10j) residual solvents in pharma -...

Residual Solvents in Residual Solvents in

PharmaceuticalsPharmaceuticals

USP Method 467USP Method 467USP Method 467USP Method 467

• Organic Volatile Impurities (OVIOrganic Volatile Impurities (OVIOrganic Volatile Impurities (OVIOrganic Volatile Impurities (OVI’’’’s) s) s) s)

• Done Usually in Bulk, WaterDone Usually in Bulk, WaterDone Usually in Bulk, WaterDone Usually in Bulk, Water----Soluble Soluble Soluble Soluble PharmaceuticalsPharmaceuticalsPharmaceuticalsPharmaceuticals

• Applicable to about 60% of Drugs Tested.Applicable to about 60% of Drugs Tested.Applicable to about 60% of Drugs Tested.Applicable to about 60% of Drugs Tested.

• Also Need to do WaterAlso Need to do WaterAlso Need to do WaterAlso Need to do Water----Insoluble DrugsInsoluble DrugsInsoluble DrugsInsoluble Drugs

USP 467USP 467USP 467USP 467

• Method I: Direct Aqueous Injection

• Method II: Purge and Trap

• Method IV: Static Headspace

• Method V: Direct Aqueous Injection

• Method VI: Direct Aqueous Injection

• Method for Coated Tablets: Static Headsapce

What OVIWhat OVIWhat OVIWhat OVI’’’’s to Look For, Old Version s to Look For, Old Version s to Look For, Old Version s to Look For, Old Version First published in 1990First published in 1990First published in 1990First published in 1990

• Methylene Chloride, 100 ppm limitMethylene Chloride, 100 ppm limitMethylene Chloride, 100 ppm limitMethylene Chloride, 100 ppm limit

• Benzene, 100 ppm limitBenzene, 100 ppm limitBenzene, 100 ppm limitBenzene, 100 ppm limit

• Trichloroethylene, 100 ppm limitTrichloroethylene, 100 ppm limitTrichloroethylene, 100 ppm limitTrichloroethylene, 100 ppm limit

• Dioxane, 100 ppm limitDioxane, 100 ppm limitDioxane, 100 ppm limitDioxane, 100 ppm limit

• Chloroform, 50 ppm limitChloroform, 50 ppm limitChloroform, 50 ppm limitChloroform, 50 ppm limit

• Ethylene Oxide, 10 ppm limitEthylene Oxide, 10 ppm limitEthylene Oxide, 10 ppm limitEthylene Oxide, 10 ppm limit

• Others, up to 24 totalOthers, up to 24 totalOthers, up to 24 totalOthers, up to 24 total

• In new revisions, expect these limits to drop In new revisions, expect these limits to drop In new revisions, expect these limits to drop In new revisions, expect these limits to drop significantly.significantly.significantly.significantly.

What OVIWhat OVIWhat OVIWhat OVI’’’’s to Look For, new version s to Look For, new version s to Look For, new version s to Look For, new version

published revision in January 2000published revision in January 2000published revision in January 2000published revision in January 2000

• Limits match those for EP (European Limits match those for EP (European Limits match those for EP (European Limits match those for EP (European Pharmacopoeia) and the ICHPharmacopoeia) and the ICHPharmacopoeia) and the ICHPharmacopoeia) and the ICH

• Benzene, 2 Benzene, 2 Benzene, 2 Benzene, 2 µµµµg per gg per gg per gg per g

• Chloroform, 60 Chloroform, 60 Chloroform, 60 Chloroform, 60 µµµµg per gg per gg per gg per g

• 1,4 1,4 1,4 1,4 ––––Dioxane, 380 Dioxane, 380 Dioxane, 380 Dioxane, 380 µµµµg per gg per gg per gg per g

• Methylene Chloride, 600 Methylene Chloride, 600 Methylene Chloride, 600 Methylene Chloride, 600 µµµµg per gg per gg per gg per g

• Trichloroethylene, 80 Trichloroethylene, 80 Trichloroethylene, 80 Trichloroethylene, 80 µµµµg per gg per gg per gg per g

• Ethylene Oxide, 10 Ethylene Oxide, 10 Ethylene Oxide, 10 Ethylene Oxide, 10 µµµµg per g*g per g*g per g*g per g*

* Analyzed only when specified in individual * Analyzed only when specified in individual * Analyzed only when specified in individual * Analyzed only when specified in individual monograph.monograph.monograph.monograph.

