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How Do I Minimize Carryover in Headspace Analysis of Residual Solvents?
Pharmaceutical manufacturers must ensure that residual solvents are below regulated levels in pharmaceutical formulations. One common way to confirm the level is headspace analysis in combination with gas chromatography (GC) with a DB-624 column. A potential problem in headspace analysis of residual solvents is sample carryover. This can occur because many of the common solvents used in pharmaceutical manufacturing lack water solubility, so you must extract them in organic solvents such as N,N-dimethylacetamide (DMA), DMF, pyridine, or 1,3-dimethyl-2-imidazolidinone (DMI). These are high-boiling solvents that have the potential to remain in the headspace sampler pathway from one analysis to the next. Fortunately, there are ways to minimize this carryover.
Inert sample pathway
One mechanism for carryover is adsorption or reaction of sample components with the materials in the sample pathway. This is a common problem, particularly with older systems. To minimize carryover, choose a headspace system with a nonreactive, nonadsorptive sample flow path. An example is the Agilent Network Headspace Sampler coupled with an Agilent 6890N GC with inert volatiles interface and a 5973 inert MSD. This entire system is engineered to prevent sample adsorption. The sampler itself is fabricated with a Siltek sample path. The sample path tubing, sampling needle, transfer line, and purge lines are all deactivated. Figure 1 shows a residual solvent analysis using this system, and Table 1 lists the analytes in the chromatogram.
Figure 1. Total ion chromatogram of residual solvents analyzed with Agilent 6890N/5973 inert system.
 Table 1. Residual solvents by peak number.
High-temperature zones
A second mechanism for carryover is condensation of sample along the sample pathway. This typically happens when the pathway is not heated uniformly, or is just not hot enough. Again, it is important to choose a headspace analyzer such as the Agilent system that has been designed and tested for thermal uniformity and high temperature operation. Second, it is important to set temperatures high enough to avoid condensation, and to analyze blanks to confirm suitable settings. For example, carryover tests were performed on the Agilent system with alternate vials of water and pure DMI, a solvent that boils at 225 ºC. When the headspace oven was equilibrated at 220 ºC, and the sample loop and transfer line were kept at 250 ºC, the DMI carryover into the water blanks was very low-under 0.003 percent.
Programmed vent purge
A third source of carryover is residual sample in the headspace sampling loop. To avoid this, the sampling loop should be purged after the sample has been transferred to the GC. The G1888 Network Headspace Sampler has a unique programmable vent line purge capability that allows you to set a purge time from 30 seconds up to a maximum of the analysis cycle time. Studies have shown that a 20-minute purge time works well to prevent this source of carryover.
Conclusion
For the analysis of residual solvents in pharmaceutical formulations, sample carryover is minimized with an inert sample pathway, uniform high-temperature heated zones, and a programmable vent purge.
Get ahead!
For instrument settings for residual solvent analysis, as well as details on preventing carryover, download an application note (5989-1263EN). By Roger L. Firor
Agilent Technologies senior applications chemist
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