Interactions between a pharmaceutical drug and its delivery device can result in changes in drug concentration and leachable contamination. Flucloxacillin, amiodarone and cyclosporin were investigated for drug concentration changes and leachable contamination after delivery through an intravenous administration set.
Flucloxacillin, amiodarone and cyclosporin were delivered through an intravenous administration set and the eluate analysed by HPLC-UV and HPLC-MS.
The average recovery of flucloxacillin was 99.7% and no leachable compounds were identified. The average recovery of cyclosporin was 96.1%, which contrasts previous findings that have reported up to 50% loss of cyclosporin. This is likely due to the use of DEHP-free administration sets in this study, as adsorption of cyclosporin is linearly related to DEHP content. The average recovery of amiodarone was 91.5%. 5-hydroxymethylfurfural was identified in the amiodarone solution following delivery through the administration set as well as the 5% glucose solution used for delivery.
Drug/administration set interactions may modify pharmaceuticals during delivery. In this study, only 90% of the amiodarone was delivered through a generic administration set. Given the growing use of generic administration sets in hospital settings, validation of the suitability of their use is required to ensure patient safety and expected levels of efficacy.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
Active pharmaceutical ingredient
European Medicines Authority
Food and Drug Administration
High-performance liquid chromatography
International Council for Harmonisation
Liquid chromatography-mass spectroscopy
- MP A:
Mobile phase A
- MP B:
Mobile phase B
PR Newswire. Global Peripheral I.V. Catheter Market 2014–2018. 2015 8 November, 2015. Available from: http://www.prnewswire.com/news-releases/globalperipheral-iv-catheter-market-2014–2018-257019061.html.
Alexandrou E, Ray-Barruel G, Carr PJ, Frost S, Inwood S, Higgins N, et al. International prevalence of the use of peripheral intravenous catheters. J Hosp Med. 2015;10(8):530–3.
Story D, Leeder J, Cullis P, Bellomo R. Biologically active contaminants of intravenous saline in PVC packaging: Australasian, European, and North American samples. Anaesth Intensive Care. 2005;33(1):78–81.
Pearson SD, Trissel LA. Leaching of diethylhexyl phthalate from polyvinyl chloride containers by selected drugs and formulation components. Am J Health Syst Pharm. 1993;50(7):1405–9.
Lee HJJ, Meinardi S, Pahl MV, Vaziri ND, Blake DR. Exposure to potentially toxic hydrocarbons and halocarbons released from the dialyzer and tubing set during hemodialysis. Am J Kidney Dis. 2012;60(4):609–16.
de Lemos ML, Hamata L, Vu T. Leaching of diethylhexyl phthalate from polyvinyl chloride materials into etoposide intravenous solutions. J Oncol Pharm Pract. 2005;11(4):155–7.
Rastegari F, Amin MM, Ebrahim K. Risk of phthalate exposure among hospitalized patient via intravenous fluids receiving. Iran J Toxicol. 2017;11(3):33–8.
Zidan AS, Aqueel SM, Alayoubi A, Mohammad A, Zhang J, Rahman Z, et al. Leachable diphenylguanidine from rubber closures used in pre-filled syringes: a case study to understand solid and solution interactions with oxytocin. Int J Pharm. 2017;532(1):491–501.
Solomon P, Nelson J. Profiling extractable and leachable inorganic impurities in ophthalmic drug containers by ICP-MS. Pharm Dev Technol 2017:1–8.
Jenke D. Identification, analysis and safety assessment of leachables and extractables. TrAC Trends Anal Chem. 2017;101:56–65.
Broschard TH, Glowienke S, Bruen US, Nagao LM, Teasdale A, Stults CL, et al. Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics–current challenges and approaches. Regul Toxicol Pharmacol. 2016;81:201–11.
United States Code of Federal Regulations. https://www.gpo.gov/fdsys/browse/collectionCfr.action?collectionCode=CFR.
International Council for Harmonisation Guidelines. http://www.ich.org/products/guidelines.html.
European Medicines Agency. http://www.ema.europa.eu/ema/.
Sutherland R, Croydon E, Rolinson G. Flucloxacillin, a new isoxazolyl penicillin, compared with oxacillin, cloxacillin, and dicloxacillin. Br Med J. 1970;4(5733):455–60.
Papiris SA, Triantafillidou C, Kolilekas L, Markoulaki D, Manali ED. Amiodarone: review of pulmonary effects and toxicity. Drug Saf. 2010;33(7):539–58.
Pollard S, Nashan B, Johnston A, Hoyer P, Belitsky P, Keown P, et al. A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporin A. Clin Ther. 2003;25(6):1654–69.
Stähelin H. The history of cyclosporin A (Sandimmune®) revisited: another point of view. Experientia. 1996;52(1):5–13.
