CN111751454B - 一种异丙托溴铵中间体i的含量和有关物质的检测方法 - Google Patents
一种异丙托溴铵中间体i的含量和有关物质的检测方法 Download PDFInfo
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Abstract
本发明提供一种异丙托溴铵中间体I的含量和有关物质的检测方法,采用高效液相色谱法,以丙烷基硅烷键合硅胶为色谱柱,流动相由A相和B相组成,以含有阳离子对的磷酸盐缓冲液为流动相A,乙腈为流动相B,流动相A:流动相B为90~98:2~10,采用紫外检测器,检测波长为210nm~230nm。本发明的有益效果是该方法可以快速准确检测还原物中的外型异构体杂质,具有良好的专属性及灵敏度,流动相便宜易得,操作过程简单方便,准确性、重复性好。
Description
技术领域
本发明属于药物领域,尤其是涉及一种异丙托溴铵中间体I的含量和有关物质的检测方法。
背景技术
异丙托溴铵,是对支气管平滑肌M受体有较高选择性的强效抗胆碱药,松弛支气管平滑肌作用较强,对呼吸道腺体和心血管系统的作用较弱。用于缓解慢性阻塞性肺病(COPD)引起的支气管痉挛、喘息症状;防治哮喘、尤适用于因用β受体激动药产生肌肉震颤、心动过速而不能耐受此类药物的患者。
随着药品研发水平的提升以及相关制剂的不良反应日益被关注,医药监管机构对制剂产品中的有关物质的关注度也在日渐提高。异丙托溴铵原料药一般用于吸入给药,安全风险等级较高,更需要对其中的潜在杂质进行检测。异丙托溴铵原料药制备过程中,还原物是异丙托溴铵合成中的重要中间体,还原物(结构式如式I所示)的产生过程中,易生成外型异构体(结构式如式II所示),需对外型异构体含量进行控制。
经文献调研,未查到任何文献及药典对异丙托溴铵中间体还原物外型异构体的测定方法进行报道和收载。故本发明根据化合物的理化性质,开发了一套液相色谱体系对其进行测定。
发明内容
本发明的目的是提供一种能够检测异丙托溴铵中间体(也称异丙托溴铵还原物)的内型和外型的高效液相色谱方法。
本发明的技术方案是:
一种异丙托溴铵中间体I的含量和有关物质的检测方法,采用高效液相色谱法,以丙烷基硅烷键合硅胶为色谱柱,流动相由A相和B相组成,以含有阳离子对的磷酸盐缓冲液为流动相A,乙腈为流动相B,流动相A:流动相B的比例为94~98:2~6,用紫外检测器,检测波长为210nm~230nm。
所述一种异丙托溴铵中间体I的含量和有关物质的检测方法,所述磷酸盐缓冲液中还含有体积比为1:100~1:150的三乙胺,
所述一种异丙托溴铵中间体I的含量和有关物质的检测方法,所述阳离子对试剂选自四丙基氯化铵、四丁基氯化铵;
所述一种异丙托溴铵中间体I的含量和有关物质的检测方法,所述四丙基氯化铵、四丁基氯化铵的浓度为0.005~0.007mol/L;
所述含有阳离子对的磷酸盐缓冲液的pH为4.5~5.5;
所述含有阳离子对的磷酸盐缓冲液的pH为4.8~5.2;
所述含有阳离子对的磷酸盐缓冲液的pH为5.0;
所述流动相A:流动相B为95:5;
所述流动相A:流动相B为96:4;
所述流动相A:流动相B为94:6;
所述一种异丙托溴铵中间体I的含量和有关物质的检测方法,色谱柱柱温为45℃~55℃;
所述一种异丙托溴铵中间体I的含量和有关物质的检测方法,色谱柱柱温为50℃;
所述一种异丙托溴铵中间体I的含量和有关物质的检测方法,流动相流速为0.5ml/min~1.5ml/min;
所述一种异丙托溴铵中间体I的含量和有关物质的检测方法,流动相流速为1.0ml/min;
本发明具有的优点和积极效果是:在开发该方法时,通过对不同的离子对缓冲液进行筛选,最终选择阳离子缓冲液四丙基氯化铵和四丁基氯化铵的磷酸盐缓冲液,加三乙胺能减少拖尾,达到更好的峰形,实验中发现乙腈比例太大会导致保留时间缩短,还原物和外型异构体无法分开,而乙腈比例太小会导致峰扩散,峰形受影响,而且水的比例太大会缩短柱子的使用寿命;本发明的技术方案通过比较各种填充材料色谱柱,最终选择丙烷基硅烷键合硅胶为色谱柱以达到分离还原物和外型异构体。该方法可以快速准确检测还原物中的外型异构体杂质,具有良好的专属性及灵敏度,流动相便宜易得,操作过程简单方便,准确度、重复性好。
