Photodegradation of the H1 Antihistaminic Topical Drugs Emedastine, Epinastine, and Ketotifen and ROS Tests for Estimations of Their Potent Phototoxicity

Abstract

In this study, important H1 antihistaminic drugs, i.e., emedastine (EME), epinastine (EPI), and ketotifen (KET), were irradiated with UV/Vis light (300–800 nm) in solutions of different pH values. Next, they were analyzed by new high performance liquid chromatography (HPLC) methods, in order to estimate the percentage of degradation and respective kinetics. Subsequently, ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) was used to identify their photodegradation products and to propose degradation pathways. In addition, the peroxidation of linoleic acid and generation of singlet oxygen (SO) and superoxide anion (SA) were examined, together with the molar extinction coefficient (MEC) evaluation, to estimate their phototoxic risk. The photodegradation of all EME, EPI, and KET followed pseudo first-order kinetics. At pH values of 7.0 and 10.0, EPI was shown to be rather stable. However, its photostability was lower at pH 3.0. EME was shown to be photolabile in the whole range of pH values. In turn, KET was shown to be moderately labile at pH 3.0 and 7.0. However, it degraded completely in the buffer of pH 10.0. As a result, several photodegradation products were separated and identified using the UPLC-MS/MS method. Finally, our ROS assays showed a potent phototoxic risk in the following drug order: EPI < EME < KET. All of these results may be helpful for manufacturing, storing, and applying these substantial drugs, especially in their ocular formulations.

LC-UV and UPLC-MS/MS Methods for Analytical Study on Degradation of Three Antihistaminic Drugs, Ketotifen, Epinastine and Emedastine: Percentage Degradation, Degradation Kinetics and Degradation Pathways at Different pH

“…This suggests poor stability of KETO under strong basic conditions which was visibly supported by the present results. However, the sensitivity of KETO to strong acidic conditions should also be considered, especially since the previous experiments from our laboratory showed high photodegradation of KETO at pH 3.0 [18]. On the other hand, we can now summarize the results from both experiments and conclude that KETO is visibly more sensitive to light than to high temperature under the same pH conditions.…”

“…The calculated t0.5 values were 3.58 h and 4.57 h (0.1 M HCl and buffer of pH 3.0), 2.95 h (pH 7.0 and 10.0) and 2.08 h (0.1 M NaOH) (Table 2). At the same time, EME was shown to be much more sensitive to high temperature than to UV/VIS irradiation at similar pH conditions [18]. When UPLC-MS/MS analysis was performed, EME 5).…”

“…However, no degradation product was detected in the samples stressed at high temperature. On the contrary, two degradation products of EME were detected and identified after photodegradation, when either the ethoxy moiety or 1,4-diazepine ring in the EME molecule were affected [18]. A literature survey revealed one more study in which acidic degradation of EME was described.…”

“…What is more, no papers on the identification of their decomposition products using LC-MS methods were found in the literature. On the other hand, previous experiments from our laboratory showed the sensitivity of KETO, EPI and EME to UV/VIS light in the range 300-800 nm and their pH-dependent photodegradation [18]. Considering the importance of these frequently prescribed drugs and the lack of reports concerning their stability, the primary goal of the present experiment was to explore their sensitivity to different pH conditions at high temperature.…”

“…[18].When UPLC-MS/MS analysis was performed, EME showed a protonated molecule, [M + H] + , at m/z 303.2, while its MS/MS showed the product ions at m/z 246.2, 232.1, 218.1, 200.1, 174.1, 146.1 and 134.1 (Table…”