高效液相色谱-串联质谱法分析硫酸特布他林雾化气溶胶含量及空气动力学粒径分布

Quantification and aerodynamics particle size distribution of terbutaline sulfate aerosol determined by HPLC-MS/MS

建立了一种高效液相色谱-三重四极杆串联质谱法测定雾化吸入装置中硫酸特布他林雾化液气溶胶含量和分析空气动力学粒径分布情况的方法。确定50%甲醇水为最优提取溶剂。采用BEH C18色谱柱分离,0.1%甲酸水和乙腈为流动相进行等度洗脱,分析时间为2 min,正离子模式下多反应监测模式测定。采用该方法对雾化5 min和25 min气溶胶的平均药物浓度和空气动力学粒径分布进行了分析。结果显示,硫酸特布他林在0.5~600 ng/mL范围内线性关系良好(r>0.999),定量限为0.5 ng/mL;硫酸特布他林日内及日间相对标准偏差(RSD)分别为0.3%~4.5%和0.8%~4.8%。雾化气溶胶的平均提取回收率为98.5%,RSD为2.6%。抽气采集法下雾化5 min和25 min气溶胶的平均药物含量分别为15.8和15.9 mg/m^(3),总体RSD为2.5%,撞击器采集法下雾化5 min和25 min时的平均药物含量分别为16.2和16.8 mg/m^(3),平均质量中值空气动力学粒径(MMAD)分别为2.32和2.28μm。本方法用于硫酸特布他林雾化气溶胶的浓度测定和空气动力学粒径分布分析,在吸入装置中雾化5 min后药物浓度即达到均一。随着雾化时间延长,雾化装置内硫酸特布他林雾化气溶胶的空气动力学粒径分布相对稳定。

A rapid high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS)method was established for the determination of aerosol concentration and the aerodynamic particle size distribution of terbutaline sulfate inhalation solution in atomization inhalation device.50%methanol water was the optimized extraction solvent.The stationary phase of BEH C18 column,and the mobile phase of 0.1%formic acid water and acetonitrile for isocratic elution were used,and the analysis time was 2 min.A multiple reaction monitoring(MRM)in positive mode was adopted in mass spectrometry acquisition.The average drug concentration and aerodynamic particle size distribution of aerosol atomized for 5 min and 25 min were analyzed.The results showed that the linear range of the standard curve was 0.5 to 600 ng/mL(r>0.999)and the limit of quantification was 0.5 ng/mL.The relative standard deviations(RSDs)of inter-day and intro-day of terbutaline sulfate were 0.3%-4.5%and 0.8%-4.8%,respectively.The average extraction recovery of atomized aerosol was 98.5%with the RSD of 2.6%.The average drug concentrations of aerosols atomized for 5 min and 25 min by air extraction collection method were 15.8 and 15.9 mg/m^(3),respectively,and the overall RSD was 2.5%.Under the impactor collection method,the cumulative deposition of atomization for 5 min and 25 min was 16.2 and 16.8 mg/m^(3),respectively.The average mass median aerodynamic diameters(MMAD)were 2.32 and 2.28μm,respectively.The developed method was applied for the determination of terbutaline sulfate aerosol concentration and the analysis of aerodynamic particle size distribution,and the drug concentration basically reached uniformity after 5 min.The aerodynamic particle size distribution of terbutaline sulfate aerosol in the atomizer was relatively stable with the extension of atomization time.