Dual Effect of Histidine on Polysorbate 20 Stability: Mechanistic Studies

• Published in: Pharmaceutical research Vol. 35; no. 2; pp. 33 - 18
• Main Authors: Zhang, Lin, Yadav, Sandeep, John Wang, Y., Mozziconacci, Olivier, Schӧneich, Christian
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2018; Springer; Springer Nature B.V
• Subjects: Acetates; Acetates - chemistry; Acetic acid; Amidines - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Buffers; Chemistry, Pharmaceutical; Comparative analysis; Degradation products; Drug Stability; Excipients - chemistry; Histidine; Histidine - chemistry; Liquid chromatography; Mass Spectrometry; Mass spectroscopy; Medical Law; Oxidants - pharmacology; Oxidation; Oxidation-Reduction - drug effects; Pharmacology/Toxicology; Pharmacy; Polysorbates - chemistry; Research Paper; Solutions - chemistry; Stability tests; Stable isotopes; Surface active agents; Water - chemistry; oxidation; L-histidine; peroxyl radical, Polysorbate 20; free fatty acid
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-017-2321-1

Purpose L-Histidine (L-His) and polysorbate 20 (PS20) are two excipients frequently included in parenteral products to stabilize biotherapeutics. The objective of the current work was to investigate the impact of L-His on PS20 stability in aqueous solutions when subjected to forced oxidation and accelerated stability testing. Methods The stability of PS20 in L-His buffer was compared with that in acetate buffer. Forced oxidation of PS20 in these two buffer systems was initiated by a free radical generator, 2,2′-azobis (2-amidinopropane) hydrochloride (AAPH), while accelerated stability tests were carried out at 40°C. Ultra-performance liquid chromatography mass spectrometry was utilized to monitor intact PS20 and to analyze degradation products. Results Our results demonstrate a dual effect of L-His on PS20 stability. During exposure to AAPH, L-His protects PS20 from oxidation. Stable isotope labeling of L-His with 13 C was employed for mechanistic investigations. The protection of L-His was abrogated when acetate was added to L-His buffer, implying that the anti-oxidative activity of L-His may be compromised by specific counter ions. The replacement of L-His by various His derivatives led to significant changes in the protection of PS20 against AAPH-induced degradation. In contrast to forced degradation, the addition of L-His promoted oxidative PS20 degradation during accelerated storage at 40°C in solution, generating mainly short chain POE-laurates. Conclusion L-His exhibits a dual effect on the stability profile of PS20, protecting against AAPH-induced oxidation but promoting oxidative degradation during accelerated stability testing.