美国药典通则467残留溶剂的检测

美國藥典通則467殘留溶劑的檢測467RESIDUALSOLVENTSSpectrum质检部斯百全化学（上海）有限公司800.720.5720通則適用範圍•所有藥品原料，輔料，製劑中可能存在的溶劑通則目標•為病人的安全，規定藥品中可接受的殘留溶劑量殘留溶劑分類•一類（class1）:已知會產生不可接受毒性的一些溶劑（Solventsthatareknowtocauseunacceptabletoxicities）•二類（class2）：與並不嚴重毒性相關的一些溶劑（Solventsassociatedwithlessseveretoxicity）•三類（class3）：較少毒性的溶劑（Lesstoxicsolvents）•其他殘留溶劑：無足夠毒理學數據（Otherresidualsolvents）未列在本通則的溶劑怎麼處理？•當工廠使用經法定監管機構批准使用的未在本通則中羅列的新溶劑時，工廠有責任告知USP在該品種標準中這一溶劑的鑒定、限度、測試方法，USP將會在個論中加上這一項。•ICH認可的新溶劑，USP將直接加在該通則中。測試範圍•使用過的溶劑•生產或純化過程中產生的溶劑測試方式•直接測最終產品•或者各成份累加：如果各成分累加的值大于本通则的限度，则需测最终产品。Colchicine秋水仙堿•Colchicine•C22H25NO6399.44•Acetamide,N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)-,(S)-.Colchicine[64-86-8].•»ColchicineisanalkaloidcontainedinvariousspeciesofColchicumandinothergenera.Itcontainsnotlessthan94.0percentandnotmorethan101.0percentofC22H25NO6,calculatedontheanhydrous,solvent-freebasis.•Caution—Colchicineisextremelypoisonous.•Packagingandstorage—Preserveintight,light-resistantcontainers.•USPReferencestandards11—USPColchicineRS.•Identification,InfraredAbsorption197K—[note—Disregardanypeakoccurringat1735cm1.]•Specificrotation781S:between240and250,calculatedontheanhydrous,solvent-freebasis.Testsolution:10mgpermL,inalcohol.•Water,MethodI921:notmorethan2.0%.•Limitofcolchiceine—To5mLofasolution(1in100)add2dropsofferricchlorideTS:nodefinitegreencolorisproduced.•Limitofethylacetate—Internalstandardsolution—Dilute0.5mLofn-propylalcoholwithwaterto100.0mL.•Standardsolution—Pipet1mLofethylacetateand0.5mLofn-propylalcoholintoa1000-mLvolumetricflask,addwatertovolume,andmix.EachmLofStandardsolutioncontains0.90mgofethylacetate.•Testsolution—Placeabout250mgofColchicine,accuratelyweighed,ina10-mLvolumetricflask,dissolveinabout8mLofwater,andadd1.0mLofInternalstandardsolution.Addwatertovolume,andmix.•Procedure—Determineappropriatesensitivitysettingsonagaschromatograph(seeChromatography621)fittedwitha4-mm×1.5-mcolumnpackedwith20%(w/v)phaseG14onsupportS1,maintainingthecolumntemperatureat75,usingnitrogenasthecarriergas,andusingaflame-ionizationdetector.InjecttheStandardsolutionandtheTestsolution,determinethepeakheightforethylacetaterelativetothepeakheightforn-propylalcohol,andcalculatethepercentage,byweight,ofethylacetateintheportionofColchicinetaken:notmorethan8.0%isfound.•Chromatographicpurity—Thesumoftheresponsesofanypeaksotherthanthatduetocolchicine,elutingwithin1.5timestheretentiontimeforcolchicine,isnotmorethan5.0%ofthesumofallresponses,obtainedasdirectedintheAssay.