USP Method 467, Method IV vs. IIUSP Method 467, Method IV vs. IIUSP Method 467, Method IV vs. IIUSP Method 467, Method IV vs. II

• Method II uses Purge and Trap as the Method II uses Purge and Trap as the Method II uses Purge and Trap as the Method II uses Purge and Trap as the concentration system.concentration system.concentration system.concentration system.

• Why Use Static Headspace?Why Use Static Headspace?Why Use Static Headspace?Why Use Static Headspace?– SimplerSimplerSimplerSimpler

– Less Solvent UseLess Solvent UseLess Solvent UseLess Solvent Use

– No FoamingNo FoamingNo FoamingNo Foaming

– Less Potential for ContaminationLess Potential for ContaminationLess Potential for ContaminationLess Potential for Contamination

– Can detect benzene at 2 ppm limitCan detect benzene at 2 ppm limitCan detect benzene at 2 ppm limitCan detect benzene at 2 ppm limit

Method Parameters Method Parameters Method Parameters Method Parameters

• 0.53mm x 30m fused silica column, with a 50.53mm x 30m fused silica column, with a 50.53mm x 30m fused silica column, with a 50.53mm x 30m fused silica column, with a 5µµµµm m m m column (G27 stationary phase)column (G27 stationary phase)column (G27 stationary phase)column (G27 stationary phase)

• Temperature Program: 35 degrees for 5 Temperature Program: 35 degrees for 5 Temperature Program: 35 degrees for 5 Temperature Program: 35 degrees for 5 minutes; increased to 175 degrees at 8 degrees minutes; increased to 175 degrees at 8 degrees minutes; increased to 175 degrees at 8 degrees minutes; increased to 175 degrees at 8 degrees per minute; increased to 260 degrees at 35 per minute; increased to 260 degrees at 35 per minute; increased to 260 degrees at 35 per minute; increased to 260 degrees at 35 degrees per minute. Maintain at least 16 degrees per minute. Maintain at least 16 degrees per minute. Maintain at least 16 degrees per minute. Maintain at least 16 minutes.minutes.minutes.minutes.

• Carrier Gas: Helium at 35 cm per second. 4.1 psi Carrier Gas: Helium at 35 cm per second. 4.1 psi Carrier Gas: Helium at 35 cm per second. 4.1 psi Carrier Gas: Helium at 35 cm per second. 4.1 psi constantconstantconstantconstant

• Injection Port Temperature: 70 degreesInjection Port Temperature: 70 degreesInjection Port Temperature: 70 degreesInjection Port Temperature: 70 degrees

• Detector Temperature: 260 degreesDetector Temperature: 260 degreesDetector Temperature: 260 degreesDetector Temperature: 260 degrees

• Detector: FIDDetector: FIDDetector: FIDDetector: FID

The Effect of Sample Loop Pressure on Peak The Effect of Sample Loop Pressure on Peak The Effect of Sample Loop Pressure on Peak The Effect of Sample Loop Pressure on Peak AreaAreaAreaArea

AREAAREAAREAAREA AREAAREAAREAAREA % Increase% Increase% Increase% Increase

14.7 psi14.7 psi14.7 psi14.7 psi 21.7 psi21.7 psi21.7 psi21.7 psi

Data CountsData CountsData CountsData Counts Data CountsData CountsData CountsData Counts

MeClMeClMeClMeCl2222 143992143992143992143992 191290191290191290191290 133133133133

CHClCHClCHClCHCl3333 91149911499114991149 123962123962123962123962 136136136136

BenzeneBenzeneBenzeneBenzene 1046162104616210461621046162 1430586143058614305861430586 137137137137

TCETCETCETCE 214732214732214732214732 290579290579290579290579 135135135135

1,41,41,41,4----DioxaneDioxaneDioxaneDioxane 351530351530351530351530 481474481474481474481474 137137137137

The Effect of Sample Loop Volume on Peak AreaThe Effect of Sample Loop Volume on Peak AreaThe Effect of Sample Loop Volume on Peak AreaThe Effect of Sample Loop Volume on Peak Area


250 250 250 250 µµµµllll 1.0 ml1.0 ml1.0 ml1.0 ml

Data countsData countsData countsData counts Data countsData countsData countsData counts




TCETCETCETCE 290579290579290579290579 881470881470881470881470 303303303303

1,4 Dioxane1,4 Dioxane1,4 Dioxane1,4 Dioxane 481474481474481474481474 142179142179142179142179 295295295295

