STABILITY OF THE IV AND ORAL FORMULATIONS OF ETOPOSIDE IN SOLUTION

Etoposide is a widely used cytotoxic drug that requires complex formul ation for both the i.v. and oral preparation to ensure drug stability. Data on the stability of the i.v. formulation when diluted in infusio n fluids are contradictory, and there is little information on the sta bility of the oral preparation in gastric or intestinal fluids. The st ability of both i.v. and oral etoposide was therefore evaluated in the present investigation. The stability of the i.v. preparation was inve stigated across a range of concentrations in infusion fluids, being de termined by regular sampling for high-performance liquid chromatograph y (HPLC) analysis and by visual inspection. The stability of the oral preparation was studied in both artificial gastric and intestinal flui ds, again with regular sampling for HPLC analysis, and the influence o f pH, concentration and the addition of ethanol and bile salts on oral stability was determined. The i.v. preparation showed a marked decrea se 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 (minim al 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 degrees C, as compared with 8-12 degrees C. Loss of stability was ind icated by a decrease in etoposide concentration (measured by HPLC) and the appearance of a fine white precipitate, shown to be pure etoposid e. Importantly, the appearance of precipitate was as sensitive as a sp ecific HPLC assay in detecting loss of stability and was in many cases apparent when the etoposide concentration was within 5% of the starti ng concentration. The oral formulation also showed a marked concentrat ion-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%, respecti vely). 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 co mpared with pH 1 or in intestinal fluid at pH 7.5. Stability in artifi cial intestinal fluid, pH 7.5, was also significantly improved by the addition of the bile salt sodium tauroglycocholate (2 mg/ml) at etopos ide concentrations of 1 (P < 0.0001) and 2 mg/ml (P < 0.0001) and by t he 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 concen tration-dependent stability of both the i.v. and the oral formulation of etoposide, that the appearance of precipitate is a sensitive indica tor of loss of stability in i.v. fluids, and that stability in artific ial intestinal fluid can be modulated by the use of other agents.