Analysis Of Extractable/Leachable Compounds From Generic . - Agilent
Analysis of Extractable/LeachableCompounds from Generic LiquidDrug Formulations Using GC/MSDSystemsApplication NoteAuthorsAbstractDiana M. Wong and Roger L. FirorPharmaceutical liquid formulations are commonly stored in plastic containers at allAgilent Technologies, Inc.risk categories. A pharmaceutical suspension was used as model for investigating2850 Centerville Rd,compound migration from packaging material. Two Agilent 5977A Series GC/MSDWilmington, DE 19808Systems were used. Fatty acid plasticizers were identified using the 7697AUSAHeadspace Sampler and a 7890A GC coupled with a 5977A MSD. Phthalate plasticizers were found using the MMI 7890A GC coupled with a 5977A MSD. Single ionmonitoring (SIM) confirmed the identification of these plasticizers.
Introductionregulatory guidance in the area of extractables and leachables, which is also recognized by the FDA. Guidance is alsoprovided in USP 87 , USP 88 , USP 661 , EP 3.1, EP 3.2,ISO10993, and ICHQ6A for the evaluation of materials for drugpackaging. USP 1663 and USP 1664 provide frameworkand assessments of extractables and leachables associatedwith pharmaceutical packaging/delivery systems, respectively. These assessments do not establish criteria or specificguidelines, only information and discussion on analysis of particular delivery systems.Pharmaceutical liquid products are stored in a variety of packaging materials ranging from low to high risk categories.Liquid drug products represent a broad range of dosage forms(aerosols, solution, suspensions, ointments, gels, and sprays).Drug products in liquid form have a significant potential ofleaching compounds from the packaging material due to theclose contact. The U.S. Food and Drug Administration (FDA)has ranked liquid drug formulations in several risk categoriesdepending on the route of administration and the likelihood ofinteraction between the drug product and the packagingmaterial (Table 1). Inhalation and injection solutions are recognized as the highest risk because the drug product is incontact with multiple/complex components in the medicaldevice with immediate drug delivery. For instance, a prefilledsyringe contains drug suspension that is in contact with therubber plunger, plastic barrel, and the metal needle with directinjection into the bloodstream.Extractables and leachables studies using gas chromatography-mass spectrometry (GC/MS) are designed to detectvolatile and some semivolatile compounds from medicaldevices and closure systems. The sources of extractables areraw materials, additives, stabilizers, accelerants, and breakdown/degradation products that provide protective and physical properties to packaging material. Extractables testinginvolves exposing the packaging component to appropriatesolvent, high temperatures, or an extended period of time tosimulate a leachable profile in the worst-case scenario.Leachables studies are conducted on the actual drug productunder normal usage or accelerated storage conditions.Leachable compounds are typically a subset of extractablesbecause of the direct contact with the packaging material.New leachables may also form from the interaction betweenthe drug product and the packaging material.Guidance and assessments have been provided for the analysis of extractables and leachables testing in medical devices.The FDA 21 CFR 211.94(a) states that “Drug product containers and closure shall not be reactive, additive, or absorptiveso as to later the safety, identity, strength, quality, or purity ofthe drug beyond the official or established requirements”.The Product Quality Research Institute (PQRI) has developedTable 1.Risk Associated with Various Pack Types Based on the Degree of Concern