Kalariya Pradipbhai D, Raju B, Borkar Roshan M, Namdev Deepak, Gananadhamu S, Nandekar Prajwal P, Sangamwar Abhay T, Srinivas R
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, AP, India.
J Mass Spectrom. 2014 May;49(5):380-91. doi: 10.1002/jms.3351.
Ketorolac, a nonsteroidal anti-inflammatory drug, was subjected to forced degradation studies as per International Conference on Harmonization guidelines. A simple, rapid, precise, and accurate high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (LC/ESI/Q/TOF/MS/MS) method has been developed for the identification and structural characterization of stressed degradation products of ketorolac. The drug was found to degrade in hydrolytic (acidic, basic, and neutral), photolytic (acidic, basic, and neutral solution), and thermal conditions, whereas the solid form of the drug was found to be stable under photolytic conditions. The method has shown adequate separation of ketorolac tromethamine and its degradation products on a Grace Smart C-18 (250 mm × 4.6 mm i.d., 5 µm) column using 20 mM ammonium formate (pH = 3.2): acetonitrile as a mobile phase in gradient elution mode at a flow rate of 1.0 ml/min. A total of nine degradation products were identified and characterized by LC/ESI/MS/MS. The most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation of the M + H ions of ketorolac and its degradation products. In silico toxicity of the drug and degradation products was investigated by using topkat and derek softwares. The method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per International Conference on Harmonization guidelines.
酮咯酸，一种非甾体抗炎药，按照国际协调会议指南进行了强制降解研究。已开发出一种简单、快速、精确且准确的高效液相色谱结合电喷雾电离四极杆飞行时间串联质谱法（LC/ESI/Q/TOF/MS/MS），用于鉴定酮咯酸的应激降解产物并进行结构表征。发现该药物在水解（酸性、碱性和中性）、光解（酸性、碱性和中性溶液）及热条件下会降解，而该药物的固体形式在光解条件下是稳定的。该方法在Grace Smart C - 18（250 mm×4.6 mm内径，5 µm）色谱柱上，使用20 mM甲酸铵（pH = 3.2）：乙腈作为流动相，以梯度洗脱模式、流速1.0 ml/min，实现了酮咯酸氨丁三醇及其降解产物的充分分离。通过LC/ESI/MS/MS共鉴定和表征了9种降解产物。基于酮咯酸及其降解产物的M + H离子的碎裂比较，提出了降解产物形成的最可能机制。使用topkat和derek软件研究了该药物及其降解产物的计算机模拟毒性。按照国际协调会议指南，对该方法在特异性、线性、准确性、精密度和稳健性方面进行了验证。