附图说明
图1是本发明实施例1的高效液相色谱图;
图2是本发明实施例2的高效液相色谱图;
图3是本发明实施例3的高效液相色谱图;
图4是本发明实施例4的高效液相色谱图;
图5是本发明实施例5的高效液相色谱图;
图6是本发明实施例6的高效液相色谱图;
图7是本发明对照实施例1的高效液相色谱图;
图8是本发明对照实施例2的高效液相色谱图;
图9是本发明对照实施例3的高效液相色谱图;
具体实施方式
下面将通过实施例对本发明作进一步的描述,这些描述并不是对本发明内容作进一步的限定。本领域的技术人员应理解,对本发明的技术特征所作的等同替换,或相应的改进,仍属于本发明的保护范围之内。
溶液配制
溶样液:即流动相,5.0g磷酸二氢钾,1.36g四丙基氯化铵,8ml三乙胺加入到1L水中,用磷酸调pH至5.0;
空白溶液:流动相
供试品溶液:取供试品约10mg,精密称定,置10ml量瓶中,加流动相溶液稀释定容至刻度,摇匀,作为供试品溶液。精密量取供试品溶液1ml,置100ml量瓶中,加流动相稀释定容至刻度,摇匀,作为对照溶液。
系统适用性溶液:取还原物99mg,外型异构体0.1mg,精密称定,置10ml量瓶中,加入流动相溶液稀释定容至刻度,摇匀,作为系统适用性溶液。
精密量取对照品溶液和供试品溶液各20μl注入液相色谱仪,记录色谱图。按外标法以峰面积计算,即得含量。
实施例1-实施例5进样为系统适用性溶液;
实施例6的系统适用性溶液:取还原物9.0mg,外型异构体1.0mg,精密称定,置10ml量瓶中,加入流动相溶液稀释定容至刻度,摇匀,作为系统适用性溶液。
实施例7进样供试品。
对照实施例1-2进样为系统适用性溶液
实施例1系统适用性试验
色谱条件:
色谱柱:丙烷基硅烷键合硅胶为填充剂的色谱柱(3.0×150mm,3.5μm)
流动相A:5.0g磷酸二氢钾,1.36g四丙基氯化铵,8ml三乙胺加入到1L水中,用磷酸调pH至5.0;
流动相B:乙腈
流动相A:流动相B=95:5
检测波长:220nm 柱温:50℃
流速:1.0ml/min 进样量:10μl
检测结果:见图1
名称 | 保留时间 | 分离度 |
还原物外型异构体 | 6.328 | |
还原物 | 6.995 | 1.7 |
实施例2
色谱条件:
色谱柱:丙烷基硅烷键合硅胶为填充剂的色谱柱(3.0×150mm,3.5μm)
流动相A:5.0g磷酸二氢钾,1.36g四丙基氯化铵,8ml三乙胺加入到1L水中,用磷酸调pH至5.0;
流动相B:乙腈
流动相A:流动相B=96:4
检测波长:220nm 柱温:45℃
流速:1.0ml/min 进样量:10μl
检测结果:见图2
名称 | 保留时间 | 分离度 |
还原物外型异构体 | 7.355 | |
还原物 | 8.196 | 1.9 |
实施例3
色谱条件:
色谱柱:丙烷基硅烷键合硅胶为填充剂的色谱柱(3.0×150mm,3.5μm)
流动相A:5.0g磷酸二氢钾,1.36g四丙基氯化铵,8ml三乙胺加入到1L水中,用磷酸调pH至5.0;
流动相B:乙腈
流动相A:流动相B=94:6
检测波长:220nm 柱温:52℃
流速:1.0ml/min 进样量:10μl
检测结果:见图3
名称 | 保留时间 | 分离度 |
还原物外型异构体 | 5.457 | |
还原物 | 5.942 | 1.5 |
实施例4
色谱条件:
色谱柱:丙烷基硅烷键合硅胶为填充剂的色谱柱(3.0×150mm,3.5μm)
流动相A:5.0g磷酸二氢钾,1.50g四丁基氯化铵,8ml三乙胺加入到1L水中,用磷酸调pH至5.0;
流动相B:乙腈
流动相A:流动相B=96:4
检测波长:220nm 柱温:50℃
流速:1.0ml/min 进样量:10μl
检测结果:见图4
名称 | 保留时间 | 分离度 |
还原物外型异构体 | 6.383 | |
还原物 | 7.054 | 1.7 |
实施例5
色谱条件:
