(725f) Surfactant/Preservative Instability in Injectable Pharmaceutical Formulation

Recent study of incompatibility between surfactant molecules and antimicrobial agents has caused concerns for future protein formulation of multi-dose therapeutic drugs in the pharmaceutical industry. In particular, polysorbate 80 (PS80), a nonionic surfactant widely used in formulation, has been found to be incompatible with m-cresol, a commonly used antimicrobial agent. This incompatibility results in increased turbidity caused by unsteady micelle aggregation or coalescence that can progress over weeks. Here, small-angle neutron scattering (SANS) is used to fundamentally understand the structural origins of this incompatibility. We observed that PS80/m-cresol solution instability is influenced by storage temperature, ionic strength, and component concentration. SANS analysis of PS80/m-cresol solutions over a pharmaceutically relevant concentration range of each component reveals the cause of aggregation, the coalescence mechanism and aggregate structure. Our results identify two concentration-dependent stability regimes at low (below ≈ 2 mg/mL) and high (5 mg/mL) m-cresol concentrations. In these stable formulations, micelle morphology is highly sensitive to m-cresol concentration. PS80/m-cresol solutions aggregate at m-cresol concentration between the two stable regimes. SANS results reveal the aggregation mechanism, and kinetic modelling of the results provides a simplified empirical equation capable of describing and predicting the multiple aggregation phases observed in these solutions. This work aims to develop insight into surfactant/preservative stability for pharmaceutical formulation, which can be leveraged to better understand the effect of excipients on surfactant self-assembly.