Based on Route and the Likelihood ofInteraction with the Drug ProductLikelihood of interaction between packaging component and dosage formDegree of concern associatedwith route of administration HighMediumLowHighestInhalation aerosols and solutionInjections and injectable suspensionsHighOphthalmic solutions and suspensionsTransdermal ointments and patchesNasal aerosols and spraysLowTopical solutions and suspensionsTopical and lingual aerosolsOral solutions and suspensionsSterile powdersInjection powdersInhalation powdersTopical powdersOral powdersOral tabletsOral hard capsulesOral soft gelatin capsulesAdapted from Guidance for Industry; Container Closure Systems for Packaging Human Drug and Biologics, US Department ofHealth and Human Services, Food and Drug Administration, Rockville, MD, May 1999.2
In this application note, a pharmaceutical liquid formulationwas investigated for leachable compounds using the complementation of two GC/MS systems. Volatile and semivolatileorganic compounds were identified using high temperatureheadspace sampling and large volume liquid injection techniques. Leachable compounds were chosen for further investigation based on toxicological information on extractables,peak intensity, migration potential, and polymer functionaladditives. Single ion monitoring (SIM) was used to furtherconfirm the identification of leachable compounds.Table 2.Instrument Parameters for Headspace GC/MS AnalysisHeadspaceAgilent 7697AVial pressurization gasHeliumLoop size1.0 mLVial standby flow50 mL/minTransfer line0.53 mm id deactivated fused silicaHS oven temperature250 CHS loop temperature250 CHS transfer line temperature 270 CVial equilibration timeExperimentalMaterials and instrumentationTwo types of analysis were performed for the identification ofleachable compounds in aqueous drug formulation.Components in the drug suspension were analyzed at hightemperatures using the 7697A Headspace Sampler and a7890A GC coupled with a 5977A MSD (Headspace GC/MS).Solvent extracts of drug components were analyzed using the7693A Automatic Liquid Sampler and a 7890A GC coupledwith a 5977A MSD (ALS GC/MS). The ALS GC/MS isequipped with a multimode inlet (MMI) operated in solventvent mode. The liquid drug formulation used in this work wasacquired from a generic pharmaceutical company for extractables and leachables testing. Dichloromethane (DCM) (650463)was purchased from Sigma-Aldrich.Headspace GC/MS analysisThe drug suspension was centrifuged at 3,000 rpm for 20 minutes. Solid and supernatant (liquid) components were transferred into separate 10-mL headspace vials and allowed toconcentrate by evaporation at room temperature. Bothcomponents were purged with nitrogen and sealed with ahigh-performance PTFE crimp cap before investigation atheadspace equilibration temperature of 250 C (Table 2).325 minutes, level 2 shakeGC run time64 minutesVials10 mL, PTFE/silicone septumVial fill modeFlow to pressureVial fill pressure15 psiLoop fill modeCustomLoop ramp rate20 psi/minLoop final pressure1.5 psiLoop equilibration time0.05 minutesCarrier control modeGC carrier controlExtraction modesingleVent after extractionONPost injection purge100 mL/min for 1 minuteGCAgilent 7890AInjection portSplit/SplitlessLiner0.75-mm ultra-inert, straight, tapered(p/n 5190-4048)Inlet temperature280 CInlet flowConstant flow, 1.3 mL/minSplit ratio8:1Carrier gasHeliumOven program35 C (3 min) to 280 C (3 min) at 8 C/minColumnsAgilent J&W HP-5ms UI, 30 m 0.25 mm,0.5 µm (p/n 19091S-133UI)MSDAgilent 5977ATransfer line280 CMS source280 CMS quad180 CTuneatune.uScan15 to 600 amu, 2.5 scans/secThreshold0Gain factor1.0SoftwareAgilent MassHunter B.07.01
