Structural and Spectroscopic Characterization of TPGS Micelles: Disruptive Role of Cyclodextrins and Kinetic Pathways

The aggregation and structure of d-α-tocopheryl polyethylene glycol succinate micelles, TPGS-1000, an amphiphilic derivative of vitamin E, were characterized using scattering and spectroscopic methods, and the impact of different cyclodextrins (CDs) on the self-assembly was investigated, with the view of combining these two versatile pharmaceutical excipients in drug formulations. Combined small-angle neutron scattering (SANS), dynamic light scattering, and time-resolved and steady-state fluorescence emission experiments revealed a core–shell architecture with a high aggregation number (<i>N</i>_agg ≈ 100) and a highly hydrated poly­(ethylene oxide) corona (∼11 molecules of solvent per ethylene oxide unit). Micelles form gradually, with no sharp onset. Structural parameters and hydration of the aggregates were surprisingly stable with both temperature and concentration, which is a critical advantage for their use in pharmaceutical formulations. CDs were shown to affect the self-assembly of TPGS in different ways. Whereas native CDs induced the precipitation of a solid complex (pseudopolyrotaxane), methylated β-CDs led to different outcomes: constructive (micellar expansion), destructive (micellar rupture), or no effect, depending on the number of substituents and whether the substitution pattern was regular or random on the rims of the macrocycle. Time-resolved SANS studies on mixtures of TPGS with regularly dimethylated β-CD (DIMEB), which ruptures the micelles, revealed an almost instantaneous demicellization (<100 ms) and showed that the process involved the formation of large aggregates whose size evolved over time. Micellar rupture is caused by the formation of a TPGS–DIMEB inclusion complex, involving the incorporation of up to three macrocycles on the tocopherol, as shown by proton nuclear magnetic resonance (NMR) and ROESY NMR. Analysis of NMR data using Hill’s equation revealed that the binding is rather cooperative, with the threading of the CD favoring the subsequent inclusion of additional CDs on the aliphatic moiety

Remarkable Viscoelasticity in Mixtures of Cyclodextrins and Nonionic Surfactants

We report the effect of native cyclodextrins (α, β, and γ) and selected derivatives in modulating the self-assembly of the nonionic surfactant polyoxyethylene cholesteryl ether (ChEO₁₀) and its mixtures with triethylene glycol monododecyl ether (C₁₂EO₃), which form wormlike micelles. Cyclodextrins (CDs) generally induce micellar breakup through a host–guest interaction with surfactants; instead, we show that a constructive effect, leading to gel formation, is obtained with specific CDs and that the widely invoked host–guest interaction may not be the only key to the association. When added to wormlike micelles of ChEO₁₀ and C₁₂EO₃, native β-CD, 2-hydroxyethyl-β-CD (HEBCD), and a sulfated sodium salt of β-CD (SULFBCD) induce a substantial increase of the viscoelasticity, while methylated CDs rupture the micelles, leading to a loss of the viscosity, and the other CDs studied (native α- and γ- and hydroxypropylated CDs) show a weak interaction. Most remarkably, the addition of HEBCD or SULFBCD to pure ChEO₁₀ solutions (which are low-viscosity, Newtonian fluids of small, ellipsoidal micelles) induces the formation of transparent gels. The combination of small-angle neutron scattering, dynamic light scattering, and cryo-TEM reveals that both CDs drive the elongation of ChEO₁₀ aggregates into an entangled network of wormlike micelles. ¹H NMR and fluorescence spectroscopy demonstrate the formation of inclusion complexes between ChEO₁₀ and methylated CDs, consistent with the demicellization observed. Instead, HEBCD forms a weak complex with ChEO₁₀, while no complex is detected with SULFBCD. This shows that inclusion complex formation is not the determinant event leading to micellar growth. HEBCD:ChEO₁₀ complex, which coexists with the aggregated surfactant, could act as a cosurfactant with a different headgroup area. For SULFBCD, intermolecular interactions via the external surface of the CD may be more relevant

Using Inclusion Complexes with Cyclodextrins To Explore the Aggregation Behavior of a Ruthenium Metallosurfactant

The aggregation behavior of a chiral metallosurfactant, bis­(2,2′-bipyridine)­(4,4′-ditridecyl-2,2′-bipyridine)­ruthenium­(II) dichloride (Ru₂⁴C₁₃), synthesized as a racemic mixture was characterized by small-angle neutron scattering, light scattering, NMR, and electronic spectroscopies. The analysis of the SANS data indicates that micelles are prolate ellipsoids over the range of concentrations studied, with a relatively low aggregation number, and the micellization takes place gradually with increasing concentration. The presence of cyclodextrins (β-CD and γ-CD) induces the breakup of the micelles and helps to establish that micellization occurs at a very slow exchange rate compared to the NMR time scale. The open structure of this metallosurfactant enables the formation of very stable complexes of 3:1 stoichiometry, in which one CD threads one of the hydrocarbon tails and two CDs the other, in close contact with the polar head. The complex formed with β-CD, more stable than the one formed with the wider γ-CD, is capable of resolving the Δ and Λ enantiomers at high CD/surfactant molar ratios. The chiral recognition is possible due to the very specific interactions taking place when the β-CD coversvia its secondary rimpart of the diimine moiety connected to the hydrophobic tails. A SANS model comprising a binary mixture of hard spheres (complex + micelles) was successfully used to study quantitatively the effect of the CDs on the aggregation of the surfactant