Oxidative Degradation of Itraconazole, Identification and Characterization of Novel Degradation Products

Itraconazole is a broad-spectrum triazole antifungal agent widely employed in the treatment of systemic and superficial fungal infections. The present study was undertaken to evaluate the stability profile of itraconazole under stress conditions and to identify degradation products generated during forced degradation studies. Stress testing was performed in accordance with ICH guidelines under acidic, alkaline, and oxidative conditions. LC–MS analysis demonstrated that itraconazole was susceptible to oxidative degradation, leading to the formation of two major degradation products, while no significant degradation was observed under acidic or alkaline conditions. The major degradation product, DP-1, was isolated using preparative HPLC and subsequently characterized by high-resolution mass spectrometry (HRMS), LC–MS/MS, and one- and two-dimensional NMR spectroscopy. Spectroscopic investigations indicated that DP-1 was formed through oxidative modification of the piperazine moiety of itraconazole. Structural elucidation was achieved using accurate mass measurements, fragmentation studies, and detailed NMR analyses. A comprehensive literature survey revealed that the identified degradation products have not been previously reported. The findings provide valuable insight into the oxidative degradation pathway of itraconazole and contribute to impurity profiling, stability evaluation, and the development of stability-indicating analytical methods for pharmaceutical quality assurance.