^(1)H核磁共振波谱绝对定量法和相对定量法测定氘代新药甲苯磺酸多纳非尼中非氘代杂质的含量

^(1)H qNMR absolute quantitative method and relative quantitative method of non-deuterium impurity in donafenib tosilate,a new deuterated drug

目的:建立1H核磁共振波谱绝对定量法和相对定量法测定氘代新药甲苯磺酸多纳非尼中非氘代杂质的含量。方法:采用氘代二甲基亚砜-重水(10∶1)混合溶剂,以90°脉冲,弛豫延迟时间15 s,扫描次数64次,测试温度25℃为采样条件。加入马来酸作为内标物,以马来酸化学位移δ6.29的内标峰和非氘代杂质δ2.79的特征定量峰计算非氘代杂质的绝对含量;不加入任何内标物,以δ8.63的芳香1H峰和δ2.79的非氘代杂质特征1H峰为定量峰,计算非氘代杂质对甲苯磺酸多纳非尼的相对含量。并将2种定量方法测定结果与液质联用法进行比较。结果:2种测定方法的定量限、线性、精密度、准确度及稳定性经验证均符合要求。对3批商业化样品进行测定,2种定量方法测定结果分别为0.14%、0.14%、0.14%和0.14%、0.13%、0.14%,与液质联用法测定结果基本一致。结论:建立的1H核磁共振波谱绝对定量法和相对定量法准确、灵敏,可用于测定甲苯磺酸多纳非尼中非氘代杂质的含量,且具有操作简单、分析时间短、无需杂质对照品的优势,也为其他氘代药物中非氘代杂质的测定提供了借鉴。

OBJECTIVE To establish the 1H qNMR absolute quantitative method and relative quantitative method for determination of the non-deuterium impurity in donafenib tosilate,a new deuterated drug.METHODS The mixture of DMSO-d6 and D2O(10∶1)was used as the solvent.1H qNMR spectra were recorded at the temperature of 25℃with 90°pulse,15 s relaxation delay time and 64 scanning times.The absolute content of the non-deuterium impurity was determined by the internal standard peak of maleic acid atδ6.29 and the quantitative peak of the non-deuterium impurity atδ2.79.The relative content of the non-deuterium impurity with respect to donafenib tosilate was calculated by the quantitative peak of aromatic proton atδ8.63 and methyl proton atδ2.79 without any internal standard substances.The testing results of the two 1H qNMR methods were subsequently compared with those of the LC-MS method.RESULTS Both of methods were validated in terms of quantitation limit,linearity,precision,accuracy and stability,proving to meet the validation requirements.The two methods were applied to the samples of three commercial batches and the testing results were 0.14%,0.14%,0.14%and 0.14%,0.13%,0.14%,respectively,which were almost consistent with those of the LC-MS method.CONCLUSION Both of established methods were sensitive,accurate and applicable for determination of the non-deuterium impurity in donafenib tosilate.It also provides a reference for the determination of non-deuterium impurities in other deuterated drugs.