Degradation Kinetics and Mechanisms of Moricizine Hydrochloride in Acidic Medium

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AbstractThe degradation kinetics of moricizine hydrochloride (1) were examined over a pH range of 0.6 to 6.0 at an ionic strength of 0.3 and 60°C. The disappearance of intact 1 was followed by a stability‐indicating HPLC assay. The degradation products, which had approximate solubilities of <100 μg/mL, precipitated in aqueous solution. The precipitate was collected for HPLC analysis and identification of degradation products. Degradation of 1 was catalyzed by acetate and phosphate buffers and was pH dependent, with the pH of the minimum rate constant located between 2.8 and 3.2. At pH 0.6‐2.0, 1 degraded via amide hydrolysis to yield first ethyl (10H‐phenothiazin‐2‐yl) carbamate (2), an amide hydrolysis product, which further oxidized in parallel to give ethyl (3‐oxo‐3H‐phenothiazin‐2‐yl) carbamate (3), ethyl (10H‐phenothiazin‐2‐yl) carbamate S‐oxide (4), and diethyl (3, 10′‐bi‐10H‐phenothiazine‐2,2′‐diyl)bis(carbamate) (5), the dimer of the amide hydrolysis product. At pH 2.2‐6.0, 1 degraded via a reverse Mannich reaction, to form the reverse Mannich product ethyl [10‐(1‐oxo‐2‐propenyl)‐10H‐phenothiazin‐2‐yl] carbamate (6), and by parallel reaction via the described amide hydrolysis pathway. The dimer of the amide hydrolysis product was not detectable at pH >2.8. At pH >4.0, the reverse Mannich product was the predominant degradation product. Degradation of 1 was subject to positive and negative kinetic salt effects at pH 1.0 and 4.0, respectively. Arrhenius plots determined at pH 1.0 and 6.0 were linear between 37 and 70°C. Predicted shelf lives at room temperature (22 °C) at pH 1.0 and 6.0 were identical to the shelf lives determined experimentally.