罗氟司特原料药中矿物油残留测定

目的:建立正相液相色谱-蒸发光散射检测法用于罗氟司特粗品、精制中间体和终产品中残留矿物油的检查。方法:以丙酮为溶剂,采用SiO₂正相色谱柱(Welch Materials,4.6 mm×250 mm,5 μm),以乙醇-正己烷为流动相,梯度洗脱,流速0.8 mL·min^-1;分离后以蒸发光散射检测器(Alltech ELSD2000ES)检测,漂移管温度50℃,载气流速1.4 L·min^-1。外标曲线法计算样品中矿物油含量,以矿物油中所有烷烃组分作为一个整体进行定量分析。结果:矿物油与罗氟司特主药及其他杂质有效分离,专属性良好。矿物油质量浓度在3.24~81.04 μg·mL^-1范围内线性关系良好(r²=0.9970),精密度(RSD)为1.24%,检出限为19.45 ng,定量限为32.42 ng,回收率为90%~110%。结论:本方法可用于罗氟司特原料药中矿物油残留检查并准确测定矿物油残留量,为评价乙醚精制中间体质量,保证终产品残留矿物油的去除提供依据。

Objective:To establish a method of normal phase high performance liquid chromatography with evaporative light-scatter detector(HPLC-ELSD)for determination of the mineral oil residue in crude roflumilast. Methods:The analysis was carried out on a SiO₂ chromatography column(Welch Materials,4.6 mm×250 mm,5 μm)using acetone as the solvent.The ethanol and n-hexane were adopted as mobile phases with linear gradient elution,and the flow rate was 0.8 mL·min^-1.The evaporative light scattering detector(Alltech ELSD 2000ES)was used after separation,in which the drift tube temperature was 50℃ and the flow rate of carrier gas was 1.4 L·min^-1.The content of the tested mineral oil products were calculated using external standard curve method, in which all alkane groups in mineral oil as a whole were quantitatively analyzed.Results:Good retention and separations were achieved for the mineral oil,roflumilast and other miscellaneous.The calibrations of the mineral oil was linear(r²=0.9970)within 3.24-81.04 μg·mL^-1 and precision(RSD),recovery,limit of detection and limit of quantification of the established method were 1.24%,90%-110%,19.45 ng and 32.42 ng,respectively.Conclusion:The established method can accurately determinate and quantify the mineral oil residue in roflumilast raw materials,as well as the quality evaluation of ether purification of intermediates.The method can provide reference for guarantee of the mineral oil residue removed from final products.