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Polysorbate HLB (PS) is an amphiphilic non-ionic surfactant that belongs to the most widely used class of surfactants in biopharmaceutical formulations. It effectively prevents protein denaturation, aggregation, surface adsorption, and flocculation during the freeze-thaw process, and is primarily used as a protein stabilizer in formulations. With excellent biocompatibility and low toxicity, Polysorbate HLB significantly enhances protein stability. Even at low concentrations, Polysorbate 20 and Polysorbate 80, due to their high hydrophilic-lipophilic balance (HLB) values and low critical micelle concentration (CMC), provide sufficient stability to proteins.
Interfacial Competition: The surface activity of Polysorbate 20 and Polysorbate 80 far exceeds that of typical therapeutic proteins (e.g., monoclonal antibodies). These surfactants can competitively block interfacial sites, preventing proteins from adsorbing onto air-liquid interfaces. This property is highly beneficial in manufacturing, sample handling, and storage (covering mixing, filtration, pumping, shaking, stirring, and freeze-thawing processes), as it effectively prevents proteins from unfolding at interfaces. Additionally, it helps prevent protein adsorption onto product contact surfaces such as filters, primary containers, sealed containers, and intravenous tubing, which is crucial for ensuring accurate drug delivery to patients.
Direct Interaction: Polysorbate 20 and Polysorbate 80 can also stabilize proteins by interacting directly with hydrophobic patches on protein surfaces, increasing their colloidal stability and preventing aggregation and further unfolding. However, the direct interaction between surfactants and proteins, and the resultant improvement in colloidal stability, is protein-specific and not universally applicable. For example, thermodynamic studies have shown that Polysorbate HLB can bind to human serum albumin, but it has a very weak binding affinity with the three immunoglobulins studied, which is nearly negligible.
Since the degradation of Polysorbate HLB can have unintended effects on the quality, efficacy, safety, and stability of protein formulations, regulatory agencies have become more stringent in reviewing control strategies for Polysorbate HLB, aiming to ensure that its concentration remains stable throughout the product's shelf life.
Hydrolysis: Hydrolysis of Polysorbate HLB leads to the cleavage of ester bonds in the fatty acid chain, releasing free fatty acids and potentially forming visible or sub-visible particles. It is believed that enzyme-induced hydrolysis of Polysorbate HLB is a major cause of visible and sub-visible particle formation in product quality issues. However, under typical pH conditions for protein formulations, the hydrolysis of Polysorbate HLB is somewhat limited.
Auto-Oxidation: Polysorbate HLB may undergo auto-oxidation due to factors such as temperature, light exposure, or trace amounts of transition metals. The resulting peroxides can trigger protein oxidation, and the generated acids may lead to a decrease in solution pH.
Other Factors: Polysorbate 80, which degrades via hydrolysis, may slow down surface adsorption rates. Additionally, the insoluble particles formed by free fatty acids released during hydrolysis can negatively affect the protein's quality and stability. Furthermore, common protein formulation buffers, such as histidine, can exert complex effects on the degradation of Polysorbate HLB.
In summary, Polysorbate HLB plays a central role as a protein stabilizer in biopharmaceutical formulations, ensuring protein stability through interfacial competition and direct interaction mechanisms. However, its hydrolysis and oxidation degradation can negatively impact formulation quality, with degradation being influenced by various factors. A thorough understanding of Polysorbate HLB's role in formulations, its stabilization mechanisms, and degradation factors is essential for optimizing biopharmaceutical formulation strategies, ensuring drug quality and safety, and meeting regulatory requirements.