色谱柱:丙烷基硅烷键合硅胶为填充剂的色谱柱(3.0×150mm,3.5μm)
流动相A:5.0g磷酸二氢钾,1.50g四丁基氯化铵,8ml三乙胺加入到1L水中,用磷酸调pH至5.2;
流动相B:乙腈
流动相A:流动相B=96:4
检测波长:220nm 柱温:50℃
流速:1.0ml/min 进样量:10μl
检测结果:见图5
名称 | 保留时间 | 分离度 |
还原物外型异构体 | 6.595 | |
还原物 | 7.224 | 1.7 |
实施例6不加三乙胺
色谱条件:
色谱柱:丙烷基硅烷键合硅胶为填充剂的色谱柱(3.0×150mm,3.5μm)
流动相A:5.0g磷酸二氢钾,1.50g四丁基氯化铵加入到1L水中,用磷酸调pH至4.8;
流动相B:乙腈
流动相A:流动相B=96:4
检测波长:220nm 柱温:50℃
流速:1.0ml/min 进样量:10μl
检测结果:见图6
实施例7
色谱条件:
色谱柱:丙烷基硅烷键合硅胶为填充剂的色谱柱(3.0×150mm,3.5μm)
流动相A:5.0g磷酸二氢钾,1.36g四丙基氯化铵,8ml三乙胺加入到1L水中,用磷酸调pH至5.0;
流动相B:乙腈
流动相A:流动相B=95:5
检测波长:220nm 柱温:50℃
流速:1.0ml/min 进样量:10μl
检测结果:见图7,样品中不存在还原物外型异构体。
对照实施例1甲磺酸钠
色谱条件:
色谱柱:丙烷基硅烷键合硅胶为填充剂的色谱柱(3.0×150mm,3.5μm)
流动相A:5.0g磷酸二氢钾,0.63g甲磺酸钠,8ml三乙胺加入到1L水中,用磷酸调pH至5.0;
流动相B:乙腈
流动相A:流动相B=95:5
检测波长:220nm 柱温:50℃
流速:1.0ml/min 进样量:10μl
检测结果:见图8
名称 | 保留时间 | 分离度 |
还原物外型异构体 | 4.573 | |
还原物 | 4.813 | 0.68 |
对照实施例2AD-H手性柱
色谱条件:
色谱柱:CHIRALPAK AD-H为填充剂的色谱柱(3.0×150mm,3.5μm)
流动相A:5.0g磷酸二氢钾,1.50g四丁基氯化铵,8ml三乙胺加入到1L水中,用磷酸调pH至5.0;
流动相B:乙腈
流动相A:流动相B=95:5
检测波长:220nm 柱温:50℃
流速:1.0ml/min 进样量:10μl
检测结果:见图9,还原物外型异构体和还原物完全重合,不能分开。
以上对本发明的一个实施例进行了详细说明,但所述内容仅为本发明的较佳实施例,不能被认为用于限定本发明的实施范围。凡依本发明申请范围所作的均等变化与改进等,均应仍归属于本发明的专利涵盖范围之内。
Claims (6)
1.一种异丙托溴铵中间体I的含量和有关物质Ⅱ的检测方法,其特征在于:采用高效液相色谱法,以丙烷基硅烷键合硅胶为色谱柱,流动相由A相和B相组成,以含有阳离子对的磷酸盐缓冲液为流动相A,乙腈为流动相B,流动相A:流动相B为95:5、96:4或94:6,采用紫外检测器,检测波长为210nm~230nm;
所述流动相A为含有阳离子对和三乙胺的磷酸二氢钾溶液,其中阳离子对试剂选自四丙基氯化铵、四丁基氯化铵,浓度为0.005~0.007mol/L;磷酸二氢钾溶液中的含有体积比为1:100~1:150的三乙胺,流动相pH值为4.8-5.2。
2.根据权利要求1所述的一种异丙托溴铵中间体I的含量和有关物质Ⅱ的检测方法,其特征在于:流动相A的pH为5.0。
3.根据权利要求1所述的一种异丙托溴铵中间体I的含量和有关物质Ⅱ的检测方法,其特征在于:色谱柱柱温为45℃~55℃。
4.根据权利要求1所述的一种异丙托溴铵中间体I的含量和有关物质Ⅱ的检测方法,其特征在于:色谱柱柱温为50℃。
5.根据权利要求1所述的一种异丙托溴铵中间体I的含量和有关物质Ⅱ的检测方法,其特征在于:流动相流速为0.5ml/min~1.5ml/min。
6.根据权利要求5所述的一种异丙托溴铵中间体I的含量和有关物质Ⅱ的检测方法,其特征在于:流动相流速为1.0ml/min。
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