CN115248261A - 一种磷酸特地唑胺原料药中有关物质的hplc分析检测方法 - Google Patents
一种磷酸特地唑胺原料药中有关物质的hplc分析检测方法 Download PDFInfo
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Abstract
本发明属于化学药物分析技术领域,具体涉及一种磷酸特地唑胺原料药中有关物质的检测方法,所述检测方法采用高效液相色谱法检测,色谱条件包括:色谱柱的固定相用十八烷基硅烷键合硅胶作为填充剂,以pH8.0~9.0的磷酸盐为流动相A,以乙腈为流动相B实施洗脱,对磷酸特地唑胺及其杂质实施检测。本发明提供的检测方法能够实现主成分与14种已知杂质质之间的有效分离,且专属性强、重现性好、准确度高。
Description
技术领域
本发明涉及化学药物分析检测技术领域,尤其涉及一种磷酸特地唑胺中有关物质的检测方法。
背景技术
磷酸特地唑胺(商品名)是一种噁唑烷酮类抗菌药物,Sivextro是一种前药,在体内可被磷酸酶迅速转化为具有生物活性的特地唑胺。后者能够和细菌的核糖体50S亚基结合,从而抑制蛋白质的合成。适用于治疗由以下革兰阳性微生物的易感菌株引起的急性细菌性皮肤和皮肤结构感染(ABSSSI):金黄色葡萄球菌(包括耐甲氧西林[MRSA]和甲氧西林敏感[MSSA]分离株),化脓性链球菌,无乳链球菌,咽峡炎链球菌群(咽峡炎链球菌、中间链球菌和星座链球菌)以及粪肠球菌。于2014年6月由FDA批准在美国上市。
磷酸特地唑胺,化学名为(5R)-(3-{3-氟-4-[6-(2-甲基-2H-四唑-5-基)吡啶-3-基]苯基}-2-氧噁唑烷-5-基)甲基二氢磷酸酯,分子式为C17H16FN6O6P,分子量为450.32,CAS号为,结构式如下:
有关物质的检测方法是药品质量研究中的重要组成部分,能够有效把控药品质量。目前,关于磷酸特地唑胺中有关物质的检测方法鲜有文献报道,或虽有专利报道,例如CN201610545390.X、CN201710406797.9及进口注册标准JX20160162分别公开了高效液相测定磷酸特地唑胺及其有关物质,但其测定杂质个数较少,杂质谱覆盖面较小,主成分保留时间较短,对关键的降解杂质未能准确定量。同时对文件对药品质量的评估存在一定的风险。
发明内容
针对上述技术问题,本发明提供一种磷酸特地唑胺中有关物质的检测方法。
为解决上述技术问题,本发明提供的技术方案是:
一种磷酸特地唑胺中有关物质的检测方法,该检测方法采用高效液相色谱法,其色谱条件包括:采用流动相A和流动相B的混合溶液进行梯度洗脱,所述流动相A为磷酸二氢钠溶液,所述流动相B为乙腈,所述检测方法经一次进样,对14个杂质实现定性与定量的检测,磷酸特地唑胺峰与相邻杂质峰的分离度≥1.5,各所述杂质峰间的分离度≥1.5。
在一些优选的实施例中,所述十八烷基硅烷键合硅胶柱Waters Xterra ShieldRP184.6×150mm,3.5μm。
在一些优选的实施例中,所述流动相A的浓度为0.01~0.03mol/L,优选为0.02mol/L。
在一些优选的实施例中,所述流动相A的pH值为8.0~9.0,优选为8.5。
在一些优选的实施例中,所述流动相A采用氢氧化钠溶液调节pH值。
在一些优选的实施例中,所述梯度洗脱条件如下:
0~30分钟,流动相A和流动相B的体积比从98∶2匀速渐变至60∶40;
30~30.1分钟,流动相A和流动相B的体积比从60∶40匀速渐变至98∶2;
30.1~35分钟,流动相A和流动相B的体积比保持98∶2不变。
在一些优选的实施例中,检测波长为295nm~305nm,优选为300nm。
在一些优选的实施例中,柱温为35℃~45℃,优选为40℃。
在一些优选的实施例中,流速为0.9ml/min~1.1ml/min,优选为1.0mlmin。
在一些优选的实施例中,进样体积为10μl。
本发明具有的积极效果:
(1)本发明的方法通过选择合适的流动相以及洗脱条件,能够将磷酸特地唑胺原料药与14种杂质在同一色谱条件下进行快速有效的分离,主峰与相邻杂质峰、各杂质峰之间能达到基线分离,而现有对比文件中只能分离其中的5~7种杂质,对比结果见表2。
