CN112710758A - 一种盐酸他喷他多原料药中残留溶剂的检测方法 - Google Patents
一种盐酸他喷他多原料药中残留溶剂的检测方法 Download PDFInfo
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- ZELFLGGRLLOERW-YECZQDJWSA-N 3-[(2r,3r)-1-(dimethylamino)-2-methylpentan-3-yl]phenol;hydrochloride Chemical compound Cl.CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 ZELFLGGRLLOERW-YECZQDJWSA-N 0.000 title claims abstract description 22
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Abstract
本发明为一种检测盐酸他喷他多原料药中残留溶剂的方法,采用顶空气相色谱方法,具体为:利用氢火焰离子化检测器(FID),经程序升温,顶空进样方式,按照外标法,检测甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃和N,N‑二甲基甲酰胺7种有机溶剂。本方法操作简单,灵敏度高,精准度好,适合盐酸他喷他多原料药中7种溶剂残留溶剂的检测。
Description
技术领域
本发明涉及一种盐酸他喷他多原料药中残留溶剂的检测方法,采用气相色谱法,按照外 标法检测盐酸他喷他多中甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲 基甲酰胺的含量,属于药物分析检测领域。
背景技术
盐酸他喷他多(Tapentadol Hydrochloride),化学名:(-)-(1R,2R)-3-(3-二甲氨基-1-乙基-2- 甲基丙基)苯酚盐酸盐,是一种新型双重作用方式的中枢性镇痛药,既能激动μ阿片受体,又 能抑制去甲肾上腺素再摄取。于2008年11月由美国FDA批准上市(商品名:NUCNTA),临 床上使用的速释片有50、75、100mg3种规格,用于缓解中度及重度急性疼痛。
本发明针对盐酸他喷他多原料药合成工艺中用到的有机溶剂甲醇、丙酮、异丙醇、二氯 甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺,使用气相色谱准确测定7种残留溶剂的含 量。
发明内容
本发明的目的是建立一种盐酸他喷他多原料药中有机残留溶剂的检测方法,利用气相色 谱法,迅速、准确地检测盐酸他喷他多中甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢 呋喃、N,N-二甲基甲酰胺7种有机溶剂残留量。该方法的优点:1、该方法普遍,实用性高, 操作简单;2、具有足够的灵敏度,分离度好,可对杂志进行有效的控制。
本发明提供了一种盐酸他喷他多原料药中残留溶剂的检测方法,步骤如下:
(1)取甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺适量, 精密称定,置于100ml量瓶,加入二甲亚砜溶剂并稀释至刻度,摇匀,制成甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺分别为300、500、500、60、500、 75、90ug/ml的混合对照品溶液;
(2)精密称取盐酸他喷他多500mg,置一10ml顶空瓶中,加入5ml二甲亚砜,密封,轻轻摇匀,作为供试品溶液;
(3)采用气相色谱法,FID检测器,经程序升温,顶空进样,检测空白溶液、对照品溶液和供试品溶液,记录图谱,按外标法计算甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四 氢呋喃、N,N-二甲基甲酰胺残留溶剂含量。
进一步地,本发明所述的检测方法中,采用聚硅氧烷毛细管色谱柱,起始温度为30℃~ 50℃,进样口温度180℃~230℃,检测温度200℃~260℃,载气为惰性气体,流速1.0~ 4.0ml/min,分流比5~20:1。
更进一步地,本发明所述的检测方法中,色谱柱为Agilent DB-624(30m×0.32mm,1.8μm); 起始温度优选35℃~45℃,最优值为40℃;进样口温度优选200℃~210℃,最优值为200℃; 检测温度优选200℃~220℃,最优值为200℃;载气为N2;流速优选2.0ml/min~4.0ml/min, 最优值为3.0ml/min;分流比优选10~15:1,最优值为10:1。
本发明与已有技术相比的积极效果在于:
1、本发明中气相色谱条件适用于盐酸他喷他多原料药有机溶剂残留的检测,可快速准确 的检测出甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺7种残 留溶剂含量。
2、本发明检测方法准确,操作简捷,重现性好,灵敏度高,可以充分满足盐酸他喷他多 原料药有机溶剂残留测定的要求,能更好的控制产品质量,保证药品安全性。
附图说明
图1.空白溶剂气相色谱图
图2.甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺混合系 统适应性气相色谱图
