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Abstract

We report on a new isomeric impurity of danazol. This impurity designated as isodanazol was detected by reversed-phase high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC). Its structure was determined after separation by preparative HPLC. Mass spectrometry revealed the isomeric nature of the impurity while the UV spectrum indicated profound difference in the isoxazole moieties. The structure of the isomeric isoxazole ring in isodanazol was determined by NMR spectroscopy using COSY, HETCOR and NOE measurements. The difference between the UV spectra of danazol and isodanazol is explained on the basis of the difference between the aromaticities of their isoxazole rings supported by quantum chemical calculations. The quantitative determination of the impurity down to the 0.05% level can be performed by HPLC, gas chromatography and TLC densitometry.

Recent Advances in the Analysis of Steroid Hormones and Related Drugs

“…20 role, 253 while HPLC-NMR and HPLC-MS were necessary to determine the structures of five most interesting structures (a hydroperoxide and four different dimers) in the course of oxidative and light-stress studies of ethinylestradiol. 254 Of the other hormonal drugs, several impurities originating from the Birch reduction step were identified in norethisterone, 239,250 an isomeric impurity in danazol 255 and several oxidative degradation products in tipredane. 225,256 Of the non-hormonal steroid drugs pipecuronium bromide is mentioned.…”

Chemical and analytical characterization of related organic impurities in drugs

“…Two further interesting side reaction products are an isomer of danazol, where the difference between the drug and impurity is in the position of the nitrogen and oxygen atoms in the isoxazole ring attached to ring A [47] and an impurity in hexestrol with a methyl group attached to the phenolic ring [45]. The reason for the presence of the latter is that in the course of the removal of the methyl groups of the phenol ether-type last intermediate these partly methylate the aromatic nucleus.…”

“…If TLC is used, reflection UV spectra are similarly easily available [9]. Although UV spectroscopy is the least effective among the spectroscopic techniques, often very important information is obtainable for the structure elucidation [17,34,36,37,41,43,44,45,46,47,49,58,65,66,69,70].…”

“…More typically, at least one more step is necessary and this is usually mass spectrometry [15,35,36,37,40,43,44,46,47,48,49,52,55,56,57,58,65,66]. Due to its high sensitivity, small samples obtained from the TLC plate or analytical HPLC fraction are suitable to take good quality spectra in the off-line mode.…”

“…If NMR spectroscopy [16,30,33,35,36,37,41,43,44,46,47,48,49,52,55,56,63] is also necessary for the structure elucidation, somewhat larger sample size is necessary. These samples are usually obtained by semi-preparative HPLC [21].…”