The Effect of Sample Loop Temperature on The Effect of Sample Loop Temperature on The Effect of Sample Loop Temperature on The Effect of Sample Loop Temperature on Peak AreaPeak AreaPeak AreaPeak Area


85858585°°°° C C C C 150150150150°°°° C C C C

DDDData ata ata ata countscountscountscounts DDDData ata ata ata countscountscountscounts




TCETCETCETCE 165386165386165386165386 214732214732214732214732 130130130130

1,4,1,4,1,4,1,4,----DioxaneDioxaneDioxaneDioxane 273740273740273740273740 351530351530351530351530 128128128128

Overall Increase in Area with Optimized PTV Overall Increase in Area with Optimized PTV Overall Increase in Area with Optimized PTV Overall Increase in Area with Optimized PTV ParametersParametersParametersParameters


OriginalOriginalOriginalOriginal OptimizedOptimizedOptimizedOptimized

Data countsData countsData countsData counts Data countsData countsData countsData counts




TCETCETCETCE 165386165386165386165386 881470881470881470881470 533533533533

1,41,41,41,4----DioxaneDioxaneDioxaneDioxane 273740273740273740273740 1421179142117914211791421179 519519519519

Solvent Selection: Water vs OrganicSolvent Selection: Water vs OrganicSolvent Selection: Water vs OrganicSolvent Selection: Water vs Organic

• Most OVIMost OVIMost OVIMost OVI’’’’s Have Relatively Low Partition s Have Relatively Low Partition s Have Relatively Low Partition s Have Relatively Low Partition Coefficients in WaterCoefficients in WaterCoefficients in WaterCoefficients in Water

• Problems Arise With Drugs Only Soluble Problems Arise With Drugs Only Soluble Problems Arise With Drugs Only Soluble Problems Arise With Drugs Only Soluble in Organic Solvents in Organic Solvents in Organic Solvents in Organic Solvents

OVIs OVIs OVIs OVIs OVIs OVIs OVIs OVIs

in H2O at 85 C in Na2SO4 in H2O at 85 C in Na2SO4 in H2O at 85 C in Na2SO4 in H2O at 85 C in Na2SO4 (aq) at 85 C(aq) at 85 C(aq) at 85 C(aq) at 85 C

MeCl2 4.1 MeCl2 4.1 MeCl2 4.1 MeCl2 4.1 2.62.62.62.6CHCl3 3.0 CHCl3 3.0 CHCl3 3.0 CHCl3 3.0 1.91.91.91.9

Benzene 2.5 Benzene 2.5 Benzene 2.5 Benzene 2.5 1.71.71.71.7TCE 1.9 TCE 1.9 TCE 1.9 TCE 1.9 1.61.61.61.6

1,41,41,41,4----Dioxane 4.2 1.4Dioxane 4.2 1.4Dioxane 4.2 1.4Dioxane 4.2 1.4

Partition CoefficientsPartition CoefficientsPartition CoefficientsPartition Coefficients

How to Use Organic SolventsHow to Use Organic SolventsHow to Use Organic SolventsHow to Use Organic Solvents

• Select an Organic Solvent That Can Have Select an Organic Solvent That Can Have Select an Organic Solvent That Can Have Select an Organic Solvent That Can Have the Matrix Modified by Saturated Salt the Matrix Modified by Saturated Salt the Matrix Modified by Saturated Salt the Matrix Modified by Saturated Salt SolutionsSolutionsSolutionsSolutions– N,NN,NN,NN,N----Dimethylformamide (DMF)Dimethylformamide (DMF)Dimethylformamide (DMF)Dimethylformamide (DMF)

– N,NN,NN,NN,N----Dimethylacetamide (DMA)Dimethylacetamide (DMA)Dimethylacetamide (DMA)Dimethylacetamide (DMA)

– Dimethylsulfoxide (DMSO)Dimethylsulfoxide (DMSO)Dimethylsulfoxide (DMSO)Dimethylsulfoxide (DMSO)

– 1,31,31,31,3----dimethyldimethyldimethyldimethyl----2222----imidazolidinone (DMI), no salt imidazolidinone (DMI), no salt imidazolidinone (DMI), no salt imidazolidinone (DMI), no salt addedaddedaddedadded

Organic Solvent Process: One ChoiceOrganic Solvent Process: One ChoiceOrganic Solvent Process: One ChoiceOrganic Solvent Process: One Choice

• Use DMF to Dissolve PharmaceuticalUse DMF to Dissolve PharmaceuticalUse DMF to Dissolve PharmaceuticalUse DMF to Dissolve Pharmaceutical

