复方氨基酸注射液(18AA-Ⅱ)中甲硫氨酸氧化杂质的研究

邵天舒; 周长明; 李辉; 郭雷

doi:10.11665/j.issn.1000-5048.20210609

复方氨基酸注射液(18AA-Ⅱ)中甲硫氨酸氧化杂质的研究

北京市药品检验研究院，国家药品监督管理局仿制药研究与评价重点实验室，北京 102206

基金项目: 国家药品评价性抽验资助项目（2019年）

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出版历程
- 收稿日期: 2021-05-20
- 修回日期: 2021-11-05
- 刊出日期: 2021-12-24

Oxidized related substance of methionine in compound amino acid injection (18AA-Ⅱ)

NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Institute of Drug Control, Beijing 102206, China

Funds: This study was supported by the National Drug Evaluation Surveillance (2019)

摘要

摘要: 建立柱前衍生-HPLC同时测定复方氨基酸注射液（18AA-Ⅱ）中甲硫氨酸亚砜和甲硫氨酸砜含量的方法，以此方法考察了155批样品中这两种杂质的含量，并对其产生的原因进行分析。采用邻苯二甲醛-巯基丙酸溶液柱前衍生高效液相色谱法，色谱柱为Agilent Poroshell 120 EC-C₁₈，荧光检测器激发波长233 nm，发射波长441 nm，流动相A为醋酸钠/四氢呋喃溶液，流动相B为醋酸钠溶液-乙腈-甲醇（200∶400∶400）（梯度洗脱），流速为0.5 mL/min，柱温为40 ℃，进样体积8 μL。以此方法对2019年国家评价性抽验的155批样品中甲硫氨酸亚砜及甲硫氨酸砜的含量进行测定，并用顶空气体测定仪测定上述样品的残氧量。结果显示，甲硫氨酸亚砜、甲硫氨酸砜的检测质量浓度线性范围分别为0.128 1 ~ 10.250 0 μg/mL（r = 0.999 9）和0.261 0 ~ 10.440 0 μg/mL（r = 0.999 8）；定量限分别为0.13和0.26 μg/mL，检测限分别为0.04和0.09 μg/mL；精密度、稳定性、重复性试验的RSD < 1.3％；回收率分别为98.00％ ~ 100.79％（RSD = 1.15％，n = 9）和98.19％ ~ 102.31％（RSD = 1.33％，n = 9）。不同厂家的样品中甲硫氨酸氧化产物含量差异较大，样品中甲硫氨酸氧化产物含量与残氧量具有一定相关性，但与样品中抗氧剂焦亚硫酸钠添加量并无明显相关性。本方法可有效监控复方氨基酸注射液（18AA-Ⅱ）中甲硫氨酸亚砜和甲硫氨酸砜的含量，在质量标准中增设甲硫氨酸氧化杂质的检查项很有必要，生产厂家应加强对产品残氧量的控制。
- 复方氨基酸注射液 /
- 甲硫氨酸 /
- 氧化杂质 /
- 含量测定
Abstract: TA method for the content determination of methionine sulfoxide and methionine sulfone in compound amino acid injection (18AA-II) was established in order to investigate their level in 155 batches of this product, and to explore the reason for the generation of these two impurities.The determination was performed on an Agilent Poroshell 120 EC-C₁₈ column with mobile phases of sodium acetate/tetrahydrofuran solution (A) and sodium acetate solution -acetonitrile-methanol (B, 200∶400∶400) (gradient elution) at the flow rate of 0.5 mL/min.The excitation wavelength and the emission wavelength of the fluorescence detector were 233 nm and 441 nm, respectively.The column temperature was 40 °C, and the injection volume was 8 μL.The contents of methionine sulfoxide and methionine sulfone from 155 batches of compound amino acid injection (18AA-II) was determined using this method, and the residual oxygen content was detected by headspace gas analyzer.The results showed that the linear range of methionine sulfoxide and methionine sulfone were 0.128 1-10.250 0 μg/mL (r = 0.999 9) and 0.261 0-10.440 0 μg/mL (r = 0.999 8), respectively.The limits of quantitation were 0.13 μg/mL and 0.26 μg/mL, respectively; the limits of detection were 0.04 μg/mL and 0.09 μg/mL, respectively.RSDs of precision, stability and repetitive test were all lower than 1.3%.The recoveries ranged 98.00%-100.79% (RSD = 1.15%, n = 9) and 98.19%-102.31% (RSD = 1.33%, n = 9).The content level of oxidized related substances from different manufacturers showed significant difference, showing relevance with the residual oxygen content to some extent, yet no significant correlation with the added amount of antioxygen (sodium pyrosulfite).The method is validated to be useful for the content control of methionine sulfoxide and methionine sulfone in compound amino acid injection (18AA-II).It is quite necessary to include the determination of oxidized related substance into the quality specification.Manufacturers should strengthen the control of remaining oxygen in their products.
- compound amino acid injection /
- methionine /
- oxidized related substance /
- determination of content

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参考文献(13)

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施引文献(3)

期刊类型引用(3)

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