Kinetic study and structural elucidation of the main ketoconazole metabolite

Abstract

Ketoconazole (KTZ) is a commonly used drug worldwide for both skin and systemic treatment of mycotic infections. A major concern regarding the oral use of this drug is the possibility of severe hepatotoxicity caused mainly by its major metabolite, namely, N-deacetyl-KTZ (DAK), which is also found as a KTZ impurity. Based on the toxicological relevance of DAK, here we assessed the time-dependent KTZ concentration in pH 2 and 37 °C by quantitative 1H nuclear magnetic resonance (NMR) with high specificity and sensitivity, and obtained for the first time a crystal form of DAK, as a dihydrochloride salt. The overall conformation of DAK resembles that found in the crystal structure of racemic KTZ and of its pure 2S,4R-enantiomer. The molecules are line-shaped, with the imidazole ring laid back on itself due to an intramolecular CH … π interaction between one methylene group and the imidazole ring. Centrossymetric dimers made up of two DAKH2Cl2 units held together by four classical NH⋯Cl-hydrogen bonds build the three-dimensional network. Besides such structural knowledge, its crystal structure provides an analytical pattern in the solid state for this relevant toxic metabolite and impurity from KTZ.