Development and validation of HPLC methods for the determination of potential extractables from elastomeric stoppers in the presence of a complex surfactant vehicle used in the preparation of parenteral drug products

J Pharm Biomed Anal. 2007 Jan 17;43(2):558-65. doi: 10.1016/j.jpba.2006.08.020. Epub 2006 Oct 16.


HPLC methods were developed and validated for potential extractables [zinc dithiocarbamate, 2,6-di-tert-butyl-para-cresol (BHT), octylated diphenylamine antioxidant, sulfur, pentylphenol, and tetrakis(methylene(3,5-di-tert-butyl-4-hydroxyhydro cinnamate))methane] from commercial elastomeric stoppers in a complex surfactant matrix. These stoppers were proposed to be part of the container-closure system for experimental formulations containing the surfactant, polyoxyethylated Castor oil (USP/NF) (POE Castor oil) and ethanol. The presence of POE Castor oil in the formulation posed unique challenges to the development and validation of the HPLC methods. POE Castor oil, also known as Cremophor, is a viscous and complex solubilizing agent with a number of uncharacterized fractions. Hence the goal was to identify HPLC conditions that would be suitable for the separation, detection, and quantitation of the potential stopper extractables in the presence of such a complex drug product matrix. A number of experiments were performed to evaluate the effects of different columns, mobile phase composition, injection volume, and gradient profile on the separation and detection of the potential stopper extractables. The quantitation limits of these stopper extractables are between 1 and 10 ppm. The methods demonstrate good linearity, acceptable accuracy, and precision.

Publication types

  • Validation Study

MeSH terms

  • Butylated Hydroxytoluene / analysis
  • Chemistry, Pharmaceutical
  • Chromatography, High Pressure Liquid / methods*
  • Cinnamates / analysis
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / analysis
  • Dosage Forms
  • Drug Contamination
  • Drug Packaging*
  • Elastomers / chemistry*
  • Ethanol / chemistry
  • Linear Models
  • Pharmaceutical Solutions / chemistry*
  • Pharmaceutical Vehicles / chemistry*
  • Phenols / analysis
  • Polyethylene Glycols / chemistry*
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Spectrophotometry, Ultraviolet / methods
  • Sulfur Compounds / analysis
  • Surface-Active Agents / chemistry*
  • Thiocarbamates / analysis
  • Zinc Compounds / analysis


  • Cinnamates
  • Dosage Forms
  • Elastomers
  • Pharmaceutical Solutions
  • Pharmaceutical Vehicles
  • Phenols
  • Sulfur Compounds
  • Surface-Active Agents
  • Thiocarbamates
  • Zinc Compounds
  • Butylated Hydroxytoluene
  • cremophor
  • Ethanol
  • Polyethylene Glycols
  • Diphenylamine