• Use 2ml Sample in Headspace VialUse 2ml Sample in Headspace VialUse 2ml Sample in Headspace VialUse 2ml Sample in Headspace Vial

• Add 1 ml of Saturated Sodium Sulfate Add 1 ml of Saturated Sodium Sulfate Add 1 ml of Saturated Sodium Sulfate Add 1 ml of Saturated Sodium Sulfate SolutionSolutionSolutionSolution

• Cap and Seal the Vial for AnalysisCap and Seal the Vial for AnalysisCap and Seal the Vial for AnalysisCap and Seal the Vial for Analysis

Reproducibility of OVIReproducibility of OVIReproducibility of OVIReproducibility of OVI’’’’ssss

• Ethanol 3.13% RSDEthanol 3.13% RSDEthanol 3.13% RSDEthanol 3.13% RSD

• Acetone 3.04Acetone 3.04Acetone 3.04Acetone 3.04

• Isopropanol 3.31Isopropanol 3.31Isopropanol 3.31Isopropanol 3.31

• Methylene Chloride 3.94Methylene Chloride 3.94Methylene Chloride 3.94Methylene Chloride 3.94

• Ethyl Acetate 3.39Ethyl Acetate 3.39Ethyl Acetate 3.39Ethyl Acetate 3.39

• Tetrahydrofuran 2.63Tetrahydrofuran 2.63Tetrahydrofuran 2.63Tetrahydrofuran 2.63

• Chloroform 4.64Chloroform 4.64Chloroform 4.64Chloroform 4.64

• Benzene 4.18Benzene 4.18Benzene 4.18Benzene 4.18

• Trichloroethene 4.89Trichloroethene 4.89Trichloroethene 4.89Trichloroethene 4.89

• nnnn----Butanol 6.49Butanol 6.49Butanol 6.49Butanol 6.49

Impurity Reproducibility in Drug SampleImpurity Reproducibility in Drug SampleImpurity Reproducibility in Drug SampleImpurity Reproducibility in Drug Sample

• Acetone 2.9 ppm 5.12 %RSDAcetone 2.9 ppm 5.12 %RSDAcetone 2.9 ppm 5.12 %RSDAcetone 2.9 ppm 5.12 %RSD

• Isopropanol 1.0 ppm 3.46Isopropanol 1.0 ppm 3.46Isopropanol 1.0 ppm 3.46Isopropanol 1.0 ppm 3.46

• Ethyl Acetate 66.0 ppm 4.52Ethyl Acetate 66.0 ppm 4.52Ethyl Acetate 66.0 ppm 4.52Ethyl Acetate 66.0 ppm 4.52

• Tetrahydrofuran 5.7 ppm 4.53Tetrahydrofuran 5.7 ppm 4.53Tetrahydrofuran 5.7 ppm 4.53Tetrahydrofuran 5.7 ppm 4.53

• Chloroform 1.9 ppm 4.51 Chloroform 1.9 ppm 4.51 Chloroform 1.9 ppm 4.51 Chloroform 1.9 ppm 4.51

Water as Solvent Process: Second PotentialWater as Solvent Process: Second PotentialWater as Solvent Process: Second PotentialWater as Solvent Process: Second Potential

• Water Soluble DrugsWater Soluble DrugsWater Soluble DrugsWater Soluble Drugs– Weight 100Weight 100Weight 100Weight 100----110 mg of Sample Into Vial110 mg of Sample Into Vial110 mg of Sample Into Vial110 mg of Sample Into Vial

– Add 1 g of Anhydrous Sodium SulfateAdd 1 g of Anhydrous Sodium SulfateAdd 1 g of Anhydrous Sodium SulfateAdd 1 g of Anhydrous Sodium Sulfate

– Add 5 ml of Water (or other diluent such as 0.1N HCl Add 5 ml of Water (or other diluent such as 0.1N HCl Add 5 ml of Water (or other diluent such as 0.1N HCl Add 5 ml of Water (or other diluent such as 0.1N HCl or 0.1M pH 9 Ammonium Carbonate Buffer)or 0.1M pH 9 Ammonium Carbonate Buffer)or 0.1M pH 9 Ammonium Carbonate Buffer)or 0.1M pH 9 Ammonium Carbonate Buffer)

• AlternativeAlternativeAlternativeAlternative– Dissolve 2.0 g Sample in 100 ml of Appropriate Dissolve 2.0 g Sample in 100 ml of Appropriate Dissolve 2.0 g Sample in 100 ml of Appropriate Dissolve 2.0 g Sample in 100 ml of Appropriate

SolventSolventSolventSolvent

– Seal Flask Tightly. Dissolve.Seal Flask Tightly. Dissolve.Seal Flask Tightly. Dissolve.Seal Flask Tightly. Dissolve.

