ENTECAVIR: METODOLOGIA ANALÍTICA POR CLAE, ESTUDO DE ESTABILIDADE E COMPATIBILIDADE IFA-EXCIPIENTES

• Ano de defesa: 2021
• Autor(a) principal: Fiorot, Ariadne Botto
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal do Espírito Santo; BR; Mestrado em Ciências Farmacêuticas; Centro de Ciências da Saúde; UFES; Programa de Pós-Graduação em Ciências Farmacêuticas
• Palavras-chave em Português: Entecavir; estabilidade; cinética de degradação; compatibilidade de formulação farmacêutica; subject.br-rjbn; Farmácia
• Link de acesso: http://repositorio.ufes.br/handle/10/15253

Entecavir (ETV) is an inhibitor of hepatitis B virus (HBV) DNA synthesis and has been widely prescribed in the treatment of chronic infections caused by the virus. In 2015, ETV was included on the List of Essential Medicines of the World Health Organization (WHO) and, in Brazil, it appears in the National List of Essential Medicines (RENAME) 2020. Entecavir presents polymorphism and its active crystalline form houses a molecule of water; it also presents stereoisomerism due to the presence of three chiral centers in its molecular structure. Despite the great therapeutic relevance and presence in the world market, there are still research gaps in studies of ETV degradation kinetics and its compatibility with excipients used in pharmaceutical formulations. In this work, degradation studies of entecavir in liquid medium and evaluation of drug-excipient compatibility of ETV and the inputs declared in the market formulations were carried out. The determination of ETV was performed through High Performance Liquid Chromatography (HPLC), with a method developed and validated under the following conditions: mobile phase of water and acetonitrile in the proportion 92:8, flow of 1.0 mL.min-1, temperature of 30 °C, injection of 50 μL, octadecylsilane column (RP-18) of 250 x 4.6 mm with 5 μm particles and detection at 254 nm. The forced degradation study was performed with 0.01 M HCl as the diluent of the IFA standard solution (pH 2.0) and revealed that ETV is stable when exposed to heat, UV light, metal ions and neutral, basic and acid hydrolysis; however, the drug showed vulnerability to oxidation when exposed to 3% hydrogen peroxide, with a significant reduction in the content. Kinetic degradation studies were performed under oxidative condition in two different media: pH 2.0 (with HCl 0.01 M, the validated method diluent) and pH 6.0 (with citrate buffer, present in the oral formulation of ETV). In acidic medium, extrapolated calculations demonstrated that the useful lifetime (t90) of ETV at 25 °C is 2.26 days when in contact with H2O2 3%. In a medium with citrate buffer and pH 6.0, ETV was stable and its content was not reduced under oxidative conditions, which indicates an important influence of pH on the stability of liquid formulations of entecavir. Thermal analyses by Thermogravimetry (TGA) and Differential Thermal Analysis (DTA) indicated compatibility of entecavir with the excipients microcrystalline cellulose, crospovidone, titanium dioxide, magnesium stearate, hypromellose, polyethylene glycol (macrogol), povidone and sodium citrate, which was confirmed by the HPLC technique. Compatibility tests by HPLC showed no chemical interaction of ETV with the excipients anhydrous citric acid and mannitol. Lactose monohydrate was shown to be incompatible with ETV in compatibility tests by thermal analyses and HPLC. It is recommended, for liquid formulations containing ETV: use of an antioxidant in adequate concentration, with a medium pH equal to 6.0; use of amber bottle; filling with maximum volume of the bottle and using helium gas in the agitation tank; keeping the drug away from light and heat. For solid ETV formulations, it is recommended to replace the lactose soluble diluent by the excipient mannitol, which has the same function in the formulation.