Nakka Srinivas, Katari Naresh Kumar, Muchakayala Siva Krishna, Jonnalagadda Sreekantha Babu, Manabolu Surya Surendra Babu
Department of Chemistry, School of Science, GITAM Deemed to be University, Hyderabad 502329, India.
School of Chemistry & Physics, College of Agriculture, Engineering & Science, Westville Campus, University of KwaZulu-Natal, P Bag X 54001, Durban 4000, South Africa.
ACS Omega. 2024 Feb 15;9(8):8773-8788. doi: 10.1021/acsomega.3c05170. eCollection 2024 Feb 27.
Globally, the pharmaceutical industry has been facing challenges from nitroso drug substance-related impurities (NDSRIs). In the current study, we synthesized and developed a rapid new UPLC-MS/MS method for the trace-level quantification of ciprofloxacin NDSRIs and a couple of N-nitroso impurities simultaneously. (Q)-SAR methodology was employed to assess and categorize the genotoxicity of all ciprofloxacin -nitroso impurities. The projected results were positive, and the cohort of concern (CoC) for all three impurities indicates potential genotoxicity. AQbD-driven mixture design was used to optimize the mixture of solvents in the method. The chromatographic resolution was accomplished using an Agilent Poroshell 120 Aq-C18 column (150 mm × 4.6 mm, 2.7 μm) in isocratic elution mode with 0.1% formic acid in a mixture of water, acetonitrile, and methanol in the ratio of 475:500:25 v/v/v at a flow rate of 0.5 mL/min. Quantification was carried out using triple quadrupole mass detection with electrospray ionization (ESI) in a multiple reaction monitoring technique. The finalized method was validated successfully, affording ICH guidelines. All -nitroso impurities revealed excellent linearity over the concentration range of 0.00125-0.0250 ppm. The Pearson correlation coefficient of each -nitroso impurity was >0.999. The method accuracy recoveries ranged from 93.98 to 108.08% for the aforementioned -nitrosamine impurities. Furthermore, the method was effectively applied to quantify -nitrosamine impurities simultaneously in commercially available formulated samples, with its efficiency recurring at trace levels. Thus, the current method is capable of determining the trace levels of three -nitroso ciprofloxacin impurities simultaneously from the marketed tablet dosage forms for commercial release and stability testing.
在全球范围内，制药行业一直面临着与亚硝基药物相关杂质（NDSRIs）有关的挑战。在当前的研究中，我们合成并开发了一种快速的新型超高效液相色谱-串联质谱法（UPLC-MS/MS），用于同时对环丙沙星NDSRIs和几种N-亚硝基杂质进行痕量定量分析。采用（Q）-SAR方法评估和分类所有环丙沙星亚硝基杂质的遗传毒性。预测结果为阳性，所有三种杂质的关注队列（CoC）表明具有潜在的遗传毒性。采用质量源于设计（AQbD）驱动的混合设计来优化方法中的溶剂混合物。使用安捷伦Poroshell 120 Aq-C18柱（150 mm×4.6 mm，2.7μm）在等度洗脱模式下进行色谱分离，流动相为水、乙腈和甲醇的混合物，比例为475:500:25 v/v/v，含有0.1%甲酸，流速为0.5 mL/min。采用电喷雾电离（ESI）的三重四极杆质量检测，在多反应监测技术中进行定量分析。最终方法成功通过验证，符合国际人用药品注册技术协调会（ICH）指南。所有亚硝基杂质在0.00125-0.0250 ppm浓度范围内显示出良好的线性。每种亚硝基杂质的皮尔逊相关系数均>0.999。上述亚硝胺杂质的方法准确度回收率在93.98%至108.08%之间。此外，该方法有效地应用于同时定量市售制剂样品中的亚硝胺杂质，其效率在痕量水平上得以重现。因此，当前方法能够同时从市售片剂剂型中测定三种环丙沙星亚硝基杂质的痕量水平，用于商业放行和稳定性测试。
