Forced degradation studies of elagolix sodium with the implementation of high resolution LC-UV-PDA-MSn (n = 1,2,3…) and NMR structural elucidation

• Published in: Journal of pharmaceutical and biomedical analysis 2023-02, Vol.224, p.115198-115198, Article 115198
• Main Authors: Zhong, Xueni, Lv, Qianqian, Yong, Qiyun, Hu, Wenping, Li, Dan, Ji, Shuhui, Zhan, Liuyue, Chen, Wenbin, Li, Min, Lin, Jinsheng, Sun, Cuirong
• Format: Article
• Language: English
• Subjects: Elagolix sodium; Forced degradation; LC-MS; MTO mediated-degradation; NMR
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2022.115198

Elagolix sodium (ELS) is a marketed product using to release moderate to severe endometriosis-associated pain. It contains functional groups such as carboxyl group, secondary amino group, 2,4-dioxo pyrimidinyl and several benzyl or benzyl-like position hydrogen atom that are susceptive to occur stress degradation. Forced degradation studies of ELS reveal different degradation profiles of the drug substance which are conducted under photo, thermal, acidic, neutral, alkaline and hydrogen peroxide oxidative conditions in the direction of the ICH guidances. With structural elucidation of LC-PDA/UV-MSn and NMR, the degradants were identified, and seven new degradants are reported in this study. It is confirmed that most of the degradation behaviors of ELS are related to the carboxyl group and secondary amino group in the 3-carboxyl propylamine side chain. Under the oxidative condition using hydrogen peroxide as the oxidant, the secondary amine was oxidized to form an N-hydrogen amine degradant and two further degradants of amine and carbonyl analogs were generated. Under the alkaline degradation condition, the ELS is proven to be stable and no obvious degradants are produced. On the other hand, under the acidic and neutral degradation condition, the 2,4-dioxo pyrimidinyl core of elagolix sodium is stable but the carboxyl group and secondary amine will occur ring cyclization to form the δ-lactam analogs of elagolix sodium. The plausible mechanisms for the degradation of acidic, thermal, photo-degradative and hydrogen peroxide mediated oxidative of elagolix sodium are proposed. It is worth to note that DP-3–4 are the potential degradants which are only found in the solution degradation and are not the real impurities of elagolix sodium. •The comprehensive forced degradation studies of elagolix sodium (ELS) were conducted according to ICH guidelines for the first time.•The nine degradation products of elagolix sodium were characterized by LC-PDA/UV-MSn (n = 1,2,3…) and NMR and four novel chemical structures (DP-1–4) have been proposed.•The possible degradation mechanisms of elagolix sodium are proposed for the first time and this study will help to guide the follow-up quality control of elagolix sodium (ELS) drug substance and its final drug product in the drug research and development.