ALS GC/MS analysisCompound identificationFive microliters of drug suspension were extracted with5.0 mL of DCM by sonication for 5–8 hours in a 12-mL ambervial and allowed to sit for 24 hours. The organic layer wastransferred to a glass insert inside an autosampler vial foranalysis. Ten microliters of extract was injected using theMMI operated in solvent vent mode. The solvent eliminationwizard was used to develop starting MMI parameters specificto the analysis of DCM extracts (Table 3).Compounds were characterized using the MSD ChemstationData Analysis F.01.01, MassHunter Unknowns AnalysisB.07.00, and AMDIS 2.72. Mass spectra of all compoundswere matched with the NIST Library 2.2. Compounds with amass spectral match of ¡ 80 were considered, and the topmatch was used in the investigation.Table 3.Results and DiscussionThe focus of this investigation centered on studying themigration of additives with characteristics of a high-densitypolyethylene (HDPE) or polypropylene (PP) packagingmaterial. The drug suspension was analyzed for Irganox 1010,Irgafos 168, palmitic acid, stearic acid, butylated hydroxytoluene (BHT), hexadecane, and 2,4-di-tert-butylphenol.Irganox 1010, BHT, Irgafos 168, and 2,4-di-tert-butyphenol areantioxidants added to HDPE to provide protection during processing and stability from long term heating (molding) [1].Stearic acid and palmitic acid provide mechanical propertiesto HDPE or PP [2,3], while hexadecane is a solvent used in theproduction of ink for printing [4]. Stearic acid, palmitic acid,and hexadecane were identified in this investigation.Irganox 1010 would be more suitable for analysis by LC/MSdue to its high molecular weight. BHT, Irgafos 168, and2,4-di-tert-butylphenol were not observed in the drug suspension, however these additives were identified in extractablestudies of plastic materials using the same procedures.Several other additives in HDPE material [5] were identified inthis investigation.Instrument Parameters for Analysis Using the ALS GC/MSGCAgilent 7890AInjection portMultimode Inlet (MMI), CO2 coolingModeSolvent ventInlet program–5 C (0.7 minutes) to 325 C (5 minutes) at600 C/minLiner2 mm id ultra inert, dimpled (p/n 5190-4006)Inlet vent100 mL/min (5 psi) for 0.7 minutesCarrier gasHeliumPurge flow to split vent 60 mL/min at 3.15 minutesOven program50 C (3 minutes) to 340 C (5 minutes) at 6 C/minColumnsAgilent J&W HP-5ms UI, 30m 250 µm, 0.25 µm(p/n 19091S-433UI)MSDAgilent 5977ATransfer line280 CMS source300 CMS quad175 CTuneatune.uScan29 to 700 amu, 2.2 scans/secThreshold150Gain factor1.0SoftwareAgilent MassHunter B.07.00Plasticizers, flavor, fragrance, pharmaceutical compounds, andtheir precursors were identified in the liquid drug formulationusing GC/MS analysis by headspace and large volume liquidinjection. A summary of all compounds identified using bothGC/MS systems are listed in Table 4. Pharmaceutical, flavor,and fragrance compounds are common ingredients in drugproducts. Plasticizers were further pursued in this investigation since these compounds are highly related to leachablesmigration from the packaging material.*Initial temperature and initial hold time differ depending on solvent extract4
Table 4.Compounds Detected in Drug Suspension Using Headspace and ALS GC/MSCompoundGC/MS(R)-( )-1-BenzylglycerolHS (S)1,2,3-Propanetriol, 1-acetateALS and HS1,2-Benzenediol, opentanedione, 3-methyl-HS (S)1,2-Epoxy-3-propyl acetateHS (L)Common uses1,2-Ethanediamine, mine, N,N-dimethyl-ALS1-DodecanolALS and HS (L)1-DodeceneALS1-HexadecanolHS (L)Plasticizer1-Hydroxy-2-butanoneHS (L)Flavor1-Tetradecanamine, N,N-dimethyl-ALS and HSPlasticizer1-Tridecanamine, N,N-dimethyl-HS (L)1-Undecanamine, N,N-dimethyl-ALS2(3H)-Furanone, 3-acetyldihydro-3-methyl-HS ButanedioneHSFlavor2,3-HexanedioneHS (L)Flavor2,3-PentanedioneHSFlavor or asticizer2,5-Furandione, 3,4-dimethyl-HS (S)2,5-Furandione, 