CN114113419A - 沙格列汀及其异构体的色谱分离方法 - Google Patents
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Abstract
本发明提供一种采用色谱法分离沙格列汀及其异构体的方法，所述分离方法为色谱法。该方法选用大赛璐AD‑H色谱柱，以加入二乙胺和水的乙醇与正己烷的混合溶液为流动相，进行等度洗脱。本发明通过色谱条件的选择，能够同时将沙格列汀及其七种对映、非对映异构体相互分离，具有快速、简便、高效等特点。
Description
技术领域：
本发明属于药物分析技术领域，具体涉及用色谱法对沙格列汀及其异构体进行分离的方法。
背景技术：
沙格列汀是由Bristol-Myers Squibb公司与Astra Zeneca公司联合开发的一种高效二肽基肽酶-4(DPP-4)选择性和竞争性抑制剂，主要用于Ⅱ型糖尿病治疗。该药的主要作用机制是通过可逆的、竞争性和选择性抑制二肽基肽酶-4(DPP-4)，减少胰高血糖素样肽-1(GLP-1)水解，增加胰岛素释放从而降低血糖。该药降血糖作用明显、毒副作用小、安全性高。沙格列汀的化学名为(1S,3S,5S)-2-[(2S)-2-氨基-2-(3-羟基三环[3.3.1.13,7]癸烷-1-基)乙基]-2-氮杂双环[3.1.0]己烷-3-腈，结构如式I所示。
沙格列汀的化合物结构中含有4个手性中心，因其中两个手性中心处于三元环上，因此理论上一共有8种异构体，其结构式如表1所示。对于含有多个手性中心的化合物的异构体的分离与检测一直是药物质量控制的难点，沙格列汀异构体的分析测定至今未见报道。因此，提供一种高效简便的分离沙格列汀及其7种异构体的方法是本领域急需解决的技术问题。
表1沙格列汀及其7种异构体杂质
发明内容：
本发明的目的是提供一种快速、简便、高效的沙格列汀及其7种异构体的色谱分离方法。
本发明采用的技术方案如下：选用大赛璐AD-H色谱柱，以乙醇、正己烷、二乙胺和水的混合溶液为流动相，流动相的体积比为乙醇：正己烷：二乙胺：水＝40～60:60～40:0.1:0.1，流速为0.6～1.2mL/min进行等度洗脱。
进一步，所述大赛璐AD-H色谱柱以直链淀粉-三(3,5-二甲苯基氨基甲酸酯)为填料。
更进一步，所述大赛璐AD-H色谱柱的规格为250mm*4.6mm*5um。
更进一步，所述手性色谱柱的柱温为20～30℃，优选25℃。
进一步，所述流动相为加入二乙胺和水的乙醇和正己烷的混合溶液。
更进一步，所述流动相的体积比为乙醇：正己烷：二乙胺：水＝40～60:60～40:0.1:0.1，优选乙醇：正己烷：二乙胺：水＝40:60:0.1:0.1。
更进一步，所述流动相流速为0.6～1.2mL/min，优选0.7mL/min。
进一步，所述供试液浓度为50～80mg/mL，优选80mg/mL。
进一步，进样量为10～30uL，优选20uL。
进一步，所述检测波长为210～220nm，优选218nm。
进一步，所述运行时间为70～80min，优选75min。
进一步，在我们的检测条件下，最先出峰的是SSR构型，紧跟出峰的是RRR构型，再出峰的是RSR构型，然后依次出峰的是SRR构型、RSS构型、RRS构型、SSS构型(沙格列汀)、最后出峰的是SRS构型，相邻异构体之间的分离度均大于1.5，完全符合基线分离的要求。
本发明的有益效果在于，通过在流动相中添加一定比例的水在一定程度上实现对化合物拖尾的抑制，改善化合物的峰形，优化相邻异构体之间的分离度，从而可以通过一次高效液相色谱检测，同时准确地测定出沙格列汀及其7种异构体的含量，能够达到良好的分离效果，而且在流动相中加入水，使得化合物溶解性更好，出峰的峰型更好。该方法快速、简便、高效，可以更好地控制沙格列汀的质量以及稳定性。
附图说明
图1实施例1的高效液相色谱图
