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Multi-injection pharmaceutical products such as insulin must be formulated to prevent aggregation and microbial contamination. Small-molecule preservatives and nonionic surfactants such as poloxamer 188 (P188) are thus often employed in protein drug formulations. However, mixtures of preservatives and surfactants can induce aggregation and even phase separation over time, despite the fact that all components are well dissolvable when used alone in aqueous solution. A systematic study is conducted here to understand the phase behavior and morphological causes of aggregation of P188 in the presence of the preservatives phenol and benzyl alcohol, primarily using small-angle x-ray scattering (SAXS). Based on SAXS results, P188 remains as unimers in solution when below a certain phenol concentration. Upon increasing the phenol concentration, a regime of micelle formation is observed due to the interaction between P188 and phenol. Further increasing the phenol concentration causes mixtures to become turbid and phase-separate over time. The effect of benzyl alcohol on the phase behavior is also investigated., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Pharmacists Association. All rights reserved.)

Small angle neutron scattering (SANS) studies of a model pharmaceutical formulation reveal how formulation stability depends on the compatibility of individual components. Solutions of two common protein formulation excipients, polysorbate 80 (PS80), a nonionic surfactant that prevents aggregation, and m-cresol, an antimicrobial agent for multi-dose injectable formulations, are investigated. The addition of m-cresol to PS80 solutions leads to solution turbidity and irreversibly alters PS80 micelle morphology. This slow preservative-induced destabilization of PS80 micelles progresses over days or even weeks, which highlights the essential role that aggregation kinetics plays in preservative-surfactant interactions. The temperature-dependence of PS80 micelle growth kinetics is quantified by SANS in the presence of m-cresol. Aggregation is a two-step process, where initial formation of small aggregates is followed by a period of monotonic power-law growth, providing evidence for the mechanism. Total aggregate mass stays constant after initial aggregate formation, and addition of a pH-regulating citrate buffer dramatically accelerates aggregation kinetics., (Copyright © 2020 American Pharmacists Association®. All rights reserved.)

Surfactants are commonly used in therapeutic protein formulations in biopharmaceuticals to impart protein stability; however, their solution morphology and the role of the individual components in these structurally heterogeneous commercial grade surfactants at physiologically and pharmaceutically relevant temperatures have not been investigated systematically. The micellar morphologies of Polysorbate 20 and Polysorbate 80 and their primary components monoester fractions, as well as the diester fractions, are evaluated at 4, 22°C, 40°C, and 50°C using small-angle neutron scattering to determine the aggregation number, radius of gyration, core radius, critical micelle concentration, shell thickness, and shell hydration. The sizes and aggregation numbers of the diester fractions of PS20 above 80°C and PS80 above 50°C exhibit significant changes in shape. The analysis of the small-angle neutron scattering data of PS20 confirms that the critical micellar concentration of the monoester fraction is significantly higher at 4°C compared to the diester fraction and their original material, all-laurate PS20. Overall, these experiments identify the dominant components responsible for the temperature-dependent behavior of these surfactants in pharmaceutical protein formulations., (Copyright © 2019 American Pharmacists Association®. All rights reserved.)

Shear-induced structural transitions of a micellar cubic phase during large amplitude oscillatory shear flow is studied with time-resolved oscillatory rheological small angle neutron scattering. This technique allows us to resolve the structural changes within a cycle of oscillation. By applying a strain rate near the critical melting shear rate, melting and recrystallization occurs in a cyclic mode. The maximum degree of order is observed when the shear stress reaches a plateau value during the large amplitude oscillatory shear cycle, whereas melting is maximized at the strain rate wave peaks. This structural evolution confirms the cyclic mechanism of sticking and sliding of 2D hexagonal close-packed layers [I. W. Hamley et al., Phys. Rev. E 58, 7620 (1998)].

