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

Agatonovic-Kustrin, Snezana, Lebete, Mosimotsana, Brown, Michael W., Morton, David W., and Glass, Beverley D. (2016) Chemical characterization of the photodegradation products of midazolam complexes with randomly methylated-beta-cyclodextrin by HPLC and LC-MS/MS. Journal of the Serbian Chemical Society, 81 (9). pp. 1037-1053.

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Abstract

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.

Item ID: 46664
Item Type: Article (Research - C1)
ISSN: 1820-7421
Keywords: benzodiazepine photostability, high performance liquid chromatography, liquid chromatography-tandem mass spectrometry
Date Deposited: 14 Dec 2016 07:42
FoR Codes: 03 CHEMICAL SCIENCES > 0304 Medicinal and Biomolecular Chemistry > 030404 Cheminformatics and Quantitative Structure-Activity Relationships @ 80%
11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110199 Medical Biochemistry and Metabolomics not elsewhere classified @ 20%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 100%
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