– Take 5 ml Dissolved Sample, add to Vial with 1 g Take 5 ml Dissolved Sample, add to Vial with 1 g Take 5 ml Dissolved Sample, add to Vial with 1 g Take 5 ml Dissolved Sample, add to Vial with 1 g Anhydrous NaSO4.Anhydrous NaSO4.Anhydrous NaSO4.Anhydrous NaSO4.

Water as Solvent Process: ResultsWater as Solvent Process: ResultsWater as Solvent Process: ResultsWater as Solvent Process: Results

• Relative Standard Deviation (RSD) % using 50% Relative Standard Deviation (RSD) % using 50% Relative Standard Deviation (RSD) % using 50% Relative Standard Deviation (RSD) % using 50% and 100% of USP Limit Standards. and 100% of USP Limit Standards. and 100% of USP Limit Standards. and 100% of USP Limit Standards.

ChemicalChemicalChemicalChemical RSD at 50%RSD at 50%RSD at 50%RSD at 50% RSD at 100%RSD at 100%RSD at 100%RSD at 100%

MMMMeeeethylene thylene thylene thylene ChlorideChlorideChlorideChloride 4.84.84.84.8 1.91.91.91.9

ChloroformChloroformChloroformChloroform 5.25.25.25.2 3.13.13.13.1

BenezeneBenezeneBenezeneBenezene 6.16.16.16.1 3.63.63.63.6

TCETCETCETCE 8.68.68.68.6 3.13.13.13.1

1,41,41,41,4----DioxaneDioxaneDioxaneDioxane 8.08.08.08.0 4.84.84.84.8

Organic Solvent Process: An AlternativeOrganic Solvent Process: An AlternativeOrganic Solvent Process: An AlternativeOrganic Solvent Process: An Alternative

• Use 1,3Use 1,3Use 1,3Use 1,3----dimethyldimethyldimethyldimethyl----2222----imidazolidinone (DMI) imidazolidinone (DMI) imidazolidinone (DMI) imidazolidinone (DMI) as Solvent.as Solvent.as Solvent.as Solvent.– Less Problems than DMF, DMA, or DMSOLess Problems than DMF, DMA, or DMSOLess Problems than DMF, DMA, or DMSOLess Problems than DMF, DMA, or DMSO

• Higher boiling point than DMF or DMAHigher boiling point than DMF or DMAHigher boiling point than DMF or DMAHigher boiling point than DMF or DMA

• DMSO can be aggressive on some partsDMSO can be aggressive on some partsDMSO can be aggressive on some partsDMSO can be aggressive on some parts

– Low Vapor PressureLow Vapor PressureLow Vapor PressureLow Vapor Pressure• DMI keeps in solution and elutes the at end of DMI keeps in solution and elutes the at end of DMI keeps in solution and elutes the at end of DMI keeps in solution and elutes the at end of

chromatogram after all other solventschromatogram after all other solventschromatogram after all other solventschromatogram after all other solvents

– Dissolves all class 1,2,3 ICH Residual Dissolves all class 1,2,3 ICH Residual Dissolves all class 1,2,3 ICH Residual Dissolves all class 1,2,3 ICH Residual Solvents Solvents Solvents Solvents

Organic Solvent Process: An AlternativeOrganic Solvent Process: An AlternativeOrganic Solvent Process: An AlternativeOrganic Solvent Process: An Alternative

• Sample RecoveriesSample RecoveriesSample RecoveriesSample Recoveries– Methanol, 80Methanol, 80Methanol, 80Methanol, 80----3000 ppm: 99%3000 ppm: 99%3000 ppm: 99%3000 ppm: 99%

– Ethanol, 80Ethanol, 80Ethanol, 80Ethanol, 80----3000 ppm: 97%3000 ppm: 97%3000 ppm: 97%3000 ppm: 97%

– 1111----Butanol, 80Butanol, 80Butanol, 80Butanol, 80----3000 ppm: 97%3000 ppm: 97%3000 ppm: 97%3000 ppm: 97%

– Benzene,90Benzene,90Benzene,90Benzene,90----3300 ppm: 99%3300 ppm: 99%3300 ppm: 99%3300 ppm: 99%

