Cancer Chemotherapy and Pharmacology

, Volume 37, Issue 1–2, pp 117–124 | Cite as

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

  • Simon P Joel
  • Peter I Clark
  • Maurice L. Slevin
Original Article Etoposide, Stability, Oral Formulation, Intravenous Solution, Stability-Modulating Agents


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.

Key words

Etoposide Stability Oral formulation Intravenous solution Stability-modulating agents 


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  1. 1.
    Adams PS, Haines- Nutt, RF, Rowlands CG (1985) Stability of selected cytotoxics when used by continuous infusion at low doses by home based patients (meeting abstract). EORTC symposium on continuous infusion chemotherapy, March 1985 Brussels, Abstr 9Google Scholar
  2. 2.
    Adams PS, Haines-Nutt, RF, Bradford, E, Palmer A, Rowland CG (1987) Pharmaceutical aspects of home infusion therapy for cancer patients. Pharm J 238:476–478Google Scholar
  3. 3.
    Arnold AM (1979) Podophyllotoxin derivative VP16-213. Cancer Chemother Pharmacol 3:71–80Google Scholar
  4. 4.
    Beijnen, JH, Holthuis JJM, Kerkdijk HG, Houwen OA van der, Paalman AC, Bult A, Underberg WJ (1988) Degradation kinetics of etoposide in aqueous solution. Int J Pharm 41:169–178Google Scholar
  5. 5.
    Beijnen JH, Beijnen BA, Dubbelman AC, Gijn R van, Underberg WJ (1991) Chemical and physical stability of etoposide and teniposide in commonly used infusion fluids. J Parenter Sci Technol 45:108–112Google Scholar
  6. 6.
    Bristol-Laboratories (1980) Product development research report. Bristol-Laboratory, Syracuse, New YorkGoogle Scholar
  7. 7.
    Bristol-Myers (1981) Vepesid (etoposide). Current clinical experience. Bristol-Myers, New YorkGoogle Scholar
  8. 8.
    Canetta RP, Hilgard J, Florentine S, Bedogni P, Lenaz L (1982) Current development of podophyllotoxins. Cancer Chemother Pharmacol 7:93–98Google Scholar
  9. 9.
    D'Incalci M, Erba E, Vaghi M, Morasca L (1982) In vitro cytotoxicty of VP16 on primary tumour and metastasis of Lewis lung carcinoma. Eur J Cancer Clin Oncol 18:377–380Google Scholar
  10. 10.
    Floor BJ, Klein AE, Muhammad N, Ross D (1985) Stability indicating liquid chromatographic determination of etoposide and benzyl alcohol in injectable formulations. J Pharm Sci 74: 197–200Google Scholar
  11. 11.
    Guyton AC (1981) Secretory function of the alimentary tract. In: Textbook of medical physiology. W.B. Saunders, Philadelphia, pp 809–811Google Scholar
  12. 12.
    Harvey VJ, Joel SP, Johnston A, Slevin ML (1985) High-performance liquid chromatography of etoposide in plasma and urine. J Chromatogr 339:419–423Google Scholar
  13. 13.
    Harvey VJ, Slevin ML, Joel SP, Smythe MM, Johnston A, Wrigley PF (1985) Variable bioavailability following repeated oral doses of etoposide. Eur J Cancer Clin Oncol 21:1315–1319Google Scholar
  14. 14.
    Harvey VJ, Slevin ML, Joel SP, Johnston A, Wrigley PF (1986) The effect of dose on the bioavailability of oral etoposide. Cancer Chemother Pharmacol 16:178–181.Google Scholar
  15. 15.
    Joel SP, Clark PI, Maclean MC, and Slevin ML (1989) The stability of the intravenous preparation of etoposide in isotonic fluids (meeting abstract). Proc Am Assoc Cancer Res, Vol. 30:A972Google Scholar
  16. 16.
    Maanen J van, Vries J de, Pappie D, Akker E van den, Lafleur VM, Retel J, Greef J van der, Pinedo HM (1987) Cytochrome P-450-mediatedO-demethylation: a route in the metabolic activation of etoposide (VP-16-213). Cancer Res 47:4658–4662Google Scholar
  17. 17.
    McLeod HF, Relling MV (1992) Stability of etoposide solution for oral use. Am J Hosp Pharm 49:2785Google Scholar
  18. 18.
    Rideout JM, Ayres DC, Lim CK, Peters TJ (1984) Determination of etoposide (VP16-213) and teniposide (VM-26) in serum by high performance liquid chromatography with electrochemical detection. J Pharmacol Biomed Anal 2:125–128Google Scholar
  19. 19.
    Sandoz (1969) US patent 3 524 844 1976. Chem Abst 70:79340AGoogle Scholar
  20. 20.
    Schurgers N, Blaey CJ de, Crommelin DJA (1985) Absorption of etoposide (VP16-213) from the small intestine of the rat. The potential role of mucus as an absorption rate limiting barrier. Pharm Res 4:162–165Google Scholar
  21. 21.
    Seargeant LE, Kobrinsky NL, Sus CJ, Nazeravich DR (1987) In vitro stability and compatibility of daunorubicin, cytarabine, and etoposide. Cancer Treat Rep 71:1189–1192Google Scholar
  22. 22.
    Shah JC, Chen JR, Chow D (1989) Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide. Pharm Res 6:408–412Google Scholar
  23. 23.
    Stewart CF, Hampton EM (1989) Stability of cisplatin and etoposide in intravenous admixtures. Am J Hosp Pharm 46:1400–1404Google Scholar
  24. 24.
    Underberg WJM, Kerkdijk HG, Holthuis JJM, Beijnen JH (1985) Analysis and degradation kinetics of etoposide (VP16-213) in aqueous solution. Pharm Weekbl Sci 7:291Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Simon P Joel
    • 1
  • Peter I Clark
    • 1
  • Maurice L. Slevin
    • 1
  1. 1.Department of Medical OncologySt. Bartholomew's HospitalLondonUK

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