Peter H. Gilbert, Zhenhuan Zhang, Ken K. Qian, David P. Allen, Norman J. Wagner, Yun Liu
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 micelle growth kinetics plays in preservative-surfactant interactions. The temperature-dependence of PS80 micelle growth kinetics is quantified by SANS in the presence of m-cresol. The monotonic growth of aggregate size with time follows a power-law, providing evidence for the mechanism. Addition of a pH-regulating citrate buffer accelerates micelle aggregation kinetics.