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

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-?-cyclodextrin. Thus, it is important to determine how complexation with cyclodextrin affects the rate of degradation and type of midazolam degradants that are formed. We have 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-?-cyclodextrin, what we partly confirmed in our previous work.1 By continuing our study we have found that degradation products, not observed on the photodegradation of uncomplexed midazolam are observed in significant quantities when it is complexed with randomly methylated-?-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, as well as proposed degradation mechanism of midazolam is discussed.

Inclusion complexes of pesticides in aqueous solutions of methylated-β-cyclodextrin

Disadvantage of some organic pesticides is their low water solubility. Among other substances, cyclodextrins and modified cyclodextrins were considered as agents for improving pesticides water solubility. The solubility of poorly soluble pesticides, dimethoate, simazine, linuron and thiram, was determined in aqueous solution of methylated-?-cyclodextrin (mbCD) by ultraviolet spectrophotometry. Methylated-?-cyclodextrin was obtained by the modified Hawort method and characterized by 1H NMR and HPLC data. The average degree of substitution was 13.8. Methylation was done either on C-2, C-3, and C-6 atoms of glucopyranose unit therefore obtained product can be assort as randomly m?CD. Solubility of the studied pesticides in aqueous solution of m?CD increases in relation to their solubility in water for dimethoate 506, for simazine167, for thiram 44, and for linuron 20 times. Reactions of dimethoate and simazine with m?CD were entropy-driven while the inclusion complexation of m?CD with the linuron and thiram were driven by both, enthalpy and entropy, as determined by calorimetric measurements. The observed solubility increment of the investigated pesticides in aqueous solution of m?CD, suggests that it can be efficiently used in pesticide solutions formulations and increase their bioavailability, and biodegradability.