Polysorbate 80 (PS80), a nonionic surfactant used in pharmaceutical formulation, is known to be incompatible with m-cresol, an antimicrobial agent for multi-dose injectable formulations. This incompatibility results in increased turbidity caused by micelle aggregation progressing over weeks or longer, where storage temperature, ionic strength, and component concentration influence the aggregation kinetics. Small-angle neutron scattering (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. PS80 solutions containing m-cresol concentrations below ≈2.0 mg/mL and above ≈4.5 mg/mL are kinetically stable and do not aggregate over a 50 h period. At 5 mg/mL of m-cresol, the mixture forms a kinetically stable microemulsion phase, despite being well below the aqueous solubility limit of m-cresol. Solutions containing intermediate m-cresol concentrations (2.0-4.5 mg/mL) are unstable, resulting in aggregation, coalescence, and eventual phase separation. In unstable solutions, two stages of aggregate growth (nucleation and power-law growth) are observed at m-cresol concentrations at or below ≈3.6 mg/mL. At higher m-cresol concentrations, aggregates experience a third stage of exponential growth. A single kinetic model is developed to explain the stages of aggregate growth observed in both kinetic mechanisms. This work establishes the phase diagram of PS80/m-cresol solution stability and identifies component concentrations necessary for producing stable formulations.
Keywords: micelles; pharmaceutical formulation; polysorbate; preservatives; small-angle neutron scattering.