Estudo de degradação forçada e desenvolvimento de método indicativo de estabilidade para determinação de benznidazol

Abstract

A drug product must have efficacy, safety and quality to ensure the success of pharmacological treatment. Lack of stability can impair this triad due to the loss of the therapeutic effect or patient exposure to toxic degradation products. The Brazilian National Health Surveillance Agency (ANVISA) recommended, through RE N° 1 2005, the development of stability-indicating methods. These must be selective for the drug and allow the quantification and identification of the drug and of its degradation products. For this, studies of forced degradation are performed, in which the drug is subjected to defined stress conditions. Currently, no stability indicating method for benznidazole (BZN), the only drug used in Brazil for the treatment of Chagas disease, is described in the literature. This disease is endemic in Latin American countries and is considered a neglected disease by the WHO. In this context, a forced degradation study of placebo, active pharmaceutical ingredient and tablets containing BZN was carried out in all recommended degradation conditions. A stability indicating method was developed and validated using HPLC-DAD on C18 column (150 x 4.6 mm, 5 μm). In addition, binary degradations (drug-excipient) and thermal analyzes (thermogravimetry and differential scanning calorimetry) were performed to assess drug-excipient compatibility. The drug was susceptible to alkaline and photolytic degradation. In the alkaline condition, there was formation of an additional degradation product for the tablets. Incompatibilities of BZN with lactose and magnesium stearate were observed, with a decrease in the thermal stability of the drug in the presence of these excipients. The chromatographic method was selective for the BZN and its degradation products, with a resolution of at least 1.3 between the peaks. Spectral homogeneity was also demonstrated for BZN under the tested conditions. Thus, the stability indicating method developed can be used in the stability studies and to improve formulation, ensuring the quality of the drug product distributed to the population.