Determination of the paracetamol degradation process with online UV spectroscopic and multivariate curve resolution-alternating least squares methods: comparative validation by HPLC

Abstract

Paracetamol (N-acetyl-4-amino-phenol) is a popular antipyretic and analgesic medication which has few side effects and little toxicity when used in recommended dose. After ingestion of an overdose quantity of paracetamol, the accumulation of toxic metabolites may cause severe and even fatal hepatotoxicity and nephrotoxicity. In addition, p-aminophenol is the hydrolytic product of paracetamol and has high toxicity. It may be involved in the pharmaceutical preparation of paracetamol as a synthetic intermediate or a degradation product of paracetamol. Therefore, establishing an appropriate analytical method to research the stability of the medication is quite important and necessary. In this work, a kinetic alkaline degradation process of paracetamol was investigated by online two-way dimensional UV-Vis kinetic spectroscopy combined with the chemometric method Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). The extracted concentration profiles and pure spectra of the reacting species in the reaction were obtained. These profiles indicated that there are two intermediates in the process. The possible degradation pathway and reaction mechanism of the paracetamol was postulated based on the MCR-ALS results, and the rate constants of every reaction step were resolved through subsequent model-fitting. To validate these results, a comparative offline measurement method with high performance liquid chromatography was implemented experimentally. Moreover, an ab initio calculation was also performed to evaluate the estimated reaction mechanism theoretically in energy terms.