Estudo de degradação forçada do cloridrato de ranitidina para avaliação da geração de nitrosaminas

Abstract

The administration of medications was a turning point in history, allowing previously deadly diseases to become treatable. The pharmaceutical industry is one of the largest sectors of the global economy. According to ANVISA, the sale of medications generates more than 130 billion reais per year in Brazil. This scenario implies large-scale production for consumption, making it essential to rigorously verify the quality and safety of medications to ensure that they do not pose health risks. Recently, studies indicated the formation of N-nitrosodimethylamine (NDMA), a potentially toxic compound, in medicines with the active pharmaceutical ingredient (API) ranitidine hydrochloride. The ban on marketing was worldwide, and the episode revealed the need for greater control over production. Considering the possibility of formation of these compounds with carcinogenic potential, in the present study, a forced degradation study of the drug ranitidine, used to treat gastric ulcers, was carried out to evaluate the degradation products generated and the potential generation of NDMA. The drug was subjected to stress conditions: thermolysis, acid hydrolysis, basic hydrolysis, oxidation, and photolysis. The method used was based on the ANVISA degradation guide, Resolution No. 4/2015, to evaluate the generation of nitrosamines, especially NDMA. Chromatographic analysis was performed by high-performance liquid chromatography (HPLC), using a C18 column and mobile phase composed of ACN:H2O with gradient elution and detection performed by a diode array detector at 228 nm. Forced degradation tests led to the formation of seven ranitidine degradation products (DPs). Under more extreme conditions (prolonged time and/or higher concentrations of degrading agents), complete degradation of the drug was observed. Of these DPs formed, the formation of the toxic compound NDMA stood out, observed specifically in hydrolytic degradations under heating. Confirmation of the identity of NDMA was performed by comparison with analysis of the analytical standard of NMDA, under the same analysis conditions. Ranitidine DPs were identified through chromatographic profile analysis and comparison with the ranitidine chromatograms and byproducts published in the literature. Thus, the forced degradation of ranitidine proved efficient and valuable in evaluating the potential generation of toxic products from the degradation of ranitidine hydrochloride.