonds, which enable formation of micrometer aggregates that cause turbidity and phase separation. The addition of background electrolytes to the solutions at pHs of 6 and 8 screens the electrostatic repulsion between micelles, causing partial aggregation of the micelles and gelation of solutions. As the salt concentration increases, the viscosity of the escin solution also increases, reaching a maximum—similar to the behavior observed with conventional surfactants. However, the mechanism behind this viscosity maximum is different. In solutions of conventional surfactants, the maximum is due to the formation of worm-like micelles, whereas the maximum for escin solutions is due to formation of a network of escin aggregates that imparts yield stress and elasticity to the solution. These dispersions remain stable for at least one month at room temperature and can be used as cosmetic and detergent formulations.

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.