Chemical characterization of the photodegradation products of midazolam complexes with randomly methylated-β-cyclodextrin by HPLC and LC–MS/MS

Snežana Agatonović-Kustrin, Mosimotsana Lebete, Michael E Brown, David William Morton, Beverley Glass


Midazolam, a potent anxiolytic drug with sedative properties, is susceptible to degradation by both light and hydrolysis in aqueous solution. When formulated as an intranasal product, it was found to be effective in achieving seizure control in epileptic patients. In order to deliver an adequate therapeutic dose to a patient, a nasal formulation requires the concentration of midazolam to be higher than its aqueous solubility. One way to increase mida­zolam solubility to a therapeutic concentration is complexation with randomly methylated-β-cyclodextrin. Thus, it is important to determine how complex­ation with cyclodextrin affects the rate of degradation and type of midazolam degradants that are formed. It was found that complexation with cyclodextrin decreases its photostability. More importantly, the degradation profile for midazolam is significantly altered when it is complexed with randomly methyl­ated-β-cyclodextrin, which was partly confirmed in a previous work. By con­tinuing this study, degradation products, not found in the photodegradation of uncomplexed midazolam are observed in significant quantities when it was complexed with randomly methylated-β-cyclodextrin. The decreased photo­stab­ility was accompanied by the appearance of two new degradation products, an intermediate structure and a dimer. Photoproduct formation followed the same pattern as in the forced degradation studies, further confirming the pre­sence of an intermediate. The production of these new photodegradants, char­acterized with their MS spectra, and a proposed degradation mechanism of midazolam are discussed.


benzodiazepine photostability; high performance liquid chromato¬graphy; liquid chromatography-tandem mass spectrometry

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