Chemical characterization of the photodegradation products of midazolam complexes with randomly methylated-beta-cyclodextrin by HPLC and LC-MS/MS
Journal Publication ResearchOnline@JCUAbstract
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-beta-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-beta-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-beta-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.
Journal
Journal of the Serbian Chemical Society
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Volume
81
ISBN/ISSN
1820-7421
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Issue
9
Pages Count
17
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Publisher
Serbian Chemical Society
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EISSN
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DOI
10.2298/JSC150915018A