摘 要 目的 建立测定PSI-7977原料中1,4-二氯丁烷和4-氯-1-丁醇含量的方法。方法 采用气相色谱-串联 质谱（GC-MS/MS）法测定PSI-7977中1,4-二氯丁烷和4-氯-1-丁醇毒性杂质含量。色谱柱为DB-5ms毛细管柱；采用程序升温；进样口温度为220℃；载气为氦气；流速为每分钟2.0ml；进样量为1μl；分流比为5∶1。离子源为电子轰击源，离子源温度为250 ℃；采集模式为多反应监测模式。结果 1,4-二氯丁烷和4-氯-1-丁醇与其相邻色谱峰之间的分离效果均良好，分离度均大于1.5；其线性范围分别为0.07μg/ml~1.49μg/ml、0.08μg/ml~1.51μg/ml（r≥0.990），定量限分别为0.99、36.52ng/mL，检测限分别为0.33、12.24 ng/mL，重复性试验的RSD分别为1.2%和2.2%（n＝6），精密度试验的RSD分别为0.5%和1.3%（n=6），稳定性试验的RSD分别为2.2%、3.8%（n=5），低、中、高质量浓度回收率溶液的加标回收率为97.3%～112.3%（RSD分别为1.8%、3.7%，n＝9）。在各批次PSI-7977原料药中均未检出1,4-二氯丁烷和4-氯-1-丁醇。结论 该法分离效果好、准确性高、灵敏、简便，可用于PSI-7977原料药中1,4-二氯丁烷和4-氯-1-丁醇的检测。
Abstract Objective To establish a method for
determining the content of 1,4-dichlorobutane and 4-chloro-1-butanol in PSI-7977 raw materials. Methods A gas
chromatography-tandem mass spectrometry (GC-MS/MS) method was used to determine
the content of toxic impurities 1,4-dichlorobutane and 4-chloro-1-butanol in PSI-7977. The chromatographic column was a DB-5ms
capillary column; temperature programming was employed; the injection port
temperature was 220°C; the carrier gas was helium; the flow rate was 2.0 mL per
minute; the injection volume was 1 μL; the split ratio was 5:1. The ion source
was an electron impact source with an ion source temperature of 250°C; the
acquisition mode was multiple reaction monitoring (MRM). Results The
separation effect between 1,4-dichlorobutane and 4-chloro-1-butanol and their
adjacent chromatographic peaks was good, with a separation degree greater than
1.5; their linear ranges were 0.07 μg/mL to 1.49 μg/mL and 0.08 μg/mL to 1.51
μg/mL (r≥0.990), respectively; the quantitation limits were 0.99 ng/mL and
36.52 ng/mL, respectively; the detection limits were 0.33 ng/mL and 12.24
ng/mL, respectively; the relative standard deviations (RSD) for repeatability
tests were 1.2% and 2.2% (n=6), respectively; the RSD for precision tests were
0.5% and 1.3% (n=6), respectively; the RSD for stability tests were 2.2% and
3.8% (n=5), respectively; the recovery rates of the low, medium, and high mass
concentration solutions were 97.3% to 112.3% (RSD were 1.8% and 3.7%, n=9),
respectively. Neither 1,4-dichlorobutane nor 4-chloro-1-butanol were detected
in each batch of sofosbuvir raw materials. Conclusion This method has
good separation effect, high accuracy, sensitivity, and simplicity, and can be
used for the detection of 1,4-dichlorobutane and 4-chloro-1-butanol in PSI-7977 raw materials.
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