Patel Ravi, Purohit Sanjay, Solanki Ravisinh, Khunt Dignesh, Patel Chhaganbhai, Patel Rucha, Parikh Shalin
Department of Quality Assurance, Graduate School of Pharmacy, Gujarat Technological University, Gandhinagar, India.
Department of Pharmaceutics, Graduate School of Pharmacy, Gujarat Technological University, Gandhinagar, India.
Rapid Commun Mass Spectrom. 2023 Apr 30;37(8):e9488. doi: 10.1002/rcm.9488.
Since June 2018, globally large numbers of pharmaceuticals have been recalled due to the unexpected presence of nitrosamines. Beginning with the class of pharmaceuticals known as sartans, subsequent lines of inquiry included antidiabetic medicines, antihistamines, and antibiotics. A critical review of the U.S. Food and Drug Administration database reveals that the highest number of products recall due to the presence of unacceptable levels of nitrosamines were losartan potassium drug products and their coformulations with other drug substances. The problem can be mainly attributed to naively adopted approval revisions and the lack of sufficient current analytical technologies to detect those contaminants in time. In this work, we developed a specific, selective, accurate, precise, and robust ultra-performance liquid chromatography-triple quadrupole-mass spectrometry (UPLC-TQ-MS/MS) method for the estimation of eight genotoxic nitrosamine impurities in losartan and hydrochlorothiazide (HCTZ) tablets, which is the only fixed-dosage combination approved by the USFDA to treat hypertension.
All the nitrosamine impurities along with the drug substances were separated using an Agilent Pursuit XRs Ultra diphenyl column (150 × 2.0 mm, 2.8 μm) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in methanol) at a flow rate of 0.4 ml/min using the gradient elution program. The proposed method was validated per ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Q2 (R1) guidelines to ensure the method is suitable for its intended purpose.
Limit of detection and limit of quantification were obtained in the range of 0.25-0.5 ng/mL, which was very low compared to levels specified by the USFDA, European Medicines Agency (EMA), and other regulatory authorities that ensure the sensitivity of the method in its entire life cycle.
The developed method can be incorporated into an official monograph and applied for routine quality control analysis of losartan and HCTZ fixed-dose combination tablets.
自2018年6月以来，全球大量药品因意外检出亚硝胺而被召回。从沙坦类药物开始，后续的调查范围包括抗糖尿病药物、抗组胺药和抗生素。对美国食品药品监督管理局数据库的严格审查显示，因亚硝胺含量不可接受而召回产品数量最多的是氯沙坦钾药品及其与其他药物的复方制剂。该问题主要归因于单纯采用的批准修订以及缺乏足够的当前分析技术来及时检测这些污染物。在这项工作中，我们开发了一种特异性强、选择性高、准确、精密且稳健的超高效液相色谱-三重四极杆质谱（UPLC-TQ-MS/MS）方法，用于测定氯沙坦和氢氯噻嗪（HCTZ）片剂中八种具有遗传毒性的亚硝胺杂质，这是美国食品药品监督管理局批准用于治疗高血压的唯一固定剂量复方制剂。
使用安捷伦Pursuit XRs Ultra二苯基柱（150×2.0 mm，2.8μm），以流动相A（0.1%甲酸水溶液）和流动相B（0.1%甲酸甲醇溶液）为流动相，流速为0.4 ml/min，采用梯度洗脱程序，将所有亚硝胺杂质与原料药分离。按照国际人用药品注册技术协调会（ICH）Q2（R1）指南对所提出的方法进行验证，以确保该方法适用于其预期目的。
检测限和定量限在0.25 - 0.5 ng/mL范围内，与美国食品药品监督管理局、欧洲药品管理局（EMA）和其他监管机构规定的水平相比非常低，这确保了该方法在其整个生命周期内的灵敏度。
所开发的方法可纳入官方药典，并应用于氯沙坦和HCTZ固定剂量复方片剂的常规质量控制分析。