3-methyl-ALS2,5-Furandione, dihydro-3-methylene-ALS2-Cyclopenten-1-one, 2-methyl-HS (L)2-Cyclopenten-1-one, 3,4-dimethyl-HS (L)Flavor or fragrance2-Cyclopenten-1-one, 3-ethyl-2-hydroxy-HS (S)Fragrance2-Cyclopenten-1-one, 3-methyl-HS (L)Flavor or fragrance2-Dodecene, nmethanol, acetateHS (L)Flavor or fragrance2-Furanmethanol, tetrahydro-HS (S)Plasticizer2-Furanone, 2,5-dihydro-3,5-dimethylHS (L)Flavor or fragrance2-Propanone, 1-(acetyloxy)-HS (L)2-Propanone, 1-hydroxy-HSPlasticizer2-Propen-1-olHSPrecursor to iolHS3-Chloropropionic acid, tetradecyl esterALSAcetic acidHSMonomerAcetoinHS (L)Flavor or fragranceAdipate, nzenemethanamine, N,N-dimethyl-ALS and HS (L)Benzoic acidALSPlasticizerBenzyl alcoholALS and HSPrecursor to plasticizerCatalyst5
CompoundGC/MSCommon usesBenzyl chlorideALSPrecursor to plasticizerButyrolactoneHSSolvent for flavor or plasticizerCatecholHSPrecursor to flavor or fragranceDodecanalHSFragranceDodecane, 1-chloro-ALSEstradiolALSPharmaceuticalFormic acid, ethenyl esterHS (S)Flavor or fragranceFuran, 2,2'-methylenebis-HS (S)Flavor or fragranceFuran, 2,3-dihydro-HS (L)Furan, 2-methyl-HSFlavor or fragranceFurfuralHS (S)SolventGlycerinHSPharmaceuticalGlycerol 1,2-diacetateHSFlavor or fragranceHexadecanalHS (S)HexadecaneALSPlasticizerMaltolHS (S)Flavor or fragranceN-Methyl-N-benzyltetradecanamineALS and HS (L)NonanalALSNonanoic acidALSFlavor or fragranceOctanoic acidALSFragrance or plasticizerOxiranemethanol, (R)-HS (S)Oxiranemethanol, (S)-HS (L)Palmitic acidALSPlasticizerPalmitic acid, butyl esterHS (S)PlasticizerPhenol, 2,2'-methylenebis[6-(1,1-dimethylethyl)-4-ethyl-HS (L)PlasticizerPhenol, 4-propoxy-HS (L)Phthalate, di(2-propylpentyl)ALSPropanalHSPlasticizerStearic acidALSPlasticizerStearic acid, 2-methylpropyl esterHS (S)PlasticizerTetradecanalHS (L)Tetrahydrofurfuryl chlorideHS (L)Tetrahydropyran Z-10-dodecenoateHS (S)TolueneHS (L)PlasticizerPlasticizerL liquid supernatant only; S solid component only; HS Headspace (both components); ALS Automatic liquid sampler6
Plasticizers identified using high temperature headspaceanalysis were 2-furanmethanol (flexibility),1-hydroxy-2-propanone (sealant and coating),tetrahydro-2-furanmethanol (flexibility), butyl ester palmiticacid (resin), 2-methylpropyl ester stearic acid ethyl-phenol](antioxidant), 1-dodecanol (coating), andN,N-dimethyl-1-tetradecanamine (detergent)(Figure 1, Table 5) [6-13].Counts 106A4.84.5 Solid4.23.93.63.33.02.72.452.11.81.51.220.9 10.670.3 3 46035SIM analysis confirmed the identification of butyl esterpalmitic acid and 2-methylpropyl ester stearic acid (Figure 2).Palmitic acid and stearic acid are also possible leachable plasticizers [14] since they exhibit similar ions, peak intensity, andretention time as butyl ester palmitic acid and 2-methylpropylester stearic acid, respectively.1,36.2, 38.3, 39.4,40.5, 41.6, 42.7.8, 47.9.10.11, 50.12, 54.13.14, 59.15.16.17, 23, 64.3218.34333519.20.29313321, 63.22, 61.24, 62.25.26, 66.27, 31, 71.28.29.7230.32, 34, 72.33.35.37.7343.44.45.46.74 .73.74.272031212211171814910199112428293023 251387261516121315171921Acquisition time (min)2325272527Counts7 101.6 B1.5Supernatant1.41.3501.21.141591.00.90.80.7 38540.6490.5 390.4445336 4060450.3574652370.2434751 5556 5848420.1035791113Figure 1.6463616871626570666715171921Acquisition time (min)6923Headspace GC/MS analysis of solid (A) and liquid (B) components in drug suspension.72-Propen-1-ol2,3-ButanedioneFuran, 2-methylAcetic acid2-Propanone, 1-hydroxy2,3-PentanedioneOxiranemethanol, (R)PropanalFormic acid, ethenyl pentanedione, 3-methylBenzyl alcohol2,5-Furandione, 3,4-dimethylFuran, 2,2'-methylenebis1,2,3-Propanetriol, 1-acetateMaltol2-Cyclopenten-1-one, 3-ethyl-2-hydroxyTetrahydropyran Z-10-dodecenoateCatecholGlycerinGlycerol 1,2-diacetate2(3H)-Furanone, , N,N-dimethyl(R)-( )-1-Benzylglycerol2-Furanmethanol, 2-propanediolPalmitic acid, butyl esterStearic acid, 2-methylpropyl esterFuran, 2,3-dihydroAcetoinOxiranemethanol, hydrofurfuryl chloride2-Propanone, 1-(acetyloxy)1,2-Epoxy-3-propyl acetate2-Cyclopenten-1-one, 2-methyl2-Cyclopenten-1-one, 3,4-dimethyl2-Cyclopenten-1-one, 3-methyl2-Furanmethanol, acetate2-Furanone, 2,5-dihydro-3,5-dimethylBenzenemethanamine, N,N-dimethylPhenol, 4-propoxy1-Dodecanol1-Tridecanamine, nzyltetradecanaminePhenol, 2,2'-methylenebis[6-(1,1-dimethylethyl)-4-ethyl-