– Cyclohexane, 80Cyclohexane, 80Cyclohexane, 80Cyclohexane, 80----3000 ppm: 101%3000 ppm: 101%3000 ppm: 101%3000 ppm: 101%

– 1,41,41,41,4----Dioxane, 80Dioxane, 80Dioxane, 80Dioxane, 80----3000 ppm: 100%3000 ppm: 100%3000 ppm: 100%3000 ppm: 100%

– Trichloroethylene, 90Trichloroethylene, 90Trichloroethylene, 90Trichloroethylene, 90----3300 ppm: 75%3300 ppm: 75%3300 ppm: 75%3300 ppm: 75%

– Chloroform, 40Chloroform, 40Chloroform, 40Chloroform, 40----100 ppm: 102%100 ppm: 102%100 ppm: 102%100 ppm: 102%

– 1,11,11,11,1’’’’----Oxybisethane, 80Oxybisethane, 80Oxybisethane, 80Oxybisethane, 80----3200: 102%3200: 102%3200: 102%3200: 102%

Improvement: volumeImprovement: volumeImprovement: volumeImprovement: volume----controlled injectioncontrolled injectioncontrolled injectioncontrolled injection

• Variable Injection Pressure Regulator (VIPR)

• Helps to control changes in injection volume when atmospheric pressure fluctuates.

Instrument SetInstrument SetInstrument SetInstrument Set----UpUpUpUp

• Varian 3800 GC/FIDVarian 3800 GC/FIDVarian 3800 GC/FIDVarian 3800 GC/FID

– Column: Column: Column: Column: RestekRestekRestekRestek RtxRtxRtxRtx----502.2, 30m x 0.32mm x 1.8 502.2, 30m x 0.32mm x 1.8 502.2, 30m x 0.32mm x 1.8 502.2, 30m x 0.32mm x 1.8 µµµµmmmm

– Injector: 200 degrees, Split 10:1Injector: 200 degrees, Split 10:1Injector: 200 degrees, Split 10:1Injector: 200 degrees, Split 10:1

– Oven: 40 degrees (hold 20 min), increase at 35 Oven: 40 degrees (hold 20 min), increase at 35 Oven: 40 degrees (hold 20 min), increase at 35 Oven: 40 degrees (hold 20 min), increase at 35

degrees/min to 240 degrees and hold five minutesdegrees/min to 240 degrees and hold five minutesdegrees/min to 240 degrees and hold five minutesdegrees/min to 240 degrees and hold five minutes

– Carrier: Helium at 2ml/minCarrier: Helium at 2ml/minCarrier: Helium at 2ml/minCarrier: Helium at 2ml/min

– Detector: FID at 200 degreesDetector: FID at 200 degreesDetector: FID at 200 degreesDetector: FID at 200 degrees

• VIPRVIPRVIPRVIPR

– Vial pressurization set at 12 psiVial pressurization set at 12 psiVial pressurization set at 12 psiVial pressurization set at 12 psi

– VIPR set at 9.5 psiVIPR set at 9.5 psiVIPR set at 9.5 psiVIPR set at 9.5 psi

Headspace SetHeadspace SetHeadspace SetHeadspace Set----UpUpUpUp

• Sample Temperature: 80 degreesSample Temperature: 80 degreesSample Temperature: 80 degreesSample Temperature: 80 degrees

• Sample Equilibration Time: 20 minutesSample Equilibration Time: 20 minutesSample Equilibration Time: 20 minutesSample Equilibration Time: 20 minutes

• Mixer: ON for one minuteMixer: ON for one minuteMixer: ON for one minuteMixer: ON for one minute

• Mixer Power: 5Mixer Power: 5Mixer Power: 5Mixer Power: 5

• Mix Stabilization Time: 0.10 minutesMix Stabilization Time: 0.10 minutesMix Stabilization Time: 0.10 minutesMix Stabilization Time: 0.10 minutes

• Pressurization Time: 0.40 minutesPressurization Time: 0.40 minutesPressurization Time: 0.40 minutesPressurization Time: 0.40 minutes

• Sample Loop Fill Time: 0.20 minutesSample Loop Fill Time: 0.20 minutesSample Loop Fill Time: 0.20 minutesSample Loop Fill Time: 0.20 minutes

• Loop Equilibration Time: 0.10 minutesLoop Equilibration Time: 0.10 minutesLoop Equilibration Time: 0.10 minutesLoop Equilibration Time: 0.10 minutes

• Inject Time: 1.0 minutesInject Time: 1.0 minutesInject Time: 1.0 minutesInject Time: 1.0 minutes