Although reconstitution of membrane proteins within protein detergent complexes is often used to enable their structural or biophysical characterization, it is unclear how one should rationally choose the appropriate micellar environment to preserve native protein folding. Here, we investigated model mixed micelles consisting of a nonionic glucosylated alkane surfactant from the maltoside and thiomaltoside families, bile salt surfactant, and the steryl derivative cholesteryl hemisuccinate. We correlated several key attributes of these micelles with the in vitro ligand-binding activity of hA(2)aR in these systems. Through small-angle neutron scattering and radioligand-binding analysis, we found several key aspects of mixed micellar systems that preserve the activity of hA(2)aR, including a critical amount of cholesteryl hemisuccinate per micelle, and an optimal hydrophobic thickness of the micelle that is analogous to the thickness of native mammalian bilayers. These features are closely linked to the headgroup chemistry of the surfactant and the hydrocarbon chain length, which influence both the morphology and composition of resulting micelles. This study should serve as a general guide for selecting the appropriate mixed surfactant systems to stabilize membrane proteins for biophysical analysis., (Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

We derive a statistical mechanical model for colloidal interactions mediated by polymer-like micelles (PLMs) that adsorb at the colloid surface. The model considers the end-adsorption and reversible scission of ideal chains, and is based on experimentally measurable parameters relevant to PLMs. The model predicts interparticle attractions due to micellar bridging that are stronger and longer-range than those encountered in ordinary telechelic polymers. Mapping the analytical potential onto the more familiar Double Yukawa potential allows, for the first time, accurate, a priori prediction of suspension microstructure and phase behavior when compared to experimental data for model nanoparticles dispersed in wormlike micelles over a range of solution conditions. [ABSTRACT FROM AUTHOR]

Shear banding under steady and dynamic deformation is examined using a combination of rheology and flow-small angle neutron scattering (SANS) in a model wormlike micelle solution comprised of a mixed cationic/anionic surfactant (cetyltrimethylammonium tosylate/sodium dodecyl benzene sulfonate) and sodium tosylate. Flow-vorticity plane rheo-SANS reveals long transients during shear band formation. Flowgradient plane spatially resolved flow-SANS measurements probe the microstructure during steady and dynamic shear banding. Under large amplitude oscillatory shear (LAOS) deformation, shear banding is dependent on the Deborah and Weissenberg numbers, validating recent theoretical predictions that include shear-induced breakage. Micelle segmental alignment in the flow-gradient plane during LAOS is a nonmonotonic function of cycle time, t/T, and radial position, r/H. The maximum segmental alignment under LAOS often exceeds that of the corresponding shear rate under steady shear, termed "over-orientation," which can help identify LAOS shear banding. The results of this study present new methods for identifying shear banding under steady and dynamic deformation, while providing an extensive data set for the development and further improvement of constitutive models. [ABSTRACT FROM AUTHOR]

In this work, we assess the capability of two thermodynamically consistent, microstructure-based models to predict the rheology and microstructure of a model wormlike micellar surfactant solution known to exhibit shear banding undergoing transient simple shear and large amplitude oscillatory shear deformations in a cylindrical Couette rheometer. The microstructure of the surfactant solution was simultaneously measured during the rheometric tests using small angle neutron scattering and this data is used along with the bulk rheometry to critically evaluate the models. The first model is a new, two-species model specifically developed for wormlike micelles, whereas the second model is the well-known Giesekus model with solvent and diffusion. The new model accounts for the microstructural dynamics including flow-induced micellar breakage and recombination, which is shown to be necessary to predict some of the measured rheology and microstructure. More species should be included to improve the quantitative comparison with experiments, as well as nonlinear relaxation, as judged by the success of the Giesekus model to represent certain features of the time-dependent data. More experimental research is needed to validate the role of flow-induced breakage in the nonlinear rheology of wormlike micellar surfactant solutions. [ABSTRACT FROM AUTHOR]

The rheology and shear-induced structures of a series of self-assembled surfactant wormlike micelles (WLMs) with varying levels of branching are measured using rheo- and flow-small angle neutron scattering (SANS). The degree of branching in the mixed cationic/anionic surfactant (cetyltrimethylammonium tosylate/sodium dodecyl benzene sulfonate) WLMs is controlled via the addition of the hydrotropic salt sodium tosylate and verified by cryo-transmission electron microscopy. The linear viscoelasticity of the low salt (linear) micellar solutions is well described as an extended Maxwell (Oldroyd-B) fluid, and samples exhibit shear banding under steady-shear flow. The linear viscoelasticity of more highly branched solutions deviates from Maxwellian behavior, where the plateau in G' gradually increases in slope with increasing salt content. The higher salt solutions exhibit a shear thinning regime, followed by a shear thickening regime at high shear rates. Micelle segmental alignment in the flow-gradient plane is a nonmonotonic function of salt level and radial position. Spatially resolved measurements of the segmental alignment corroborate shear banding in the linear WLMs, and the absence of shear banding with branching. Rheo-SANS measurements show that the onset of shear thickening at high rates corresponds to a structural transition. The results of this study link micellar microstructure and topology to the measured shear rheology of WLM solutions. [ABSTRACT FROM AUTHOR]

