Stability of the i.v. and oral formulations of etoposide in solution

Abstract

Etoposide is a widely used cytotoxic drug that requires complex formulation for both the i.v. and oral preparation to ensure drug stability. Data on the stability of the i.v. formulation when diluted in infusion fluids are contradictory, and there is little information on the stability of the oral preparation in gastric or intestinal fluids. The stability of both i.v. and oral etoposide was therefore evaluated in the present investigation. The stability of the i.v. preparation was investigated across a range of concentrations in infusion fluids, being determined by regular sampling for highperformance liquid chromatography (HPLC) analysis and by visual inspection. The stability of the oral preparation was studied in both artificial gastric and intestinal fluids, again with regular sampling for HPLC analysis, and the influence of pH, concentration and the addition of ethanol and bile salts on oral stability was determined. The i.v. preparation showed a marked decrease in stability with increasing drug concentration, but stability was additionally reduced in i.v. bags regularly sampled with a syringe and needle as compared with bags that were inspected visually only (minimal stability in sampled bags, 24 h at 0.5 mg/ml and 5 h at 1.0 mg/ml, as compared with 10 days and 18 h at the respective concentrations in unsampled bags). Stability was also greater at room temperature, 20–23°C, as compared with 8–12°C. Loss of stability was indicated by a decrease in etoposide concentration (measured by HPLC) and the appearance of a fine white precipitate, shown to be pure etoposide. Importantly, the appearance of precipitate was as sensitive as a specific HPLC assay in detecting loss of stability and was in many cases apparent when the etoposide concentration was within 5% of the starting concentration. The oral formulation also showed a marked concentration-dependent decrease in stability in artificial intestinal fluid at pH 7.5 (percentage of etoposide in solution after 2 h at 0.5, 1.0, 1.5 and 2.0 mg/ml, 94±2%, 80±5%, 68±13% and 41±9%, respectively). There was no concentration effect on stability in gastric fluid at pH 3.0, although stability was much greater at pH 3 and pH 5 as compared with pH 1 or in intestinal fluid at pH 7.5. Stability in artificial intestinal fluid, pH 7.5, was also significantly improved by the addition of the bile salt sodium tauroglycocholate (2 mg/ml) at etoposide concentrations of 1 (P<0.0001) and 2 mg/ml (P<0.0001) and by the addition of ethanol (10%, v/v) at etoposide levels of 1 (P<0.001) and 2 mg/ml (P<0.001). These studies clearly demonstrate the concentration-dependent stability of both the i.v. and the oral formulation of etoposide, that the appearance of precipitate is a sensitive indicator of loss of stability in i.v. fluids, and that stability in artificial intestinal fluid can be modulated by the use of other agents.