A validated chiral HPLC method for the enantiomeric separation of Remimazolam key intermediate, BHO
首发时间:2018-10-08
Abstract:A new and accurate chiral liquid chromatographic method was described for the enantiomeric separation of BHO[3-[(S)-7-bromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-1, 4-benzodiazepin-3-yl]-propionic acid methyl ester, (S)-isomer], a key intermediate of Remimazolam in bulk drugs. The enantiomers of BHO were baseline resolved on a Chiralpak AD-H (250mm×4.6 mm, 5μm) column using a mobile phase system containing Hexane: Ethanol: Diethyl amine (50:50:0.1, v/v/v). The resolution between the enantiomers was not less than ten and interestingly distomer was eluted prior to eutomer. The limit of detection and limit of quantification of (R)-methyl 3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoate [(R)-isomer] were found to be 0.5 and1.5μg/ml, respectively, for 10μl injection volume. The percentage recovery of (R)-isomer ranged from 98.0 to 101.5 in the bulk drug samples of BHO. The validated method yielded good results regarding precision, linearity, accuracy and ruggedness. The proposed method was found to be suitable and accurate for the quantitative determination of (R)-isomer in bulk drug samples of BHO.
keywords: Pharmaceutical analysis Chiral HPLC Chiralpak AD-H Ruggedness Validation Solution and mobile phase stability
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一种验证过关于瑞米唑仑关键中间体(BHO)对映体高效液相分析方法
摘要:新建立了一种准确高的手性高效液相色谱方法,分析瑞米唑仑原料药的关键中间体BHO[(3S)-7-溴-2,3-二氢-2-氧代-5-(2-吡啶基)-1H-1,4-苯并二氮卓-3-丙酸甲酯,(S)-异构体]对映体。BHO的对映体分离在Chiralpak AD-H(250mm×4.6mm,5μm)色谱柱,所使用流动相为正己烷:乙醇:二乙基胺(50:50:0.1,v / v / v)。对映体间自间的分离度不小于10,而且对映体在对映体形成之前就被洗脱了。分别注入10μl体积,检测(3R)-7-溴-2,3-二氢-2-氧代-5-(2-吡啶基)-1H-1,4-苯并二氮卓-3-丙酸甲酯(R)异构体)的检测限和定量限分别是0.5 和1.5μg / ml。(R)-异构体在BHO样品中加样回收率在98.0 ~ 101.5之间。验证结果表明,该方法在精度、线性度、精度和耐用性等方面均取得了较好的效果。结果表明,该方法适用于BHO样品中(R)-异构体的定量测定。
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一种验证过关于瑞米唑仑关键中间体(BHO)对映体高效液相分析方法
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