Table 5.RT (min)Compounds Identified in Drug Suspension Using Headspace GC/MSSolidRT 2.622,3-Butanedione2.51Furan, 2,3-dihydro-2.84Furan, 2-methyl-2.622,3-Butanedione3.43Acetic acid2.84Furan, 2-methyl-3.922-Propanone, 1-hydroxy-3.45Acetic acid4.622,3-Pentanedione3.892-Propanone, 1-hydroxy-5.19Oxiranemethanol, 5Formic acid, ethenyl ester5.17Oxiranemethanol, 12.591,2-Cyclopentanedione, 3-methyl-6.822,3-Hexanedione12.75Benzyl alcohol7.99Tetrahydrofurfuryl chloride12.842,5-Furandione, 3,4-dimethyl-8.652-Furanmethanol13.79Furan, 2,2'-methylenebis-8.932-Propanone, 1-(acetyloxy)-14.37-16.81 1,2,3-Propanetriol, 1-acetate9.691,2-Epoxy-3-propyl acetate14.42Maltol9.832-Cyclopenten-1-one, 2-methyl-14.542-Cyclopenten-1-one, opyran Z-10-dodecenoate10.602-Cyclopenten-1-one, , 3-methyl-16.20Glycerin11.832-Furanmethanol, acetate16.87Glycerol 1,2-diacetate12.012-Furanone, 2,5-dihydro-3,5-dimethyl17.542(3H)-Furanone, 3-acetyldihydro-3-methyl-12.76Benzyl alcohol19.70Dodecanal12.92Benzenemethanamine, N,N-dimethyl-14.51Glycerin21.21-24.16 1-Tetradecanamine, N,N-dimethyl22.16(R)-( )-1-Benzylglycerol15.26Glycerol 1,2-diacetate22.462-Furanmethanol, -Propanetriol, 1-acetate29.45-31.75 nol, 4-propoxy-30.15Palmitic acid, butyl ester19.70Dodecanal32.30Stearic acid, 2-methylpropyl ester20.731-Dodecanol21.201-Tridecanamine, .161-Tetradecanamine, 75Phenol, 2,2'-methylenebis[6-(1,1-dimethylethyl)-4-ethyl-8
1819202122232425262728Acquisition time (min) 104 B9SIM analysis for8 peak at 30.15 minutes 10460731292567Counts654321030.0830.10D30.1230.14 30.16 30.18 30.20Acquisition time (min)30.22CountsCounts 106A4.84.4 TIC4.03.63.22.82.42.01.61.20.80.40173132333435SIM analysis forpeak at 32.30 minutes3612917118519924128432.21 32.23 32.25 32.27 32.29 32.31 32.33 32.35 32.37 32.39Acquisition time (min)FPalmitic acid, butyl 2429Stearic acid, 2-methylpropyl ester57100430129116E40602971213 227269 283297312201007340Figure 2.199 213 227 241 255801291003407350129698397310 325OHOH836018580 100 120 140 160 180 200 220 240 260 280 300 320 340Mass-to-charge (m/z)Stearic acidO436940143 157 17160602920267O57083 97116 12915GPalmitic acid6050080 100 120 140 160 180 200 220 240 260 280 300 320Mass-to-charge (m/z)43100285239143 157 171 185 1991520O502577383 97CountsCounts5029O41OCountsCountsO115125143 157 171 185194120 140 160 180Mass-to-charge (m/z)20021329256227 2392202402600115152097406080284185143157171241199 213 227255 265100 120 140 160 180 200 220 240 260 280 300Mass-to-charge (m/z)SIM analysis of plasticizers identified using headspace GC/MS. TIC of drug suspension (A) with SIM of butyl ester palmitic acid analyzed at 30.15minutes (B) and 2-methylpropyl ester stearic acid analyzed at 32.30 minutes (C). Reference mass spectra for butyl ester palmitic acid (D), palmiticacid (E), 2-methylpropyl ester stearic acid (F), and stearic acid (G) were obtained from the NIST MS Search 2.2. (*) represents ions used for SIManalysis and color-coded to match EIC.9