图2实施例2的高效液相色谱图
图3实施例3的高效液相色谱图
图4实施例4的高效液相色谱图
图5实施例5的高效液相色谱图
图6实施例6的高效液相色谱图
图7实施例7的高效液相色谱图
图8实施例8的高效液相色谱图
图9实施例8的紫外吸收图
具体实施方式
下面结合具体实施例对本发明的技术内容作进一步的阐述，其目的是为了更好的理解本发明的内容，但本发明的保护范围不限于此。
实施例1沙格列汀的HPLC分析
色谱条件：
色谱柱：大赛璐AD-H柱，250mm*4.6mm*5um。
流动相：乙醇/正己烷/二乙胺/水(40/60/0.1/0.1，V/V/V/V)，等度洗脱。
流速：0.7mL/min。
波长：218nm。
柱温：25℃。
运行时间：75min。
稀释剂及空白：流动相。
供试液浓度：80mg/mL。
进样量：20uL。
实验步骤：
分别称取沙格列汀及其7种异构体各800mg至10mL容量瓶中，用上述稀释剂溶解稀释至刻度，摇匀，得混合液。取空白和混合液按照上述色谱条件进样，记录色谱图(图1)，其中保留时间约5.33min的峰为SSR，10.19min的峰为RRR，13.43min的峰为RSR，15.63min的峰为SRR，25.00min的峰为RSS，35.70min的峰为RRS，41.91min的峰为SSS(沙格列汀)，63.59min的峰为SRS，相邻异构体之间的分离度均大于1.5，完全符合基线分离的要求。见图1。
实施例2沙格列汀的HPLC分析
使用实施例1相同的条件和方法进行检测，仅将色谱柱替换为大赛璐IC柱，规格为150mm*4.6mm*3um，八个异构体无法实现基线分离。见图2。
实施例3沙格列汀的HPLC分析
使用实施例1相同的条件和方法进行检测，仅将色谱柱替换为大赛璐OX柱，规格为250mm*4.6mm*5um，八个异构体无法实现基线分离。见图3。
实施例4沙格列汀的HPLC分析
使用实施例1相同的条件和方法进行检测，仅将流动相比例替换为乙醇/正己烷/二乙胺(40/60/0.1，V/V/V/V)，拖尾严重，八个异构体无法实现基线分离。见图4。
实施例5沙格列汀的HPLC分析
使用实施例1相同的条件和方法进行检测，仅将流动相替换为异丙醇/正己烷/二乙胺/水(40/60/0.1/0.1，V/V/V/V)，八个异构体无法实现基线分离。见图5。
实施例6沙格列汀的HPLC分析
使用实施例1相同的条件和方法进行检测，仅将流速替换为1mL/min，八个异构体无法实现基线分离。见图6。
实施例7沙格列汀的HPLC分析
使用实施例1相同的条件和方法进行检测，仅将柱温替换为30℃，八个异构体也可以实现基线分离。见图7。
实施例8沙格列汀的HPLC分析
使用实施例1相同的条件和方法进行检测，仅将波长替换为215nm，八个异构体也可以实现基线分离，但基线略差，见图8；沙格列汀的紫外吸收图为9。
Claims (6)
1.一种沙格列汀及其异构体的色谱分离方法，其特征在于，选用大赛璐AD-H色谱柱，以乙醇、正己烷、二乙胺和水的混合溶液为流动相，流动相的体积比为乙醇：正己烷：二乙胺：水＝40～60:60～40:0.1:0.1，流速为0.6～1.2mL/min进行等度洗脱。
2.如权利要求1所述的检测方法，其特征在于，所述大赛璐AD-H色谱柱以直链淀粉-三(3,5-二甲苯基氨基甲酸酯)为填料。
3.如权利要求1所述的检测方法，其特征在于，柱温为20～30℃。
4.如权利要求1所述的检测方法，其特征在于，供试液浓度为50～80mg/mL；进样量为10～30uL。
5.如权利要求1所述的检测方法，其特征在于，检测波长为210～220nm。
6.如权利要求1所述的检测方法，其特征在于，运行时间为70～80min。
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