• Sample Loop Temperature: 100 degreesSample Loop Temperature: 100 degreesSample Loop Temperature: 100 degreesSample Loop Temperature: 100 degrees

• Transfer Line Temperature: 120 degreesTransfer Line Temperature: 120 degreesTransfer Line Temperature: 120 degreesTransfer Line Temperature: 120 degrees

OVI Standards PreparationOVI Standards PreparationOVI Standards PreparationOVI Standards Preparation

• Stock Solution of 10,000 ppm prepared by Stock Solution of 10,000 ppm prepared by Stock Solution of 10,000 ppm prepared by Stock Solution of 10,000 ppm prepared by adding 0.5 gram of each of the OVI standards adding 0.5 gram of each of the OVI standards adding 0.5 gram of each of the OVI standards adding 0.5 gram of each of the OVI standards into a 50.00 ml volumetric flaskinto a 50.00 ml volumetric flaskinto a 50.00 ml volumetric flaskinto a 50.00 ml volumetric flask– Methylene ChlorideMethylene ChlorideMethylene ChlorideMethylene Chloride

– ChloroformChloroformChloroformChloroform

– BenzeneBenzeneBenzeneBenzene

– TrichloroetheneTrichloroetheneTrichloroetheneTrichloroethene

– 1,41,41,41,4----DioxaneDioxaneDioxaneDioxane

• Dilute with Dimethylformamide (DMF)Dilute with Dimethylformamide (DMF)Dilute with Dimethylformamide (DMF)Dilute with Dimethylformamide (DMF)

• Subsequent 100 ppm standards prepared by Subsequent 100 ppm standards prepared by Subsequent 100 ppm standards prepared by Subsequent 100 ppm standards prepared by diluting 1.00 ml of stock solution in 100 ml of diluting 1.00 ml of stock solution in 100 ml of diluting 1.00 ml of stock solution in 100 ml of diluting 1.00 ml of stock solution in 100 ml of distilled waterdistilled waterdistilled waterdistilled water

• Seven replicates of each dilute Seven replicates of each dilute Seven replicates of each dilute Seven replicates of each dilute standard runstandard runstandard runstandard run

Results and DiscussionResults and DiscussionResults and DiscussionResults and Discussion

COMPONENT Data Set 1* Data Set 2* Data Set 3* Data Set 4*(VIPR Status) Installed Installed Not Installed Not Installed

Methylene Chloride 4.06% 2.47% 5.13% 3.50%

Chloroform 4.94% 3.45% 5.30% 4.37%Benzene 3.27% 2.70% 4.42% 3.11%

Trichloroethene 5.25% 3.56% 6.46% 4.64%11,4-Dioxane 4.74% 4.49% 11.29% 9.03%

* During the run for Data Set 1, the barometric pressure dropped 2.25mm Hg throughout the run cycle.During the run for Data Set 2, the barometric pressure dropped 0.75 mm HG. During the run for DataSet 3, the barometric pressure dropped 1.75 mm Hg throughout the run cycle. During the run for Data Set 4, the barometric pressure dropped 0.25 mm Hg.

• %RSD’s for OVI’s with, and without, the VIPR installed.

Results and DiscussionResults and DiscussionResults and DiscussionResults and Discussion

• Standards run with and without installation of the VIPR, during periods of marked barometric change.

New Pharmaceutical MethodNew Pharmaceutical MethodNew Pharmaceutical MethodNew Pharmaceutical Method

• Residual Solvents in (DMI 250 temp) Residual Solvents in (DMI 250 temp) Residual Solvents in (DMI 250 temp) Residual Solvents in (DMI 250 temp) 1,31,31,31,3----

dimethyldimethyldimethyldimethyl----2222----imidazolidinone imidazolidinone imidazolidinone imidazolidinone

• ICH Classes1,2,and 3 working with USP ICH Classes1,2,and 3 working with USP ICH Classes1,2,and 3 working with USP ICH Classes1,2,and 3 working with USP for New Method revision.for New Method revision.for New Method revision.for New Method revision.

