Aggregation Kinetics of Polysorbate 80/m-Cresol Solutions: A Small-Angle Neutron Scattering Study

Area of Science:

• Pharmaceutical formulation science
• Colloid and interface science
• Physical chemistry

Background:

• Polysorbate 80 (PS80) is a common nonionic surfactant in pharmaceutical formulations.
• m-cresol is an antimicrobial agent used in multi-dose injectables.
• PS80 and m-cresol exhibit incompatibility, leading to micelle aggregation and turbidity.

Purpose of the Study:

• To investigate the aggregation kinetics and mechanisms of Polysorbate 80 (PS80) and m-cresol mixtures.
• To determine the phase behavior and stability limits of PS80/m-cresol solutions.
• To develop a kinetic model for PS80/m-cresol aggregate growth.

Main Methods:

• Small-angle neutron scattering (SANS) was used to analyze PS80/m-cresol solutions.
• Solutions were studied over a range of pharmaceutically relevant component concentrations.
• Aggregation kinetics were monitored over time under various conditions.

Main Results:

• PS80 solutions with m-cresol concentrations below ~2.0 mg/mL or above ~4.5 mg/mL are kinetically stable.
• Intermediate m-cresol concentrations (2.0-4.5 mg/mL) lead to aggregation, coalescence, and phase separation.
• A microemulsion phase forms at 5 mg/mL m-cresol, demonstrating kinetic stability.
• Aggregate growth exhibits distinct stages (nucleation, power-law, exponential growth) depending on m-cresol concentration.

Conclusions:

• The study establishes the phase diagram for PS80/m-cresol solution stability.
• Specific concentration ranges for stable PS80/m-cresol formulations were identified.
• Understanding these interactions is crucial for preventing aggregation in multi-dose injectable products.