Flavor compound, 2,3-butanedione, was the only compoundidentified in the drug suspension using the full evaporationheadspace sampling technique at 85 and 100 C. Therefore,the drug solution was separated into solid and liquid components to aid with separation and compound identification.Glycerin shows poor chromatographic performance, with abroad peak from 13 to 17 minutes.Counts 1071.2 TIC21.11.00.90.80.70.60.50.40.3630.29 115140.17 8 101207911131517Plasticizers that were identified using ALS GC/MS were2,4,7,9-Tetramethyl-5-decyn-4,7-diol (adhesives), hexadecane,di(2-ethylhexyl) adipate (DEHA), n-palmitic acid, stearic acid,di(2-propylpentyl) phthalate (DPPP), octanoic acid, 1-dodecanol, and N,N-dimethyl-1-tetradecanamine (Figure 3, Table 6)[15-19].2320181413191. 2,5-Furandione, 3-methyl2. Benzyl chloride3. 2,5-Furandione, dihydro-3-methylene4. Benzyl alcohol5. 1,2,3-Propanetriol, 1-acetate6. Benzenemethanamine, N,N-dimethyl7. Nonanal8. Benzoic acid9. Octanoic acid10. 1-Dodecene11. 2-Dodecene, (Z)-1715162124211923252226252727293133Acquisition time (min)35283712. Nonanoic acid13. 2,4,7,9-Tetramethyl-5-decyn-4,7-diol14. 1-Dodecanol15. 1,2-Benzenediol, O-(2-furoyl)-O'-(pentafluoropropionyl)16. Dodecane, 1-chloro17. 1-Undecanamine, N,N-dimethyl18. 1-Dodecanamine, N,N-dimethyl19. Dodecane, 1-chloro20. 1-Tetradecanamine, N,N-dimethyl21. n-Palmitic acid22. BenzamphetamineFigure 3.Leachable analysis of drug suspension using ALS GC/MS.Table 6.Compounds Identified in Drug Suspension Using ALS GC/MS Analysis3129 303941434547495123. 1,2-Ethanediamine, N,N'-dimethyl-N,N'-bis(phenylmethyl)24. 3-Chloropropionic acid, tetradecyl ester25. Stearic acid26. N-Methyl-N-benzyltetradecanamine27. di(2-ethylhexyl) adipate28. di(2-propylpentyl) phthalate29. Estradiol30. Hexadecane31. 2-(4-Aminophenyl)-4,6-diphenylpyrimidineRT (min)CompoundRT (min)Compound7.812,5-Furandione, 3-methyl-20.23, 24.27Dodecane, 1-chloro-9.58Benzyl chloride20.881-Undecanamine, N,N-dimethyl-9.972,5-Furandione, dihydro-3-methylene-21.301-Dodecanamine, N,N-dimethyl-10.02Benzyl alcohol24.951-Tetradecanamine, N,N-dimethyl-11.571,2,3-Propanetriol, 1-acetate29.18n-Palmitic acid11.63Benzenemethanamine, 1,2-Ethanediamine, N,N'-dimethyl-N,N'-bis(phenylmethyl)-13.21Benzoic acid31.933-Chloropropionic acid, tetradecyl ester13.43Octanoic acid32.32Stearic namine14.472-Dodecene, (Z)-35.57Di(2-ethylhexyl) adipate15.67Nonanoic acid37.43Di(2-propylpentyl) 1,2-Benzenediol, minophenyl)-4,6-diphenylpyrimidine10
1061.4 A1.31.2 4.835.235.6 1042.6 B2.4 SIM analysis for2.2 peak at 35.57 .5535.5735.59Acquisition time (min)10036.036.436.837.2Acquisition time (min)129112147241 149167279113SIM analysis forpeak at 37.43 minutes35.6137.35 37.37 37.39 37.41 37.43 37.45 37.47 37.49 37.51Acquisition time (min)100Di(2-ethylhexyl)adipate (DEHA)149EDi(2-propylpentyl)phthalate CountsSIM analysis confirmed the identification of DEHA and DPPP(Figure 4). DPPP exhibit similar MS fragmentation patterns asDEHP. However, the intensities of ions 113 and 279 acquiredwith the SIM analysis closely matched the reference MS ofDPPP. High-resolution mass spectrometry analysis is necessary to further distinguish the presence of DPPP or DEHP.505750O11216770147432908310187272212169241259 284223157 183 19957313 327 341020 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380Mass-to-charge (m/z)Figure 4.7111384122 13229 50 65 76 934327918020 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400Mass-to-charge (m/z)SIM of plasticizers identified using ALS GC/MS in drug suspension (A). SIM data were collected for DEHA at 35.57 minutes (B) and DPPP at 37.43minutes (C). Reference MS of DEHA (D) and DPPP (E) were obtained from the NIST MS Search 2.2. (*) ions used for SIM anlaysis and color codedto match EIC.11