Target residual solvents Target residual solvents Target residual solvents Target residual solvents

with their ICH concentration limitswith their ICH concentration limitswith their ICH concentration limitswith their ICH concentration limits

ICH Class 2 Concentration Limit (ppm) ICH Class 3 Concentration

Limit (ppm) Acetonitrile 410 Acetone 5000

Cyclohexane 3880 2-Butanol 5000

Dichloromethane 600 Dimethyl sulfoxide (DMSO) 5000

1,2-dimethoxyethane 100 Ethanol 5000

N,N-Dimethylacetamide 1090 Ethyl Acetate 5000

N,N-Dimethylformamide (DMF) 880 Heptane 5000

2-Ethoxyethanol 160 Isopropyl Acetate 5000

Hexane 290 Methylethyl Keyone (MEK) 5000

Methanol 3000 Tert-butyl methyl ether (MTBE) 5000

Methylcyclohexane 1180 1-Pentanol 5000

N-Methylpyrrolidone 530 1-Propanol 5000 Tetrahydrofuran (THF) 720 2-Propanol 5000

Toluene 890

Xylene 2170 Other Solvents (not on ICH list)

Concentration Limit

Ethyl Benzene (17%) 369 Tert-Butanol m,p -Xylene (74%) 1606 1-Methoxy-2-Propanol

o-Xylene (9%) 195 2-Pentanone

Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products.

Agilent 6890 Gas Chromatograph conditionsAgilent 6890 Gas Chromatograph conditionsAgilent 6890 Gas Chromatograph conditionsAgilent 6890 Gas Chromatograph conditions

270°C with nitrogen make-up gas at 30 mL/min; Hydrogen: 30 mL/min; Air: 300 mL/min

Detector Detector Detector Detector

(FID) :(FID) :(FID) :(FID) :

50°C. 1°C/min to 60°C, 9.2°C/min to 115°C,

35°C/min to 220°C, hold 6.02 minutes (Total = 25 min)

Oven:Oven:Oven:Oven:

Helium, constant flow of 5 mL/min,

average velocity of 51 cm/secCarrier:Carrier:Carrier:Carrier:

250°C, split 1:18, total flow 91 mL/min,

split flow 89.4 mL/minInjector:Injector:Injector:Injector:

J&W DB-624, 60m x 0.32mm x 1.8µmColumn:Column:Column:Column:

Identification of residual solvents in DMI Identification of residual solvents in DMI Identification of residual solvents in DMI Identification of residual solvents in DMI

at their regulatory limitsat their regulatory limitsat their regulatory limitsat their regulatory limits

ConclusionsConclusionsConclusionsConclusions•The study focused on platen temperature as an active parameter and sample equilibrium time as an interactive parameter. •Sample equilibrium time was examined and found to be an interactive effect with the mixing time.

•With the mixing time set at 10 minutes, the sample would have had ample time to equilibrate during mixing, making additional sample equilibration time unnecessary.

•Platen temperature was determined to be an active affect, meaning it would influence the analytical response.

•The platen temperature was varied from 60°C to 220°C while all other parameters remained constant. •It was determined that the temperature should be optimized under110°C for the greatest response, while still maintaining a suitable low vial pressure.

ConclusionsConclusionsConclusionsConclusions•Another factor that was considered is sample degradation at temperatures above 80°C. Methods at both 140°C and 80°C were then compared. •The resulting advantages of using 140°C for the platen temperature are increased reproducibility, lower method detection limits and better linearity for the calibration curves. •Overall, it was concluded that the method using 140°C for the platen temperature would be more rugged, thus making it easily duplicated in multiple laboratories. •The method using 80°C for the platen temperature would have the advantage of reduced sample degradation for drug products and DMI that are temperature sensitive.

ConclusionsConclusionsConclusionsConclusions

• Static Headspace Offers Ability to Analyze Static Headspace Offers Ability to Analyze Static Headspace Offers Ability to Analyze Static Headspace Offers Ability to Analyze for OVIfor OVIfor OVIfor OVI’’’’s in Pharmaceutical Samples.s in Pharmaceutical Samples.s in Pharmaceutical Samples.s in Pharmaceutical Samples.

• Methodologies Developed for Both Water Methodologies Developed for Both Water Methodologies Developed for Both Water Methodologies Developed for Both Water Soluble and Insoluble Drugs.Soluble and Insoluble Drugs.Soluble and Insoluble Drugs.Soluble and Insoluble Drugs.

• Alternatives to Organic Solvent Process Alternatives to Organic Solvent Process Alternatives to Organic Solvent Process Alternatives to Organic Solvent Process include DMI include DMI include DMI include DMI

• Analytical System Can Meet System Analytical System Can Meet System Analytical System Can Meet System Analytical System Can Meet System Suitability for Validation Process. Suitability for Validation Process. Suitability for Validation Process. Suitability for Validation Process.

10j) residual solvents in pharma -...

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