Employing Novel Sample Preparation and Analysis by GC-TOFMS for Improved Target and Non-Target Detection of Leachables in Cream/Gel Drug Products

Significance of the Topic

Topical cream and gel drug products often use oil-in-water emulsions and metal or plastic packaging that can leach chemical residues into the formulation. Regulatory agencies require comprehensive leachables testing to ensure patient safety. Advanced non-targeted analytical workflows enable detection and identification of unexpected contaminants at trace levels, improving risk assessment in pharmaceutical quality control.

Objectives and Study Overview

This study evaluated two novel sample preparation strategies for extracting common leachables from cream formulations packaged in tubes and tins. Five target leachables were blind-spiked into ointment samples. The goals were to compare extraction efficiency, assess detection capabilities of a GC-TOFMS platform with automated deconvolution, and demonstrate non-targeted identification of migratory compounds without prior knowledge of spike composition.

Methodology and Instrumentation

Two preparation workflows were tested:

• Method A: Hexane liquid-liquid extraction after sonication, followed by evaporation and internal standard addition.
• Method B: Methanol extraction with SPE cleanup using a Plexa cartridge, liquid-liquid exchange into hexanes, evaporation, and internal standard addition.

All extracts were analyzed on a Pegasus BTX GC-TOFMS system. Automated data processing included ChromaTOF for deconvolution and library matching, and ChromaTOF Sync for comparative peak analysis between spiked and unspiked samples.

Key Results and Discussion

Method A consistently recovered higher peak areas for all five spiked leachables compared to Method B. Non-targeted data processing successfully flagged each spike despite low background levels in unspiked samples. Automated deconvolution resolved coeluting interferences such as dibutyl phthalate and octanoic acid ester. A brief GC×GC demonstration showed that two-dimensional chromatography could further separate analytes like 9,10-anthracenedione from matrix interferences, yielding cleaner spectra and higher library match scores.

Benefits and Practical Applications

• Non-targeted workflows reveal unexpected contaminants and confirm known leachables without prior compound lists.
• Automated deconvolution accelerates data review by distinguishing coeluted peaks in complex matrices.
• Comparative spike vs. blank analysis via ChromaTOF Sync quickly isolates elevated signals for prioritized review.

Future Trends and Applications

Integration of GC×GC-TOFMS into routine leachable screening can further enhance trace-level detection. Advances in software algorithms for library matching and deconvolution will streamline non-targeted screening. Coupling high-resolution mass spectrometry and retention modeling may enable predictive risk assessment of packaging materials, reducing development timelines and improving consumer safety.

Conclusion

This case study demonstrates that combining optimized extraction, GC-TOFMS analysis, and automated data processing provides a powerful non-targeted approach for identifying leachables in topical drug products. Method A outperformed SPE in recovery of spiked analytes, and deconvolution tools successfully uncovered targets hidden by matrix interferences. Expanding these methods with two-dimensional separations and advanced informatics will support more robust leachables testing in pharmaceutical quality control.