The degradation of poloxamer 188 in buffered formulation conditions

Abstract

Poloxamer 188 (P188) as a non-ionic surfactant is used in proteinaceous formulations to prevent protein adsorption to hydrophobic surfaces and unfolding at interfaces, preventing the formation of aggregates and particles. Its chemical intactness is crucial to the stability of drug products due to its protecting effects at interfaces. In order to identify and mitigate potential risks that might cause the degradation of P188 during the manufacturing process and storage, in the current work, the stability of P188 was investigated by forced degradation in buffered formulation conditions via oxidation and thermal stress conditions. The process of degradation was monitored through the dedicated liquid adsorption chromatography (LAC) with high sensitivity, and the degradants were characterized by high-resolution mass spectrometry. Results suggest that the vulnerability of P188 is largely related to the buffer conditions. Histidine promotes degradation in the presence of hydroxyl radicals but inhibits the degradation in the presence of H2O2 and alkyl radicals. In thermal stress conditions, histidine protects P188 from degradation at 40 °C, and activates its decay only at higher temperature, like 60 °C.

Oxidation of polysorbates – An underestimated degradation pathway?

“…For a more detailed description see Bollenbach et al (2022) . Nevertheless, poloxamers 188 are also able to be oxidized, which results in oxidized POE and PPO species such as formaldehyde, propionaldehyde, and acetaldehyde depending on the buffer system and the applied stress (solution stability of poloxamer) ( Bollenbach et al, 2022 ; Wang et al, 2019 ; Kim et al, 2014 ), which is a problem in histidine buffer as well as in presence of trace metals ( Wang et al, 2019 ; Chen et al, 2022 ). Another alternative is cyclodextrin as it is already used in some formulations, with hydroxypropyl-ß-cyclodextrin (HPßCD) being the most extensively studied ( Jenke, 2006 ; Zhou et al, 2010b ; Rowe et al, 2009 ; Wu et al, 2021 ).…”

Role of Poloxamer 188 in Preventing Ice-Surface-Induced Protein Destabilization during Freeze–Thawing

“…P188, identified to be nontoxic and nonirritating, is suitable for parenteral administration . Its degradation occurred only at high temperatures (e.g., ≥40 °C) or under specific conditions, for example, the presence of histidine, radicals, or trace metals. , However, it has not found widespread use in protein formulations. Among 131 approved antibody products for human use, only 4 contained P188 .…”

Intranasally Delivered Adenoviral Vector Protects Chickens against Newcastle Disease Virus: Vaccine Manufacturing and Stability Assessments for Liquid and Lyophilized Formulations

“…On the contrary, polysorbate-80 does not form protein–surfactant complexes; this non-ionic surfactant inhibits protein adsorption by their preferential location at an interface to which they show sufficient affinity. Also, at low concentrations, it has been reported that poloxamer 188 at 40 °C was stable for up to 6 months in certain buffer conditions [ 30 , 31 ]. The different mechanisms of action of the two non-ionic surfactants evaluated and their stability at high temperatures might have influenced the preservation of the virus differently.…”