•Residualsolvents467:meetstherequirements,exceptthatthelimitofchloroformis100ppm.二類溶劑計算選項•選項1：Dose≤10g/dayConcentration（ppm）=（1000ug/mg×PDE）/dose•選項2：根據藥品實際情況直接計算PDE是否符合要求，若超出限度則需測試。分析方法•本通则氣相色譜法•特殊情況下其他方法（seeprocedureinTestsandAssays）•乾燥失重-Class3solvents報告方式•只有三類溶劑可能存在，乾燥失重≤0.5%•只有二類溶劑X，Y,...可能存在，它們在選項1限度以下。•只有二類溶劑X，Y,...和三類溶劑可能存在，其二類溶劑在選項1限度以，三類溶劑小於0.5%。報告方式•一類溶劑需定性和定量•二類和三類溶劑超過限度需定性和定量殘留溶劑限度•EthyleneOxide10ug/g•一類溶劑：SolventConcentrationLimit（ppm）Benzene2Carbontetrachloride41,2-Dichloroethane51,1-Dichloroethene81,1,1-Trichloroethane1500殘留溶劑限度•二類溶劑No.123456789101112131415161718192021222324252627solventAcetonitrileChlorobenzeneChloroformCyclohexane1,2-Dichloroethene1,2-DimethoxyethaneN,N-DimethylacetamideN,N-Dimethylformamide1,4-Dioxane2-EthoxyethanolEthyleneglycolFormamideHexaneMethanol2-MethoxyethanolMethylbutylketoneMethylcyclohexaneMethylenechlorideN-methylpyrrolidoneNitromethanePyridineSulfolaneTetrahydrofuranTetralinTolueneTrichloroethyleneXylenePDE（mg/day）4.13.60.638.818.71.010.98.83.81.66.22.22.930.00.50.511.86.05.30.52.01.67.21.08.90.821.7ConcentrationLimit（ppm）4103606038801870100109088038016062022029030005050118060053053050200160160720100890802170Table3.Class3ResidualSolvents(limitedbyGMPorotherquality-basedrequirementsindrugsubstances,excipients,anddrugproducts)AceticacidHeptaneAcetoneIsobutylacetateAnisoleIsopropylacetate1-ButanolMethylacetate2-Butanol3-Methyl-1-butanolButylacetateMethylethylketonetert-ButylmethyletherMethylisobutylketoneCumene2-Methyl-l-propanolDimethylsulfoxidePentaneEthanol1-PentanolEthylacetate1-PropanolEthylether2-PropanolEthylformatePropylacetateFormicacidTable4.OtherResidualSolvents(forwhichnoadequatetoxicologicaldatawasfound)1,1-DiethoxypropaneMethylisopropylketone1,1-DimethoxymethaneMethyltetrahydrofuran2,2-DimethoxypropaneSolventhexaneIsooctaneTrichloroaceticacidIsopropyletherTrifluoroaceticacidWater-solubleArticles和Water-insolubleArticles的区别色谱柱分流比载气頂空進樣條件Water-solubleProcedureA0.32mm*30mfused-silica,G43,1.8um或0.53um*30mwide-bore,G43,3.0um1:5（可调）N2或He表5Water-solubleProcedureB0.32mm*30mfused-silica,G16,0.25um1.8um或0.53um*30mwide-bore,G16,0.25um1:5（可调）N2或He表5Water-insolubleProcedureA0.53um*30mwide-bore,G43,3.0um1:3（可调）He仅表5中的第三列Water-insolubleProcedureB0.32mm*30mfused-silica,G16,0.25um1.8um或0.53um*30mwide-bore,G16,0.25um1:3（可调）N2或He仅表5中的第三列表5頂空操作條件頂空操作參數系列123平衡溫度（°）8010580平衡時間（min）604560传输线温度（°）85110105注射器溫度（°）80-90105-11080-90載氣：氮氣或氦氣在適宜的壓力條件下顶空瓶加压时间（s）≥60≥60≥60進樣體積（mL）111阿莫西林石油醚Xylene精密度的問題定量時，Testsolution和Spikes