(2)与进口注册标准JX20160162相比较,本发明中流动相A使用磷酸二氢钠可以防止磷酸特地唑胺原料药进一步水解成杂质A。
表1连续6份样品中杂质A(水解杂质)检出情况
(3)本发明的方法专属性强、灵敏度高、精密度好、准确度高,能够有效控制磷酸特地唑胺原料药的质量,保证磷酸特地唑胺原料药的有效性和安全性。
附图说明
图1为实施例2中的系统适用性溶液的高效液相色谱图。
图2为实施例2中的供试品溶液高效液相色谱图。
具体实施方式
以下详细描述本发明的技术方案。本发明实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围,其均应涵盖在本发明的权利要求范围中。
本实施例中,对磷酸特地唑胺合成过程中可能存在的杂质进行了深入的分析,并鉴定了14个杂质。
本发明提供的磷酸特地唑胺有关物质的检测方法,涉及的各项杂质如下:
表2本发明涉及的各项杂质以及与对比文件研究杂质对比
实施例1:
高效液相色谱条件:色谱柱为十八烷基硅烷键合硅胶柱,型号为WatersXterraShieldRP184.6×150mm,3.5μm,以磷酸二氢钠溶液(称磷酸二氢钠2.40g,加水1000ml使溶解,用氢氧化钠酸调节pH值至8.5)为流动相A,以乙腈为流动相B,梯度洗脱,流速为1.0ml/ml;检测波长为300nm;柱温40℃;进样量10μl。稀释液为流动相A与流动相B的体积比为95∶5的混合溶液。
梯度洗脱:(1)在0~30分钟,流动相A和流动相B的体积比从98∶2匀速渐变至60∶40;(2)在30~30.1分钟,流动相A和流动相B的体积比从60∶40匀速渐变至98∶2;(3)在30.1~35分钟,流动相A和流动相B的体积比保持98∶2不变。
样品溶液的配制:
供试品溶液:取本品10mg,置50ml量瓶中,加稀释液溶解并稀释至刻度,摇匀,即得。
对照溶液:精密量取供试品溶液1ml,置50ml量瓶中,用稀释液稀释至刻度,摇匀,精密量取该溶液1ml,置20ml量瓶中,用稀释液稀释至刻度,摇匀,即得。
杂质定位溶液(杂质对照品溶液):分别取杂质C对照品、杂质D对照品、杂质E对照品、杂质G对照品、杂质J对照品、杂质K对照品和杂质N对照品对照品各10mg,精密称定,分别置各自50ml量瓶中,加稀释液溶解并稀释至刻度,摇匀,作为各杂质定位溶液;分别取杂质A对照品、杂质G对照品、杂质I对照品、杂质L对照品、杂质M对照品和杂质F对照品各10mg,精密称定,分别置各自50ml量瓶中,加二甲基亚砜溶解并稀释至刻度,摇匀,作为各杂质定位溶液;取杂质B对照品10mg,精密称定,置50ml量瓶中,加二氯甲烷-甲醇(80∶20)溶解并稀释至刻度,摇匀,作为杂质B定位溶液。
杂质混合对照溶液:分别精密量取杂质B、杂质C、杂质E、杂质H、杂质I、杂质J、杂质K、杂质L、杂质M和杂质N各1ml,杂质A、杂质D、杂质F和杂质G各2ml,置同一100ml量瓶中,用稀释液稀释至刻度,摇匀,即得。
系统适用性溶液:取磷酸特地唑胺对照品10mg,置50ml量瓶中,加稀释液适量使溶解,精密加入杂质混合对照溶液5ml,用稀释液稀释至刻度,摇匀,即得。
计算方法:主成分自身对照品法。
计算公式:
其中,A杂质:供试品溶液中杂质的峰面积;
A对照:对照溶液的峰面积;
F:杂质的校正因子
实施例2
对有关物质检测方法进行验证,如下:
1、专属性
取空白溶液、各杂质定位溶液、供试品溶液、系统适用性溶液各10μl,注入液相色谱仪,记录色谱图,考察各成分的保留时间、分离度及理论塔板数。结果见表1。
表3专属性结果
结果表明:所得的空白溶液色谱图与系统适用性溶液色谱图进行比较,在主峰及杂质峰的保留时间处无干扰;主峰与相邻杂质峰分离度为3.90,各杂质峰之间最小分离度为3.00。表明专属性良好。
2、准确度
精密称取磷酸特地唑胺9份,分别加入杂质限度浓度的50%、100%、150%的杂质对照品溶液,制成每1ml中约含磷酸特地唑胺0.2mg的溶液,分别精密量取10μl,注入液相色谱仪,记录色谱图,以各杂质的[(测得量-本底量)/加入了]计算回收率,结果见表4。
