Preservative Induced Polysorbate 80 Micelle Aggregation

Abstract

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.

Keywords: Micelles; Pharmaceutical formulation; Polysorbate; Preservatives; Small-angle neutron scattering.