Micelle Formation and Phase Separation of Poloxamer 188 and Preservative Molecules in Aqueous Solutions Studied by Small Angle X-ray Scattering

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. (c) 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Automated summary

A systematic study using small-angle x-ray scattering (SAXS) was conducted to investigate the phase behavior and morphological causes of aggregation of poloxamer 188 (P188) in the presence of phenol and benzyl alcohol. The results showed that P188 remained as unimers at low phenol concentrations, formed micelles at moderate phenol concentrations due to the interaction with phenol, and exhibited turbidity and phase separation at high phenol concentrations. The effect of benzyl alcohol on the phase behavior was also investigated.