Analysis of Residual Solvents using GC/FID with Headspace and a ...

Application Note:ANCCSRESSOLV1010Analysis of Residual Solvents using GC/FIDwith Headspace and a CyanopropylphenylPolysiloxane PhaseA. Khan, L. Pereira, Thermo Fisher Scientific, Runcorn, Cheshire, UKKey Words• TRACE TR-V1Column• Residual Solventsin PharmaceuticalProducts• USP 467 methodOverviewA Thermo Scientific TRACE Ultra GC system with aThermo Scientific TriPlus Autosampler was used for theanalysis of residual solvents in accordance with USPmethod 467. 1 The column used for the analysis was aThermo Scientific TRACE TR-V1 column.IntroductionThis application note describes the analysis of residualsolvents according to the revised (effective July 2007) USPharmacopeia (USP) method. The method is used foranalyzing trace levels of solvents that are involved in theproduction of a drug, excipient or product packaging in thepharmaceutical industry. Drug products should contain lowlevels of residual solvents as determined by safety data.The USP 467 method involves the analysis of 53solvents grouped according to their genotoxic hazards:• Class 1 solvents (known to cause unacceptable toxicities)should be avoided in the manufacturing process.• Class 2 solvents (associated with less severe toxicity)should be limited.• Class 3 solvents (less toxic) should be used where practical.Three analytical procedures are used for identificationand quantification of the residual solvents:• Procedure A is used for screening and confirmation ofthe solvents identity and use a G43 (volatiles) column.• Procedure B is used for confirmation of the solventsidentity using a G16 (wax) column.• Procedure C, which uses a G43 column, is required toquantify the amount of residual solvents.MethodsSamplesUSP 467 test mixtures solutions prepared according to USP 467 methodColumnTRACE TR-V1 30 m × 0.32 mm × 1.8 µmPart Number260V339PGC/FID ConditionsTriPlus Headspace AutosamplerSample VolumeSample Analysis Time1 mL30 minAgitator Temperature 80 °CIncubation TimeAgitator Shake45 minSyringe Temperature 100 °CPost Injection FlushTRACE GC UltraOven ProgramEquilibration TimeOn 10 s, Off 20 s30 s40 °C (20 min), 10 °C/min, 240 °C (10 min)0.5 min.Injector 140 °CSplit FlowColumn Flow40 mL/min2.0 mL/min (constant)Detector FID at 240 °CDetector Air FlowDetector H 2 FlowDetector N 2 Makeup FlowConsumables350 mL/min35 mL/min30 mL/minPart NumberTR-Green septa313G3211Thermo Scientific Split FocusLiner for 50 mm needlewith Quartz Wool453T1905Liner graphite seal 29033406Graphite ferrule for 0.32 mm ID column 290134872.5 mL headspace syringe 3650300620 mL clear crimp top vial 60180-506Aluminum 20 mm cap and Si/PTFE seal 60180-511

Measured SpecifiedPeak # Peak Identification Rt (min) S/N S/N1 1,1-Dichloroethane 4.06 108 > 32 1,1,1-Trichloroethane 9.90 186 > 53 Carbon Tetrachloride 10.53 15 > 34 Benzene 11.43 351 > 35 1,2-Dichloroethane 11.87 213 > 3Figure 1: GC/FID chromatogram for class 1 residual solventsResults and DiscussionThe acceptance criteria for USP 467,class 1 solvents, is that the signal-tonoiseratio for 1,1,1-Trichloroethane(peak 2) is greater than 5 and that thesignal-to-noise ratio obtained fromthe other compounds in the class isgreater than 3. The chromatogramand signal to noise measurementsobtained using the method describedpreviously are shown in Figure 1.The USP 467 method specificationfor class 2 solvents is that theresolution between acetonitrile anddichloromethane (peaks 2 and 3) isnot less than 1.0. The chromatogramsobtained for class 2 solvents (mixtureA and mixture B) are shown inFigures 2 and 3. The method criteriafor resolution between the criticalpair is met as these are fully resolved.All the other components are alsofully resolved, which demonstratesgood selectivity and efficiency of thechromatographic separation takingplace in the TRACE TR-V1 column.Poor response was observed for1,4-Dioxane, which was expected.Peak # Peak Identification Rt (min)1 Methanol 2.582 Acetonitrile 4.713 Dichloromethane 5.004 Trans-1,2-Dichloroethane 5.535 Cis-1,2-Dichloroethane 8.256 Tetrahydrofuran 9.167 Cyclohexane 9.948 Methylcyclohexane 15.979 1,4-Dioxane 18.3510 Toluene 23.3311 Chlorobenzene 27.1712 Ethyl Benzene 27.3913 m-Xylene/p-Xylene 27.6414 o-Xylene 28.42Figure 2: GC/FID chromatogram for class 2A residual solvents