几种手性药物在纤维素键合型手性固定相的拆分研究
摘要
目前手性药物的研究已经成为药物研发的热点。在多种手性固定相的发展中,纤维素键合型手性固定相所具有的性能稳定、拆分效果好、适用范围广的特点让其以绝对优势成为拆分手性药物最常用的手性固定相之一,为获得单一构型的对映体药物开辟了新途径。
丁苯酞(NBP)是我国自主研发的用于治疗脑卒中的一类新药,其衍生物6-溴丁苯酞(6-Br-NBP)的合成已申请专利,并成功授权。而GX-22、GX-25、GX-26和GX-30四种手性化合物是笔者所在科研机构自主研发合成的新化合物,它们结构中均含有α-亚甲基-γ-丁内酯活性基团,经初步研究表明,这四种化合物均有良好的体外抗菌活性。
本文主要进行了以下三个方面的研究：
一、采用正相高效液相色谱法对NBP及其衍生物6-Br-NBP进行手性拆分
采用正相高效液相色谱法,利用键合型纤维素Chiralpak IC柱,对NBP及其衍生物6-Br-NBP原料药进行拆分研究。系统地对影响手性药物拆分的因素：流动相的组成和配比、柱温、流速进行了考察和优化。结果表明,在Chiralpak IC柱上,对于NBP的分离,采用无水乙醇作为流动相有机改性剂,分离效果优于异丙醇,可以达到基线分离；就6-Br-NBP而言,采用异丙醇作为流动相有机改性剂分离效果明显好于异丙醇,且保留时间短,分离度较大。
二、采用正相高效液相色谱法对四种含α-亚甲基-γ-丁内酯基团的手性化合物进行手性拆分
采用正相高效液相色谱法,利用键合型纤维素Chiralpak IC柱,对四种含α-亚甲基-γ-丁内酯基团的手性化合物GX-22、GX-25、GX-26和GX-30原料药进行拆分研究。系统地对影响手性药物拆分的因素：流动相的组成和配比、柱温、流速进行了考察优化。结果表明,在Chiralpak IC柱上,对于GX-25和GX-26,采用异丙醇作为流动性有机改性剂,分离效果优于异丙醇,可使对映体达到基线分离；对于GX-22和GX-30,异丙醇和无水乙醇同时存在作为有机改性剂可使对映体达基线分离。
三、6-Br-NBP对映体体内含量测定方法研究
对六只SD大鼠进行单剂量口服灌胃给药,分别于给药后1、2、4、8h后眼眶静脉丛取血；对生物样品进行预处理后,在正相色谱条件下,利用Chiralpak IC柱进行分析,测定6-Br-NBP在大鼠血浆中的浓度。通过特异性实验,测定精密度和准确度、线性范围、提取回收率和方法回收率以及定量限等进行了方法学验证。
The quality control of chiral drugs catches people's attention increasingly,so it becomes a focus in this field. High Performance Liquid Chromatography is one of the most popular analytic techniques and the method with chiral stationary phase is more classical,convenient and fast.The method with bonded chiral stationary phase has a steady performance and now it is used widely.
NBP is approved as an anti-cerebral ischemic agent by the State Food and Drug Administration(SFDA) of China.6-Br-NBP, a derivative compound of NBP,has been proved to be more active than NBP. Four chiral compounds (GX-22、GX-25、GX-26and GX-30) are synthesized including a-methylene-y-butyrolactones and studies on the biological activities of four chiral compounds are proved to be satisfying.
Three aspects have been carried out in this study:
1.Enantioseparation of NBP and6-Br-NBP on Chiralpak IC column
HPLC methods have been developed for the chiral separation of NBP and6-Br-NBP on a Chiralpak IC column under normal phase mode. The influences of organic solvent, column temperature and flow rate were investigated and the enatiomeric separation was optimized systematically. The results showed that NBP and6-Br-NBP can be separated completely. For NBP, ethanol was better than isopropanol as a component of mobile phase. For6-Br-NBP, isopropanol was much better than rthanol.
2.Enantioseparation of four chiral compounds (GX-22、GX-25、GX-26and GX-30) including a-methylene-y-butyrolactone on Chiralpak IC column
HPLC methods have been developed for the chiral separation of four chiral compounds including a-methylene-y-butyrolactone on a Chiralpak IC column under normal phase mode. The influences of organic solvent, column temperature and flow rate were investigated and the enatiomeric separation was optimized systematically. The results showed that GX-25and GX-26can be separated completely using isopropanol as the component of mobile phase. Both GX-22and GX-30were separated completely using ethanol and isopropanol as the components of mobile phase.