图3.样品溶液气相色谱图
具体实施方式
实施例
1、仪器与试药
仪器:Agilent 7890B气相色谱仪,7697A顶空进样器,检测器:FID;Agilent色谱工作 站;
试药:所用试剂均为色谱纯;盐酸他喷他多(自制)。
2、色谱条件
色谱柱:Agilent DB-624(30m×0.32mm,1.8μm);
柱温:40℃保持6min,在30℃/min的速率升至200℃,保持6min;
进样口温度:200℃;
检测温度:200℃;
载气:N2,分流比:10:1;
进样方式:顶空进样法;
平衡时间:30min;
平衡温度:80℃。
3、溶液配制
混合对照品溶液配制:取甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺适量,精密称定,置于100ml量瓶,加入DMF溶剂并稀释至刻度,摇匀,制 成甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺分别为300、 500、500、60、500、75、90ug/ml的混合对照品溶液。
供试品溶液配制:精密称取盐酸他喷他多500mg,置于10ml顶空瓶中,加入5ml二甲亚 砜,密封,轻轻摇匀,作为供试品溶液。
4、样品测定
①系统适用性试验
精密量取空白溶剂(二甲亚砜)、甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、 N,N-二甲基甲酰胺的峰定位溶液及混合对照品溶液各5ml,顶空进样。
空白溶剂不会对有机残留溶剂造成干扰,各组分均得到完全分离,R>1.5,各组分保留 时间及分离度见表1。原始图谱见图1-3。
表1.各组分保留时间及分离度测定结果
②精密度试验
取混合对照品溶液顶空连续进样6次,RSD均在5%内,见表2。
表2.精密度试验测定结果(n=6)
③线性试验
精密量取混合对照品储备液0.2、0.3、0.5、1.0、1.5、2.0ml,分别置于10ml量瓶中,加 入二甲亚砜稀释至刻度,摇匀;精密量取5ml置10ml顶空瓶中,密封,制成一系列不同浓度 的线性混合对照品溶液。顶空进样,以对照品峰面积为纵坐标,以甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺对照品溶液浓度为横坐标,进行线性回归,测定结果见表3。
表3.线性试验测定结果
④回收率试验
精密称量盐酸他喷他多500mg共9份,分别各加入5ml的甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺混合对照品储备液,加入二甲亚砜稀释至刻度,摇匀,作为回收率样品溶液,各取5ml顶空进样,记录色谱图,由下公式计算回收率。可节 省的回收率在90%~110%(100%±10%),结果见表4。
⑤检测线及定量限
以信噪比S/N=3计算检测线,以信噪比S/N=10计算定量限,依次分别稀释甲醇、丙酮、 异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺混合对照品储备液,取5ml顶 空进样,记录色谱图,检测线及定量限测定结果见表5。
表5.各组分检测线及定量限测定结果
⑥样品检测
精密量取“3溶液配制”相下的供试品溶液和对照品溶液各5ml,顶空进样,记录色谱图, 按外标法以峰面积计算吗,含甲醇不得超过0.3%,丙酮不得超过0.5%,异丙醇不得超过0.5%, 二氯甲烷不得超过0.06%,乙酸乙酯不得超过0.5%,四氢呋喃不得超过0.072%,N,N-二甲 基甲酰胺不得超过0.088%。
按照上述方法检测样品的有机残留溶剂,甲醇不得超过0.0%,丙酮0.0%,异丙醇0.0%,二 氯甲烷0.0%,乙酸乙酯0.0%,四氢呋喃0.0%,N,N-二甲基甲酰胺0.0%。
Claims (10)
1.一种盐酸他喷他多中残留溶剂的检测方法,其特征在于采用气相色谱-外标法联合使用的检测方法,同时测定甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃和N,N-二甲基甲酰胺7种有机残留溶剂。
2.根据权利要求1所述的检测方法,其特征在于,所述检测方法采用的色谱柱为聚硅氧烷毛细管色谱柱。
3.根据权利要求1所述的检测方法,其特征在于,所述检测方法采用程序升温。
4.根据权利要求1所述的检测方法,其特征在于,所述检测方法起始温度为30℃~50℃。
5.根据权利要求1所述的检测方法,其特征在于,进样口温度180℃~230℃。
6.根据权利要求1所述的检测方法,其特征在于,检测温度200℃~260℃。
7.根据权利要求1所述的检测方法,其特征在于,载气为惰性气体,流速1.0~4.0ml/min。
8.根据权利要求1所述的检测方法,其特征在于,分流比5~20:1。
9.根据权利要求1所述的检测方法,其特征在于,采用顶空进样。
10.根据权利要求1所述的检测方法,其特征在于,该检测方法的样品检测步骤如下:
步骤一:制备待检测残留溶剂对照品溶液;
步骤二:制备供试品溶液;
步骤三:采用气相色谱法,检测空白溶液、对照品溶液和供试品溶液,记录图谱,按外标法计算甲醇、丙酮、异丙醇、二氯甲烷、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺残留溶剂含量。
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