宋劲燕+曹建英

[摘要] 目的 建立罗氟司特原料中残留溶剂的测定方法。 方法 罗氟司特中异丙醇、乙酸乙酯和N，N-二甲基甲酰胺（DMF）的残留量采用顶空进样气相色谱法，使用DB-624毛细管柱，FID检测器。采用程序升温法测定，氮气为载气，流速为2.5 ml/min，以二甲基亚砜（DMSO）为溶剂。 结果 被测溶剂均能得到良好的分离，异丙醇的浓度在199.4～598.1 μg/ml范围内线性关系良好，r=0.9998，平均回收率为96.3%，RSD为2.13%；乙酸乙酯的浓度在200.1～600.2 μg/ml范围内线性关系良好，r=0.9996，平均回收率为98.8%，RSD为1.79%；DMF的浓度在35.2～105.5 μg/ml范围内线性关系良好，r=0.9997，平均回收率为98.8%，RSD为2.42%。 结论 该方法能够准确测定罗氟司特中的残留溶剂，可用于罗氟司特原料药有机溶剂的检测。

[关键词] 顶空进样气相色谱法；罗氟司特；残留溶剂

[中图分类号] O657.7+1[文献标识码] A[文章编号] 1674-4721（2014）04（c）-0058-03

Residual solvents of roflumilast determined by headspace capillary gas chromatography

SONG Jin-yan CAO Jian-ying

Tianjin Nankai Yungong Pharmaceutical Science and Technology Co.,Ltd.,Tianjin 300384,China

[Abstract] Objective To establish a method for the determination of residual solvents in roflumilast material. Methods The residual solvents of isopropanol,ethyl acetate and N,N-dimethylformamide in roflumilast were determined by headspace gas chromatography,and DB-624 capillary column,FID detector were used.The column was subjected totemperature programming,the carrier gas was nitrogen,the flow rate was 2.5 ml/min,the solvent was dimethyl sulfoxide(DMSO). Results The result shows that the solvents were completely separated.The standard curves of isopropanol was linear in the concentration range of 199.4-598.1 μg/ml,r=0.9998,the average recovery was 96.3%,with RSD of 2.13%.The standard curves of ethyl acetate was linear in the concentration range of 200.1-600.2 μg/ml,r=0.9996,theaverage recovery rate was 98.8%,with RSD of 1.79%.The standard curves of N,N-dimethylformamide waslinear in the concentration range of 35.2-105.5μg/ml,r=0.9997,the average recovery rate was 98.8%,with RSD of 2.42%. Conclusion This method is proved to be accurate and reliable for the accurate determination of residual solvents in roflumilast.It can be used in the detection for the organic solvent of roflumilast crude drug.

[Key words] Headspace gas chromatography;Roflumilast;Residual solvents

罗氟司特是由Nycomed公司生产上市的磷酸二酯酶-4 （ PDE-4） 抑制剂，商品名Daxas。2011年2月28日，罗氟司特经美国FDA 批准上市，用于慢性阻塞性肺病（COPD）的治疗。本品为选择性PDE-4抑制剂，是10多年来首次获得欧盟批准的新一类治疗COPD的药物。本品为一日1 次用药的口服片剂，须与其他支气管扩张药合用，适用于有频繁加重病史的成人患者慢性支气管炎相关严重COPD的维持治疗。研究证明，本品可显著改善患者中至重度加重发作和舒张前FEV1，不管是否与长效β2 激动剂联用。研究还证明，与安慰剂相比，本品可显著改善患者的肺功能。本品在合成、精制过程中用到了ICH限制的溶剂，包括三类溶剂异丙醇和乙酸乙酯和及二类溶剂N，N-二甲基甲酰胺（DMF）。本文按照中国药典2010年版[1]与ICH[2-3]相关要求，建立了顶空气相色谱法测定该药中异丙醇、乙酸乙酯、DMF的残留量[4-9]。……