注射用盐酸头孢甲肟丁基橡胶塞质量控制研究

Quality Control of Butyl Rubber Stoppers of Cefmenoxime Hydrochloride for Injection

目的建立注射用盐酸头孢甲肟丁基橡胶塞的质量控制方法。方法以二氯甲烷-无水乙醇(1∶1,V/V)100℃水浴回流3.5 h处理胶塞,取续滤液。采用高效液相色谱法检测二硫化四甲基秋兰姆(简称秋兰姆)、2,6-二叔丁基-4-甲基苯酚(BHT)和单质硫,色谱柱为Shiseido CAPCELL PAK MGⅡC_(18)柱(250 mm×4.6 mm,5µm),流动相为1%三氟乙酸水溶液-乙腈(梯度洗脱),流速为1.0 mL/min,检测波长为280 nm,柱温为25℃,进样量为20µL。结果秋兰姆、BHT和单质硫的质量浓度分别在0.0002~0.0485µg/mL(r=0.9993)、0.46~230.67µg/mL(r=0.9999)和0.20~100.70µg/mL(r=0.9999)范围内与峰面积线性关系良好;精密度、稳定性试验结果的RSD均小于2.0%;平均加样回收率分别为58.22%,90.61%,104.46%,RSD分别为17.32%,5.58%,1.55%(n=9)。市场上抽取的16批空白丁基橡胶塞样品中BHT与单质硫的含量分别为0~169.88µg/g和0~102.79µg/g,均未检出秋兰姆。29批注射用盐酸头孢甲肟粉末样品中,BHT含量为0~36.61µg/g,且均未检测到单质硫和秋兰姆;包材胶塞中,BHT含量为0~125.64µg/g,单质硫的含量为0~79.93µg/g,均未检出秋兰姆,60℃下倒置5 d后与20℃及以下(阴凉库)放置比较,BHT含量无显著变化(P>0.05),单质硫含量显著减少(P<0.05)。结论所建立的方法操作简便、结果准确,可用于药用丁基橡胶塞中秋兰姆、BHT和单质硫的含量测定及注射用盐酸头孢甲肟的质量控制。

Objective To establish a quality control method for butyl rubber stoppers of Cefmenoxime Hydrochloride for Injection.Methods Rubber stoppers were treated with dichloromethane-anhydrous ethanol(1∶1,V/V)refluxed in water bath(100℃)for 3.5 h,the filtrate was collected.High-performance liquid chromatography(HPLC)method was used to detect tetramethylthiuram disulfide(referred to as thiuram),butylated hydroxytoluene(BHT)and elemental sulfur.The chromatographic column was the Shiseido CAPCELL PAK MGⅡC_(18) column(250 mm×4.6 mm,5µm),the mobile phase was 1%trifluoroacetic acid aqueous solution-acetonitrile(gradient elution),the flow rate was 1.0 mL/min,the detection wavelength was 280 nm,the column temperature was 25℃,and the injection volume was 20µL.Results The linear ranges of thiuram,BHT and elemental sulfur were 0.0002-0.0485µg/mL(r=0.9993),0.46-230.67µg/mL(r=0.9999)and 0.20-100.70µg/mL(r=0.9999)respectively.The RSDs of precision and stability tests were lower than 2.0%.The average recovery rates of the above three ingredients were 58.22%,90.61%,104.46%,with RSDs of 17.32%,5.58%,1.55%respectively(n=9).The content of BHT and elemental sulfur in 16 batches of blank butyl rubber stoppers from the market was in the range of 0 to 169.88µg/g and 0 to 102.79µg/g respectively,and no thiuram was detected.The content of BHT in the 29 batches of Cefmenoxime Hydrochloride for Injection powder was in the range of 0 to 36.61µg/g,and no elemental sulfur or thiuram was detected;the content of BHT and elemental sulfur in the packaging rubber stoppers was in the range of 0 to 125.64µg/g and 0 to 79.93µg/g respectively,and no thiuram was detected;compared with that at 20℃and below(microtherm warehouse),the BHT content showed no significant change after inversion at 60℃for 5 d(P>0.05),while the elemental sulfur content significantly decreased(P<0.05).Conclusion The established method is easy and accurate,which can be used for the determination of thiuram,BHT and elemental sulfur in pharmaceutical butyl rubber stoppers,as well as the quality control of Cefmenoxime Hydrochloride for Injection.