表4各杂质回收率测定结果
杂质 | 回收率结果(%) | 平均回收率(%) | RSD(%) |
杂质A | 98.7~105.2 | 100.6 | 1.9 |
杂质B | 98.1~101.1 | 99.5 | 1.6 |
杂质C | 97.2~103.1 | 100.2 | 1.9 |
杂质D | 96.7~99.3 | 98.4 | 0.92 |
杂质E | 93.8~97.9 | 96.8 | 1.4 |
杂质F | 98.8~101.2 | 99.9 | 0.73 |
杂质G | 98.4~100.6 | 99.4 | 0.67 |
杂质H | 98.4~103.8 | 99.4 | 2.0 |
杂质I | 98.5~101.7 | 100.1 | 1.7 |
杂质J | 97.7~101.9 | 99.1 | 1.3 |
杂质K | 97.5~100.6 | 99.1 | 1.2 |
杂质L | 94.4~105.8 | 99.6 | 4.3 |
杂质M | 95.8~98.4 | 96.7 | 1.3 |
杂质N | 95.5~99.0 | 97.7 | 1.1 |
由上表可知,各杂质回收率均在90%~108%之间,RSD均小于5.0%,回收率良好;表明本发明的方法适用于本品有关物质的测定。
3、耐用性
以单因素变化的方式考察改变流速(±0.1ml/min)、色谱柱温度(±5℃)、缓冲溶液的pH值(±0.5)、流动相的初始比例(±1%)或检测波长(±5nm)等色谱条件对检测供试品溶液的影响,主要考察改变色谱条件对供试品溶液中各有关物质间的检测结果以及分离度的影响。结果见表4~表5。
表4耐用性杂质含量结果
表5耐用性系统适应性结果
结论:在各色谱条件下,系统适用性中主峰与各杂质峰分离度均大于1.5;各条件下杂质量与原条件各杂质检出量无明显变化。表明方法耐用性良好。
本发明专属性良好,准确度高,测定杂质种类多,为磷酸特地唑胺中有关物质的快速准确监控提供方法。
应当理解的是,本文所述发明不限于特定的方法学、实验方案或试剂,因为这些是可以变化的。本文所提供的论述和实例仅是为了描述特定的实施方案呈现而非意在限值本发明的范围,本发明的范围仅受到权利要求的限定。
Claims (8)
1.一种磷酸特地唑胺中有关物质的检测方法,其特征在于采用高效液相色谱法,其色谱条件包括:采用流动相A和流动相B的混合溶液进行梯度洗脱,所述流动相A为磷酸二氢钠溶液,所述流动相B为乙腈,所述检测方法经一次进样,对14个杂质实现定性与定量的检测,磷酸特地唑胺峰与相邻杂质峰的分离度≥1.5,各所述杂质峰间的分离度≥1.5。
2.根据权利要求1所述的检测方法,其特征在于所述十八烷基硅烷键合硅胶柱WatersXterra Shield RP18 4.6×150mm,3.5μm。
3.根据权利要求1所述磷酸特地唑胺中有关物质分析方法,其特征在于,所述流动相A为磷酸二氢钠溶液;所述流动相A的浓度为0.01~0.03mol/L。
4.根据权利要求3所述磷酸特地唑胺中有关物质分析方法,其特征在于,所述流动相A的pH值为8.0~9.0。
5.根据权利要求4所述磷酸特地唑胺中有关物质分析方法,其特征在于,所述流动相A采用氢氧化钠溶液调节pH值。
6.根据权利要求1所述磷酸特地唑胺中有关物质检测方法,其特征在于,所述梯度洗脱的程序为:(1)在0~30分钟内,流动相A和流动相B的体积比从98∶2匀速渐变至60∶40;(2)在30~30.1分钟内,流动相A和流动相B的体积比从60∶40匀速渐变至98∶2;(3)在30.1~35分钟内,流动相A和流动相B的体积比保持98∶2不变。
7.根据权利要求1所述磷酸特地唑胺中有关物质检测方法,其特征在于,流速为0.9~1.1ml/min,检测波长为295~305nm;柱温35~45℃。
8.根据权利要求1所述磷酸特地唑胺中有关物质检测方法,其特征在于,进样体积是10μl。
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