Multi-injection pharmaceutical products such as insulin must meet certain requirements to ensure their safety and accurate dosage, and preserve activity of the drug. As aggregation may lead to potential immunological responses and impact the efficacy of drugs, biotherapeutics need to be formulated in solutions free from large aggregates. Thus, drug formulations often require stabilizing excipients including nonionic surfactants and antimicrobial agents. A commonly used nonionic surfactant employed in biopharmaceutical formulations is poloxamer 188 (P188), a thermoresponsive ABA triblock copolymer of polyethylene oxide and polypropylene oxide wherein the interior propylene oxide block constitutes approximately 20% by weight. Recent research shows that the combination of preservatives such as phenol and benzyl alcohol with P188 can develop large aggregates that eventually result in the drug solution becoming turbid over time. A fundamental understanding of the aggregation mechanism is therefore critical to help the industry to better design their formulation approach for future products using P188. Herein we have addressed this need through a systematic study on the molecular and morphological causes for aggregation in P188/preservative solutions using light scattering and small-angle neutron scattering.

Aggregation behavior of poloxamer 188 and common preservatives

ACS Fall 2021

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