Micellar solutions of hexadecyltrimethylammonium bromide(CTAB)in a protic ionic liquid, ethylammonium nitrate (EAN), are studiedby shear rheology, polarizing optical microscopy (POM), conductivitymeasurements, and small angle neutron scattering (SANS). Three concentrationregimes are examined: A dilute regime (with concentrations [CTAB]< 5 wt %) consisting of noninteracting spherical micelles, a semidiluteregime (5 wt % ≤ [CTAB] ≤ 45 wt %) where micelles interactvia electrostatic repulsions, and a concentrated regime (45 wt % <[CTAB] ≤ 62 wt %) where a reversible, temperature-dependentisotropic (L1) to hexatic (Hex) phase transition is observed.The L1–Hex transition, which has been predictedbut not previously observed, is characterized by (1) a sharp increasein the shear viscosity, (2) the formation of focal conical birefringencetextures (observed by POM), and (3) enhancement of the crystallineorder, evidenced by the appearance of Bragg reflections in the SANSprofiles. Ionic conductivity is not sensitive to the L1–Hex transition, which corroborates the absence of topologicaltransitions. [ABSTRACT FROM AUTHOR]

Large amplitude oscillatory shear (LAOS) is an increasingly popular nonlinear rheological test method, and the interpretation of the measurements is still an active area of research. Here, we demonstrate a new method whereby the nonlinear parameters of a popular constitutive equation used to model polymeric and other viscoelastic systems, the Giesekus model, may be determined directly from LAOS measurements without complicated, nonlinear model fitting. We define the stress response of the sample as an expansion in deformation strain and oscillation frequency. To leading order in strain, we derive the explicit analytic expressions for the first three harmonics of the stress response during LAOS for the Giesekus constitutive model. This allows for rapid determination of the Giesekus model parameters, including the nonlinear coupling parameter, directly from plots of the response obtained from modern rheological instruments. We demonstrate the validity, utility, and limits of this new method on a well-studied wormlike micelle (WLM) surfactant solution, cetyltrimethylammonium bromide (CTAB), and water. This robust and simple approach is especially advantageous for systems where steady shearing in the nonlinear regime is problematic and can provide rapid determination of parameters in rheological constitutive equations. [ABSTRACT FROM AUTHOR]

We present the first combined study of spatially resolved structure and shear rheology for a model shear banding fluid comprised of cetyltrimethylammonium bromide wormlike micelles. Combining conventional rheometry, velocimetry, flow birefringence, and flow-small angle neutron scattering (flow-SANS) in the 1–2 (flow-gradient) plane of shear completely characterizes shear banding in the system and enables comparison of local flow kinematics to local segmental orientation and alignment within the bands. The Giesekus constitutive equation with stress diffusion is shown to successfully model the viscoelasticity, steady shear viscosity, and shear banding kinematics. Flow-SANS measurements in the 1–2 plane exhibit a critical alignment and orientation required for shear banding, followed by a first order orientational transition to a paranematic state in the high-shear band. Master curves of the segmental orientation and alignment are constructed by comparing the local structural features to the locally observed shear rate. The Giesekus-diffusion model successfully predicts the measured segmental orientation and alignment, connecting the microstructure to the macroscopic rheology and shear banding kinematics. In doing so, a stress-SANS rule is developed, analogous to the stress-optic rule, that relates micellar flow alignment to the shear and normal stresses. The results confirm that shear banding is driven by a nonequilibrium shear-induced isotropic-nematic transition and suggest that the underlying phase behavior of the material is important in determining fluid microstructure and rheology during banding. [ABSTRACT FROM AUTHOR]

