Radiostability of Ketoconazole in the Solid State

Barbara      Marciniec; Katarzyna      Dettlaff; Witold      Danikiewicz; Grzegorz      Spolnik; Ewa      Jaroszkiewicz; Marek      Naskrent

doi:10.2174/1573412911309010014

Abstract

Ketoconazole (1-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy} phenyl)piperazin-1-yl]ethan-1-one) in substantia was irradiated to doses between 25 kGy (standard sterilizing dose) and 800 kGy, using high energy electrons from an electron accelerator. The irradiated and non-irradiated samples were then examined using a variety of spectroscopic (UV, MS, NMR, EPR), chromatographic (TLC, HPLC) and hyphenated (HPLC-MS) methods. With the help of an EPR method the presence of free radicals (1.40 × 1015 spin/g for dose 100 kGy) was detected. The loss of ketoconazole was ca 6%, as determined by the HPLC, for the dose of 800 kGy. The radiolytic yield of the process was 4.52 × 10-7 mol/J for the 25 kGy and it decreased to 1.29 × 10-7 mol/J for the 800 kGy dose. On the basis of the HPLC-MS measurements the structures for five main radiolysis products were proposed. It was found that the main radiodegradation processes are: dehalogenation (loss of Cl atom), dehydrogenation of the piperazine ring, Noxidation, hydrolysis and rapture of the C18-O19 bond. Our experiments indicate that ketoconazole is stable in the range of doses between 25-50 kGy and therefore could probably be sterilized using the standard sterilizing dose of 25 kGy.

Keywords: Ketoconazole, HPLC-MS, Free radicals, Radiolysis product, Radiolytic yield, NMR, EPR, dehalogenation, hydrolysis, rapture