(T1330-09-59) An Improved Multiple Headspace Extraction Workflow Using SIFT-MS

Purpose: Multiple analyses of the same sample makes conventional multiple headspace extraction (MHE) a useful, but slow and expensive, technique for quantitative analysis of volatile impurities in matrices for which calibration standards are difficult to create. Throughput challenges have been addressed through the application of selected ion flow tube mass spectrometry (SIFT-MS), which – due to calibration stability – can quantify volatile impurities routinely from one rapid headspace analysis.

Methods: A SIFT-MS instrument (Syft Tracer; Syft Technologies, Christchurch, NZ) coupled with a GERSTEL MPS Robotic Pro (Mulheim, Germany) was used in this work. Samples were incubated (50 °C for 60 min) in a GERSTEL agitator throughout its six-cycle MHE sequence. Headspace was sampled using a 2.5-mL headspace syringe (heated to 150 °C) and subsequently injected at a flow rate of 50 μL s^-1 into the SIFT-MS instrument’s autosampler inlet (heated to 150 °C) via a self-sealing GERSTEL septumless sampling head. The SIFT-MS instrument analyzes formaldehyde directly in air in 2 min. with no need for preconcentration or derivatization. Commercially available Gelucire 44/14 excipient was utilized (200 mg placed in 20 mL headspace vials). Full six-injection MHE analyses were run in triplicate on six days over a 27-day period.

Results: Headspace concentrations obtained using SIFT-MS over the 27-day period (for all replicates and their individual MHE injections) were stable with relative standard deviations (RSDs) ≤4% in the absence of recalibration or internal standards. The MHE results showed excellent linearity (R² > 0.993 across all samples) and an RSD of 4.9% across the study. Recalculation of all MHE data using the ratio of the first injection to full six-injection MHE (so-called ‘MHE calibration’) obtained on the first day of the study (average over 3 replicates) yielded an RSD of 7.7% (Figure 1). This is well within the typical intermediate precision acceptance criterion ( < 20%) for volatiles methods and indicates that the ‘MHE calibration’ is stable for at least several weeks. Hence calibration can be separated from routine analysis, reducing the time-to-result six-fold compared to chromatographic analysis, and supporting analysis of 12 samples/hr.

Conclusion: Formaldehyde is readily analyzed using MHE-SIFT-MS because ionization occurs directly in the gas phase. The ratio of the first injection to full MHE is stable for at least 27 days with SIFT-MS instruments so calibration can be conducted infrequently, benefiting analytical workflows for challenging matrices. Over 220 samples per day can be analyzed quantitatively for formaldehyde impurities using the enhanced MHE-SIFT-MS approach.

References: Perkins MJ, Langford VS (2022). Multiple Headspace Extraction-[SIFT-MS]. Part 1: A Protocol for Method Development and Transfer to Routine Analysis. Rev Sep Sci. 4(1), e22001. https://doi.org/10.17145/rss.22.001.

Figure 1. Difference in final calculated concentration of formaldehyde in Gelucire when using the Day 0 calibration factor for the 1st MHE injection compared with the full six-injection MHE calculation for each sample (including the individual Day 0 measurements in purple/pink).