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

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

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-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.

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How to Cite
[1]
S. Agatonović-Kustrin, M. Lebete, M. E. Brown, D. W. Morton, and B. Glass, “Chemical characterization of the photodegradation products of midazolam complexes with randomly methylated-β-cyclodextrin by HPLC and LC–MS/MS”, J. Serb. Chem. Soc., vol. 81, no. 9, pp. 1037–1053, Oct. 2016.
Section
Analytical Chemistry
Author Biographies

Snežana Agatonović-Kustrin, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Selangor

Department of Pharmacology and Chemistry, Professor

Mosimotsana Lebete, Faculty of Pharmacy, Rhodes University, Grahamstown

Faulty of Pharmacy, research student

Michael E Brown, Faculty of Pharmacy, Rhodes University, Grahamstown

Faculty of Pharmacy, Professor

David William Morton, The School of Pharmacy and Applied Science, La Trobe Institute of Molecular Sciences, La Trobe University, Bendigo, Victoria

School of Pharmacy & Applied Science

Beverley Glass, College of Medicine and Dentistry, James Cook University, Townsville, Queensland

College of Medicine and Dentistry, James Cook University, Townsville, Queensland

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