The shear rheology of a model wormlike micellar solution exhibits moderate shear thinning and curved flow velocity profiles without discontinuity (nonbanding case). The shear rheology and the flow kinematics are analyzed within the framework of the Giesekus constitutive equation. Macroscopically, the steady state flow curve of the solution exhibits shear thinning with a shear exponent <1 without hysteresis, indicative of a sample that does not shear band. The microstructure of the micellar network is probed by the combination of dynamic rheology, rheo-optics, and SANS. Flow kinematics in a Couette geometry are measured by particle tracking velocimetry and found to be consistent with predictions of the Giesekus constitutive equation fit to the bulk shear rheology. 1-2 plane SANS measurements of the segmental alignment under shear are also found to be in agreement with predictions of the constitutive equation, providing a coherent picture of the mechanisms by which wormlike micelles flow and shear thin. The degree of segmental alignment is found to lag behind predictions of the model, which is postulated to be a consequence of the long, branched topology of the wormlike micelles. [ABSTRACT FROM AUTHOR]

The topology of self-assembled surfactant solutions includes varying degrees of micellar branching, ranging from linear wormlike micelles to a micellar network. Micellar branching acts as an effective attraction between micelles such that network condensation can lead to phase separation. Unlike chemical branching in polymers, micellar branches are labile. Movement of branches along a micelle contour has therefore been proposed as a mechanism of stress relaxation that leads to a reduction in the structural relaxation time and thus, the zero-shear viscosity. Branching is also thought to suppress flow alignment, and for lower levels of branching, may also suppress instabilities such as shear banding. The suppression of shear banding can lead to a lesser degree of shear-thinning in the apparent viscosity at higher shear rates, as well as a reduction in extensional thickening. However, for higher levels of branching, shear can induce branching for samples in proximity to such a phase transition, which can result in shear banding due to shear-induced phase separation. Recent modeling and simulations of the energetics of branching, as well as experiments on model systems, show that the reduction in zero-shear viscosity is due to micelle branching. Current research includes efforts to develop a more mechanistic, quantitative understanding of micellar branching and more generally, its effects on micellar solution rheology. [ABSTRACT FROM AUTHOR]

The micellization of dilute solutions of Pluronic block copolymers P123 (EO20–PO70–EO20) and F127 (EO106–PO70–EO106) and comicellization of binary mixtures in partially deuterated ethylammonium nitrate (d3EAN, a protic ionic liquid) are studied by small-angle neutron scattering. The average Pluronics composition in micelles shows a linear dependence on the bulk Pluronic composition. The mole ratio between P123 molecules in the micelles to those existing as unimers in solvent increases with temperature and P123 concentration. At a fixed F127/P123 ratio, the micelle core radius, the micelle corona thickness, and the aggregation number decrease with increasing temperature, while the total micelle volume fraction increases. At a fixed temperature, increasing P123 content in the binary mixtures leads to a weak minimum in micelle core size and aggregation number and a weak maximum in micelle corona thickness and total volume fraction of micelles. The comicellization behavior in d3EAN resembles that in aqueous solutions reported experimentally and theoretically. To our knowledge, this is the first experimental report on comicellization behavior of Pluronic triblock copolymers in a protic ionic liquid. [ABSTRACT FROM AUTHOR]

Abstract: We present a systematic study of the self-assembly of wormlike micelles (WLMs) comprised of cetyltrimethylammonium bromide (CTAB) and sodium nitrate (NaNO3) in aqueous solution as a function of CTAB concentration, NaNO3 concentration, and temperature throughout the dilute and semi-dilute regions of the phase diagram where linear micelles are observed. Combining measurements using isothermal titration calorimetry, rheometry, flow-birefringence, cryo-transmission electron microscopy (cryo-TEM), and small angle neutron scattering (SANS) enables complete characterization of the structure, thermodynamics, and rheology of CTAB/NaNO3 micelles. The addition of NaNO3 is found to increase the micellization enthalpy as well as the micellar scission energy, resulting in the elongation and growth of WLMs. We find quantitative agreement between the scission energy determined from rheology and the enthalpy of micellization determined from ITC, as well as for contour lengths extracted from rheology and SANS. At fixed molar ratio of NaNO3 and CTAB, the solution rheology exhibits scaling consistent with dilute, semi-dilute overlapping, and semi-dilute entangled regimes typically found in polymer solutions, as confirmed by cryo-TEM and SANS. The transition between these scaling regimes coincides with the structural transitions identified by SANS. The results validate the relationship between structural parameters and rheological behavior underlying theories for ionic WLMs. [Copyright &y& Elsevier]