Solutions of injectable pharmaceutical products must meet certain requirements to ensure their safety and accurate dosage, and preserve activity of the drug. As aggregation can lead to denaturation or cause immunological responses, proteins need to be formulated to prevent the growth of large aggregates. Thus, drug formulations often require stabilizing excipients including nonionic surfactants and antimicrobial agents. However, the interactions between these surfactants and preservative molecules can result in undesirable aggregates. Herein, we study a commonly used nonionic surfactant employed in biopharmaceutical formulations, poloxamer 188 (P188), an ABA triblock copolymer of polyethylene oxide and polypropylene oxide. Unlike traditional polysorbate surfactants, P188 has no detected critical micelle concentration below 30°C. However, when combined with preservatives such as phenol and benzyl alcohol, P188 can aggregate and mixtures can become turbid over time, despite the fact that all individual components remain well below their respective solubility limits. We have conducted a systematic study of the morphological causes of aggregate formation in P188/preservative solutions using a variety of small-angle scattering techniques. Our results provide insights into the aggregation mechanism that can aid industrial formulation strategies for future products using P188.

Investigating the interactions between poloxamer 188 and preservative molecules in protein formulations

ACS Spring 2022

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