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Polysorbate is a family of amphiphilic, non-ionic surfactants derived from ethoxylated dehydrated sorbitol or isosorbitol (derivatives of sorbitol) esterified with fatty acids. Polysorbate esters, especially Polysorbate 20 and Polysorbate 80, are the most widely used surfactants in biopharmaceutical formulations. They prevent protein denaturation, aggregation, surface adsorption, and flocculation during formulation.
Polysorbate, used as a protein stabilizer, is a chemically diverse mixture and can be degraded via oxidation and hydrolysis pathways, with hydrolysis being either chemically induced or enzyme-catalyzed. Since the degradation of polysorbate could unintentionally affect the quality, efficacy, safety, and stability of protein formulations, regulatory agencies are increasingly scrutinizing polysorbate control strategies to ensure its content remains stable throughout the shelf life of pharmaceutical products.
Polysorbate 20 and Polysorbate 80 are used as protein stabilizers in most commercial therapeutic protein formulations. This is due to the following combination of factors: biocompatibility, low toxicity, and effective protein stabilization. Even at low concentrations, Polysorbate 20 and Polysorbate 80 provide sufficient protein stability due to their high hydrophilic-lipophilic balance (HLB) values and low critical micelle concentration (CMC). While the exact mechanism by which polysorbate stabilizes proteins is unclear, two main mechanisms have been proposed: interface competition and surfactant-protein complex formation.
It is generally believed that Polysorbate 20 and Polysorbate 80 primarily stabilize proteins through interface competition. Since their surface activity is much higher than that of typical therapeutic proteins (such as monoclonal antibodies (mAbs)), they can competitively block interfaces and prevent proteins from adsorbing to the gas-liquid interface.
Polysorbate 20 and Polysorbate 80 can also stabilize proteins through direct interactions, thereby increasing the colloidal stability of the protein. Therapeutic proteins may aggregate through their hydrophobic patches. Polysorbate esters can interact with hydrophobic patches on the protein surface through hydrophobic interactions, preventing protein aggregation and further unfolding. However, the direct interaction between surfactants and proteins, and the subsequent improvement in colloidal stability, may be protein-specific and not broadly applicable. For example, a thermodynamic study showed that polysorbate binds to human serum albumin, but the interaction with three studied immunoglobulins was very low and negligible.
