目的: 探讨阿普斯特溶液在室温条件下稳定性差,出现未知杂质的根本原因,同时提供改善溶液稳定性的策略,以提高分析方法耐用性。方法: 采用色谱柱为YMC Pack Pro C18(100 mm×4.6 mm,3 μm);以0.05 mol·L-1高氯酸钠缓释盐(pH 2.2)为流动相A,乙腈-甲醇(1∶1)为流动相B,梯度洗脱;柱温20 ℃;流速1.1 mL·min-1;进样量5 μL。在相同条件下,对容量瓶和进样小瓶的溶液稳定性进行比对,以确认未知杂质来源;根据强制降解试验、进样小瓶中储存溶液pH及ICP-MS研究,联合LC-MS/MS,确定“鬼峰”成因。结果: 强制降解试验结果提示,杂质在碱破坏条件下明显产生;ICP-MS及pH结果显示,进样小瓶储存的溶液中Na/K/B/Si水平越高,其对应溶液的pH越高,且不同品牌进样小瓶中2个未知杂质含量与溶液pH及放置时间呈正相关。经LC-MS/MS鉴定,其为阿普斯特异吲哚-1,3-二酮环上的酰亚胺水解而产生的同分异构体,分子式为C22H27N2O8S。结论: 玻璃进样小瓶表面Na+、K+等阳离子浸出,并与水溶液中H+交换,导致溶液pH升高,从而引起阿普斯特的碱催化降解。采用聚丙烯棕色小瓶储存或将溶液稀释剂pH调节到5~6,可显著改善溶液稳定性。
周爱玉, 姜曼花, 孙富周, 游劲松, 黄芳芳, 黄林正, 李翠芬, 宋学志, 贺新前
. 阿普斯特“鬼峰”:2个由进样小瓶引起的碱催化降解杂质[J]. 药物分析杂志, 2022
, 42(5)
: 831
-837
.
DOI: 10.16155/j.0254-1793.2022.05.12
Objective: To explore the exactly cause of poor stability of apremilast content solution and the formation of two unknown impurities when stored at room temperature, and suggest the means of improving solution stability to enhance the durability of analytical method. Methods: A YMC Pack Pro C18(100 mm×4.6 mm, 3 μm) column was used. 0.05 mol·L-1sodium perchlorate buffer solution(pH 2.2) was used as themobile phase A, acetonitrile-methanol(1∶1) as the mobile phase B, and gradient elution was used for analysis. The column temperature was 20 ℃. The flow rate was 1.1 mL·min-1. The injection volume was 5 μL. The source of unknown impurities was confirmed by compare the solution stability of volumetric flasks with HPLC vials under the same conditions. LC-MS/MS was used to determine the contributing factor of "ghost peak" on the basis of the forced degradation study, the pH value of the solution stored in glass HPLC vials and the results of ICP-MS. Results: The results of forced degradation study showed that the two unknown impurities were obviously produced under alkali damage conditions. ICP-MS and pH results displayed that the pH of solution increases with increasing content of Na/K/B/Si level in the HPLC vial, and the contents of two unknown impurities in different brands of glass HPLC vials were positively correlated with solution pH and storage time. The two "ghost peaks" were identified by LC-MS/MS as isomers, with the same molecular formulaof C22H27N2O8S, produced by the hydrolysis of the amide CO-N bonds in the isoindole-1,3-dione ring. Conclusions: Sodium, potassium and other cations leach from the surface of glass HPLC vials and exchang with H+ in the aqueous solution, which enhance the pH value of the solution and further lead to the alkali-catalysed degradation of apremilast. The stability of the solution can be significantly improved by storing in brown polypropylene HPLC vials or adjusting the pH of the solution diluent to 5-6.
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