Comprehensive Stability Analysis of Haloperidol: Insights from Advanced Chromatographic and Thermal Analysis

In this study, we thoroughly investigated the stability of haloperidol using a comprehensive set of chromatographic and thermal analyses. Various stress conditions were examined, including exposure to oxidizing agents (such as hydrogen peroxide), dry heat, photolytic conditions, and acid and alkaline hydrolysis. Significant degradation was observed in acidic and alkaline environments, leading to the formation of degradation by-products, specifically DPA, DPB, DPC, and DPD for acidic and basic conditions. In contrast, haloperidol demonstrated robust stability under photolytic, oxidative, and dry-heat conditions. For the analysis of the drug and its degradation products, a C-18 column was employed, coupled with a mobile phase consisting of methanol and a phosphate buffer (pH = 9.8) in a 90:10 (v/v) ratio. The analytical method was rigorously validated according to ICH Q2 (R1) guidelines, ensuring its accuracy and reliability. This method exhibited excellent linearity within a concentration range of 1 to 50 mu g/mL, with an R2 of 0.999. Additionally, this method is applicable to commercial formulations, without the need for prior extraction. LC-MS/MS analysis revealed distinct m/z values and fragmentation spectra corresponding to the degradation products, including an impurity not documented in the European Pharmacopoeia monograph for the drug. Three additional degradation products were identified based on m/z values and base fragments. Thermal analyses, including thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and differential thermal analysis (DTA), provided further evidence of the active ingredient's thermal stability, with a melting temperature of approximately 150 degrees C. These results collectively offer valuable insights into the degradation behavior of haloperidol, providing critical implications for its pharmaceutical quality and integrity under various environmental conditions.