Purpose: Materials which comprise pharmaceutical manufacturing, packaging, and delivery systems are extracted via a range of media and contact scenarios, and these media are analyzed by a range of analytical techniques, to determine the qualitative and semi-quantitative profile(s) of compounds extracted from the materials. The analysis of volatile organic compounds by headspace gas chromatography in tandem with a mass spectrometer (HS/GC/MS), unlike other analytical methodologies, typically involves the extraction of the material in a sealed vessel. Thus, consideration of the extraction stoichiometry and the partitioning factors of these compounds between the headspace of the vessel and the sample material must be considered so that the materials are thoroughly extracted and the extracted mass is accurately quantified.
The purpose of this study was to evaluate the partitioning characteristics of volatile organic extractable compounds and determine sample extraction and quantification procedures best suited to achieve a through and accurate extraction of the materials. This included an evaluation of sample mass, extraction duration, and partitioning behavior for a range of volatile organic compounds in several commonly encountered polymeric matrices. Additionally, the advantages/disadvantages of internal versus external standardization were explored.
Methods: HS/GC/MS analysis was performed using a 60 m × 0.25 mm column with a DB-624 stationary phase and 1.4 µm film thickness. A 1:10 split ratio was used. The mass spectrometer was operated in full scan mode over a range of 29 – 250 atomic mass units. A range of incubation times was evaluated in the headspace auto-sampler, but a constant temperature of 90 °C was used in all cases. The analytical system was an Agilent 7890B gas chromatograph, Agilent 5977A mass spectrometer, and Agilent 7697A headspace auto-sampler.
Results: The data obtained in the experiments performed in this study yielded the following notable results:
- The partitioning coefficient between the gas and material phases, and thus the response factor, of each compound varies significantly between the polymer or elastomer being extracted.
- The mass extracted had a significant effect on the response factor, and thus the quantitative value ultimately reported, for the extraction procedure. Specifically, the greater the mass extracted the lower the extractable value was on a per mass basis. It was determined that
0.5 g/20 mL vial was the ideal mass for obtaining adequate response while maximizing extraction of the material.
-Incubation times required to achieve an equilibrium between the compound in the vial’s headspace and the material varied for each material. Nevertheless, two hours of incubation was found to be generally sufficient to achieve this equilibrium, and thus maximum extraction of the material. However, thicker components, such as rubber stoppers, required longer incubation times to achieve an equilibrium.
- External standard calibration and quantification was found to consistently underestimate the amount of extractables present due to the fact this approach is not representative of the bi-phasic system in which the material is being characterized.
- After evaluating several candidates, diethyl Ether-d10 was selected as the internal standard for quantification purposes. This selection was based on its solubility in water (thus avoiding the need to use dimethyl sulfoxide or other problematic solvents), consistency of response across a range of materials and water, and chromatographic properties.
- A case study was presented in which the amount of extractable trimethylsilanol from a component of a pharmaceutical packaging system was quantified using both internal and external standardization. The results obtained illustrated the advantages of using diethyl ether-d10 as an internal standard.
Conclusion: The results of this study have provided insight into the optimal procedures for performing static headspace extraction of volatile organic compounds for analysis by GC/MS. Determination of the optimal mass for extraction ensured adequate representation of the extractable content of the material, and furthermore illustrated the dangers of trying to increase sensitivity by increasing mass extracted. Use of an internal standard was found to generate more accurate and reproducible results as compared to external standardization.