Hospira Australia. FLUCLOXACILLIN SODIUM flucloxacillin 1g (as sodium) powder for injection vial. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2017-PI-02096-1.
Novartis Pharmaceuticals. SANDIMMUN ciclosporin 50mg/1mL injection ampoule. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03364-3.
Sanofi-Aventis Australia. Cordarone X Intravenous 150mg/3mL Injection. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05573-3.
Pappalardo M, Pappalardo L, Brooks P. Rapid and reliable HPLC method for the simultaneous determination of dihydroxyacetone, methylglyoxal and 5-hydroxymethylfurfural in leptospermum honeys. PLoS One. 2016;11(11):e0167006.
Bhaskar V, Middha A. Liquid chromatography/tandem mass spectrometry method for quantitation of Cremophor EL and its applications. Int J Anal Chem 2013;2013.
Shibata N, Ikuno Y, Tsubakimoto Y, Hoshino N, Minouchi T, Yoshio K, et al. Adsorption and pharmacokinetics of cyclosporin A in relation to mode of infusion in bone marrow transplant patients. Bone Marrow Transplant. 2000;25(6):633.
Ciutaru D, Badea I, Lazar L, Nicolescu D, Tudose A. A HPLC validated assay of paclitaxel’s related impurities in pharmaceutical forms containing Cremophor® EL. J Pharm Biomed Anal. 2004;34(3):493–9.
Meyer T, Waidelich D, Frahm A. Polyoxyethylene-Δ 9, 11-didehydrostearate and glycerol-polyoxyethylene-Δ 9, 11-didehydrostearate: two new components of the non-ionic emulsifier Cremophor® EL. J Pharm Biomed Anal. 2002;30(2):263–71.
Perdue JD, Seaton PJ, Tyrell JA, DeVido DR. The removal of Cremophor® EL from paclitaxel for quantitative analysis by HPLC–UV. J Pharm Biomed Anal. 2006;41(1):117–23.
Windebank AJ, Blexrud MD, De Groen P. Potential neurotoxicity of the solvent vehicle for cyclosporine. J Pharmacol Exp Ther. 1994;268(2):1051–6.
Mounier P, Laroche D, Divanon F, Mosquet B, Vergnaud M, Esse-Comlan A, et al. Anaphylactoid reactions to an injectable solution of a cremophor-containing solution of multivitamins. Therapie. 1994;50(6):571–3.
Peters P, Hayball PJ. A comparative analysis of the loss of amiodarone from small and large volume PVC and non-PVC infusion systems. Anaesth Intensive Care. 1990;18(2):241–5.
Weir S, Myers V, Bengtson K, Ueda C. Sorption of amiodarone to polyvinyl chloride infusion bags and administration sets. Am J Health Syst Pharm. 1985;42(12):2679–83.
Ulbricht RJ, Northup SJ, Thomas JA. A review of 5-hydroxymethylfurfural (HMF) in parenteral solutions. Fundam Appl Toxicol. 1984;4(5):843–53.
Lovejoy F. Fatal benzyl alcohol poisoning in neonatal intensive care units: a new concern for pediatricians. Am J Dis Child. 1982;136(11):974–5.
Masi S, Cléty D, Clément S, Anslot C, Detaille T. Acute amiodarone toxicity due to an administration error: could excipient be responsible? Br J Clin Pharmacol. 2009;67(6):691–3.
Hvattum E, Yip WL, Grace D, Dyrstad K. Characterization of polysorbate 80 with liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy: specific determination of oxidation products of thermally oxidized polysorbate 80. J Pharm Biomed Anal. 2012;62:7–16.
Wuelfing WP, Kosuda K, Templeton AC, Harman A, Mowery MD, Reed RA. Polysorbate 80 UV/vis spectral and chromatographic characteristics–defining boundary conditions for use of the surfactant in dissolution analysis. J Pharm Biomed Anal. 2006;41(3):774–82.
ACKNOWLEDGMENTS AND DISCLOSURES
This research was funded by The Faculty of Science, Health, Engineering and Education, University of the Sunshine Coast. The authors would like to thank Linda Pappalardo for conducting the 5-hydroxymethylfurfural analysis, Ms. Jenny Johns and Prof. Peter Parsons for completing the LC-MS analysis and the clinical staff at the Nambour General Hospital for their expert clinical advice.
About this article
Cite this article
Woodward, Z., Brooks, P., Morris-Smith, B. et al. Adsorption and Leachable Contamination of Flucloxacillin, Cyclosporin and Amiodarone Following Delivery Through an Intravenous Administration Set. Pharm Res 35, 121 (2018). https://doi.org/10.1007/s11095-018-2409-2
- active pharmaceutical ingredient
- drug delivery
- drug product