3.Determination of enantiomers of6-Br-NBP in SD rats plasma on Chiralpak IC column by HPLC
The biological samples were pretreated and separation conditions were optimized. Concentration of enantiomers of6-Br-NBP in SD rats plasma was measured under normal mode by HPLC with fluorescence detector. Method was evaluated from specificity, precision, accuracy, linearity, recovery,etc.
丁苯酞(NBP)是我国自主研发的用于治疗脑卒中的一类新药,其衍生物6-溴丁苯酞(6-Br-NBP)的合成已申请专利,并成功授权。而GX-22、GX-25、GX-26和GX-30四种手性化合物是笔者所在科研机构自主研发合成的新化合物,它们结构中均含有α-亚甲基-γ-丁内酯活性基团,经初步研究表明,这四种化合物均有良好的体外抗菌活性。
本文主要进行了以下三个方面的研究：
一、采用正相高效液相色谱法对NBP及其衍生物6-Br-NBP进行手性拆分
采用正相高效液相色谱法,利用键合型纤维素Chiralpak IC柱,对NBP及其衍生物6-Br-NBP原料药进行拆分研究。系统地对影响手性药物拆分的因素：流动相的组成和配比、柱温、流速进行了考察和优化。结果表明,在Chiralpak IC柱上,对于NBP的分离,采用无水乙醇作为流动相有机改性剂,分离效果优于异丙醇,可以达到基线分离；就6-Br-NBP而言,采用异丙醇作为流动相有机改性剂分离效果明显好于异丙醇,且保留时间短,分离度较大。
二、采用正相高效液相色谱法对四种含α-亚甲基-γ-丁内酯基团的手性化合物进行手性拆分
采用正相高效液相色谱法,利用键合型纤维素Chiralpak IC柱,对四种含α-亚甲基-γ-丁内酯基团的手性化合物GX-22、GX-25、GX-26和GX-30原料药进行拆分研究。系统地对影响手性药物拆分的因素：流动相的组成和配比、柱温、流速进行了考察优化。结果表明,在Chiralpak IC柱上,对于GX-25和GX-26,采用异丙醇作为流动性有机改性剂,分离效果优于异丙醇,可使对映体达到基线分离；对于GX-22和GX-30,异丙醇和无水乙醇同时存在作为有机改性剂可使对映体达基线分离。
三、6-Br-NBP对映体体内含量测定方法研究
对六只SD大鼠进行单剂量口服灌胃给药,分别于给药后1、2、4、8h后眼眶静脉丛取血；对生物样品进行预处理后,在正相色谱条件下,利用Chiralpak IC柱进行分析,测定6-Br-NBP在大鼠血浆中的浓度。通过特异性实验,测定精密度和准确度、线性范围、提取回收率和方法回收率以及定量限等进行了方法学验证。
The quality control of chiral drugs catches people's attention increasingly,so it becomes a focus in this field. High Performance Liquid Chromatography is one of the most popular analytic techniques and the method with chiral stationary phase is more classical,convenient and fast.The method with bonded chiral stationary phase has a steady performance and now it is used widely.
NBP is approved as an anti-cerebral ischemic agent by the State Food and Drug Administration(SFDA) of China.6-Br-NBP, a derivative compound of NBP,has been proved to be more active than NBP. Four chiral compounds (GX-22、GX-25、GX-26and GX-30) are synthesized including a-methylene-y-butyrolactones and studies on the biological activities of four chiral compounds are proved to be satisfying.
Three aspects have been carried out in this study:
1.Enantioseparation of NBP and6-Br-NBP on Chiralpak IC column
HPLC methods have been developed for the chiral separation of NBP and6-Br-NBP on a Chiralpak IC column under normal phase mode. The influences of organic solvent, column temperature and flow rate were investigated and the enatiomeric separation was optimized systematically. The results showed that NBP and6-Br-NBP can be separated completely. For NBP, ethanol was better than isopropanol as a component of mobile phase. For6-Br-NBP, isopropanol was much better than rthanol.
2.Enantioseparation of four chiral compounds (GX-22、GX-25、GX-26and GX-30) including a-methylene-y-butyrolactone on Chiralpak IC column
HPLC methods have been developed for the chiral separation of four chiral compounds including a-methylene-y-butyrolactone on a Chiralpak IC column under normal phase mode. The influences of organic solvent, column temperature and flow rate were investigated and the enatiomeric separation was optimized systematically. The results showed that GX-25and GX-26can be separated completely using isopropanol as the component of mobile phase. Both GX-22and GX-30were separated completely using ethanol and isopropanol as the components of mobile phase.
3.Determination of enantiomers of6-Br-NBP in SD rats plasma on Chiralpak IC column by HPLC
The biological samples were pretreated and separation conditions were optimized. Concentration of enantiomers of6-Br-NBP in SD rats plasma was measured under normal mode by HPLC with fluorescence detector. Method was evaluated from specificity, precision, accuracy, linearity, recovery,etc.
引文
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