Novel Derivatives of Lamivudine. Stability Studies in Different Matrices.

GUALDESI, MARÍA S.; RAVIOLO, MÓNICA A.; ESTEVE ROMERO, JOSEP S.; BRIÑÓN, MARGARITA C.

Simposio; 36th International Symposium of High-Performance Liquid Phase and Related Techniques.; 2011

Aiming to develop antiviral agents (anti-HIV) with optimal pharmacokinetics properties, we have investigated novel derivatives of lamivudine (3TC), by association with different aliphatic alcohols. Among them, that of associate with methanol (3TC-Meta), ethanol (3TC-Eta), n-propanol (3TC-nPro), n-Butanol (3TC-Buta), n-Pentanol (3TC-Penta), n-Hexanol (3TC-Hexa) and n-Octanol (3TC-Octa) demonstrated to exhibit important biological activity against HIV and HBV. The Food and Drug Administration (FDA) Guidance for Industry concerning in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms includes a discussion on gastrointestinal stability. Stability in the gastrointestinal tract (GIT) may be confirmed by incubating the drug substance in gastric and intestinal fluids that are representative of in vivo drug exposure to these fluids; e.g., 1 h in simulated gastric fluids (SGF) and 3 h in simulated intestinal fluids (SIF). Significant degradation (>5%) of a drug assessed in this manner could suggest potential instability in the GIT. In this work, we present stability studies of 3TC and their derivatives in buffer pH´s 1.2 and 6.8; simulated gastric fluid (SGF, pH 1.2) and intestinal one (SIF, pH 6.8), all as indicated in USP 32. As analytical method we have used Micellar Liquid Chromatography (MLC), validated according to the FDA guideline.3 Both, the disappearance of reagents (3TC derivatives) and the appearance of the only degradation product (3TC) were analyzed for each compound. Zidovudine was used as internal standard for a major statistical analysis. Result: In buffer pH´s 1.2 and 6.8 as well as in SGF, no degradation of intact drugs was observed after 48 h of incubation, while in SIF different degradation process was detected, caused by the presence of pancreatin.