100149A149100 BDi(2-propylpentyl)phthalate (DPPP)Di(2-ethylhexyl)phthalate (DEHP)OOOCountsCountsOO50O167505716743574329071113 1328412250 65 76 9329279180020 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400Mass-to-charge (m/z)Figure 5.Reference MS of DPPP and DEHP for intensity comparison of SIM ions.ConclusionThe complementation of headspace sampling and largevolume liquid injection techniques allows for the broad identification of leachable plasticizers in pharmaceutical formulations. Fatty acid plasticizers were identified using headspaceGC/MS. Phthalate plasticizers were characterized using solvent extraction with ALS GC/MS analysis. A two prongedapproach using high temperature headspace and liquid sampling techniques can be used to obtain a significant amountof information regarding leachables and extractables. Theseanalytical methods are applicable to analyzing liquid drugproducts in all risk categories12OO172797111383 104 13212165 76 93162 17926139020 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400Mass-to-charge (m/z)
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regulatory guidance in the area of extractables and leach-ables, which is also recognized by the FDA. Guidance is also provided in USP 87 , USP 88 , USP 661 , EP 3.1, EP 3.2, ISO10993, and ICHQ6A for the evaluation of materials for drug packaging. USP 1663 and USP 1664 provide framework and assessments of extractables and leachables associated
Pharmacopeia (USP) provided general information on the design and analysis of extractables (USP 1663 ) and leach-ables (USP 1664 ) assessment associated with the pharma-ceutical packaging/delivery systems. USP 1663 and 1664 do not contain mandatory requirements regarding the analysis of extractable and leachable compounds in packaging .
This requirement is in line with USP 1663 : it is necessary to justify your selection of solvents, techniques, and extraction conditions as being an exaggerated condition . Extractable - Leachable correlations FDA considers the ability to make a good correlation between the extractable results and the leachable results as a requirement
guidelines and assessments on extractable and leachable testing exist, including chapters from USP 661 , USP 1663 , USP 1664 , USP 1665 , and regulations from international organizations EP 3.2.2.1 and EP 3.2.8. The intent of this appli-cation note is not to provide safety impact or toxicological information.
Spears low-extractable piping has been subjected to extensive low-level defection testing during exposure to UPW by a reputable independent laboratory. Tests under both static and on-line dynamic (fl owing) conditions analyze leachable micro contamination (TOC, anions, cations and trace metals) as well as resistivity and particles. Resistivity
extractables include plastic and elastomeric packaging components (monomers, polymeric initiators, plasticizers, etc.), ink and adhesives used in labels, and degradation products related to container processing, storage, and sterilization. Leachables are elements and other compounds that migrate from the container into the drug product under normal
Naming Compounds Review Naming Ionic, Covalent, and Polyatomic compounds Compounds Compounds: pure substances containing atoms of more than one type of element joined together by chemical bonds (electrical attractions that hold atoms or ions together) Naming Chart – to help you out as we go through this process Naming Compounds
Chapter 2-3 Carbon Compounds. A. Organic compounds- originally thought to be compounds produced by living organism, now it refers to compounds containing carbon. 6 C Carbon 12.011. a. Carbon atoms have 4 valence electrons 1. The carbon atom is unique and carbon compounds are
American Revolution Wax Museum Project Overview You will become an expert on one historical figure who played a significant role in the American Revolution. For this individual, you complete the following tasks: 1. Notes: Use at least 3 sources to research and take notes about the individualʼs life, views, and impact. At least one of
