Chromatographic Methods for the Analysis of the Antipsychotic Drug Clozapine and Its Major Metabolites: A Review.

This article provides a comprehensive review of chromatographic methods used to analyze clozapine (CLZ), a second-generation antipsychotic, and its two main metabolites, norclozapine (NCLZ) and clozapine N-oxide (CLZ-NOX), in pharmaceutical formulations, biological matrices, and environmental samples. It covers various chromatographic techniques including high-performance liquid chromatography (HPLC), liquid chromatography–mass spectrometry (LC–MS), ultra-performance liquid chromatography (UPLC), high-performance thin-layer chromatography (HPTLC), and gas chromatography (GC), highlighting their applications, sample preparation methods, and validation parameters. The review notes that HPLC and LC–MS are the most frequently reported methods, with LC–MS offering superior sensitivity and lower detection limits, though at higher cost and complexity. It also emphasizes the need for improved, automated, and miniaturized sample preparation techniques to enhance efficiency and reduce solvent use, as well as the importance of developing fast and sensitive methods for detecting CLZ in environmental samples. This synthesis aims to assist researchers and clinicians in selecting and optimizing chromatographic methods for therapeutic drug monitoring and environmental analysis of CLZ and its metabolites.