Dolutegravir(DLG)由于其可负担性,已成为大多数国家用于治疗艾滋病毒的独特一线抗逆转录病毒疗法,高功效,和低药物相互作用。然而,DLG中基因毒性杂质(GTI)的评估及其毒性评估尚未彻底探索.因此,在这项研究中,一个简单的,快,并开发了选择性分析方法,用于识别和测定7个GTI,dolutegravir钠(DLG-Na)药物的明确合成路线。一个容易的,采用快速超声辅助液-液萃取程序来分离DLG-Na中的GTI,然后使用气相色谱(GC)-电子碰撞(EI)/质谱仪(MS)定量(使用选择性离子监测模式)技术进行分析。此EI-GC/MS方法根据ICHQ2(R1)指南的当前要求进行验证。在最佳方法条件下,R在0.9959和0.9995之间实现了出色的线性度,并且在检测限(LOD)在0.15至0.63µg/g之间获得了高灵敏度,DLG中七个GTI的定量限(LOQ)在0.45至1.66µg/g之间。所获得的回收率在LOQ为98.2至104.3%之间,15微克/克,和18微克/克浓度水平(最大日剂量为100毫克)。这种开发和验证的方法是快速的,易于采用,具体,敏感,并且准确估计DLG-Na药物部分的相对复杂的钠基质中的七个GTI。作为一种方法应用,我们分析了两种不同的DLG-Na原料药制造样品的GTI归宿和预期剂量应用的药物安全性.此外,进行了计算机内QSAR毒性预测评估,以科学地证明来自警报官能团的每种杂质的潜在GTI性质。
Dolutegravir (DLG) has become a distinctive first-line antiretroviral therapy for the treatment of HIV in most countries due to its affordability, high efficacy, and low drug-drug interactions. However, the evaluation of genotoxic impurities (GTIs) in DLG and their toxicity assessment has not been explored thoroughly. Thus, in this study, a simple, fast, and selective analytical methodology was developed for the identification and determination of 7 GTIs in the comprehensive, explicit route of synthesis for the dolutegravir sodium (DLG-Na) drug. A facile, fast ultrasonication-assisted liquid-liquid extraction procedure was adapted to isolate the GTIs in DLG-Na and then analyzed using the gas chromatography (GC)-electron impact (EI)/mass spectrometer (MS) quantification (using selective ion monitoring mode) technique. This EI-GC/MS method was validated as per the current requirements of ICH Q2 (R1) guidelines. Under optimal method conditions, excellent linearities were achieved with R between 0.9959 and 0.9995, and high sensitivity was obtained in terms of detection limits (LOD) between 0.15 to 0.63 µg/g, and quantification limits (LOQ) between 0.45 to 1.66 µg/g for the seven GTIs in DLG. The obtained recoveries ranged from 98.2 to 104.3 % at LOQ, 15 µg/g, and 18 µg/g concentration levels (maximum daily dose of 100 mg). This developed and validated method is rapid, easy to adopt, specific, sensitive, and accurate in estimating the seven GTIs in a relatively complex sodium matrix of the DLG-Na drug moiety. As a method application, two different manufactured samples of DLG-Na drug substances were analyzed for the fate of the GTIs and drug safety for the intended dosage applications. Moreover, an in-silico QSAR toxicity prediction assessment was carried out to prove scientifically the potential GTI nature of each impurity from the alerting functional groups.