title: Characterization of forced degradation products of ketorolac tromethamine using LC/ESI/Q/TOF/MS/MS and in silico toxicity prediction.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, AP, India.
authors.forename: Pradipbhai D
authors.initials: PD
authors.lastname: Kalariya
authors.forename: B
authors.initials: B
authors.lastname: Raju
authors.forename: Roshan M
authors.initials: RM
authors.lastname: Borkar
authors.forename: Deepak
authors.initials: D
authors.lastname: Namdev
authors.forename: S
authors.initials: S
authors.lastname: Gananadhamu
authors.forename: Prajwal P
authors.initials: PP
authors.lastname: Nandekar
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
authors.forename: R
authors.initials: R
authors.lastname: Srinivas
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D003198:Computer Simulation; D005260:Female; D020911:Ketorolac Tromethamine / Q000737:chemistry* / Q000633:toxicity*; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*; D018675:Toxicity Tests
chemical_list: D020911:Ketorolac Tromethamine
keywords: LC/ESI/MS/MS; accurate mass measurements; anti-inflammatory; degradation products; forced degradation; in silico toxicity; ketorolac tromethamine