16第十六章药品质量控制中的现代分析方法与技术

药品质量控制中的现代分析方法与技术Modernanalyticalmethods&techniquesinqualitycontrolofdrugs第十六章现代分析方法与技术，为药学的发展提供了适时而有效的手段与动力。色谱及其联用技术：药学研究－－分子水平。手性分析：毛细管电泳及手性色谱技术－－药物研究与质量控制提供了保障。现代光谱技术：药物结构鉴定，微量杂质检定。第一节概况Capillaryelectrophoresis,CEModernchromatogr&itsapplication药物现代色谱法及其应用UPLCUltraPerformanceLC®(UPLC®)technologystartswithunique1.7µmsmall-particlechemistries.Chromatographersnolongerneedtochoosebetweenspeedandresolution—withUPLCyougetboth.MassspectroscopyMSNuclearmagneticresonancespectrometryNMRX-raydiffractionmethodNearinfraredspectrometryNIRS现代光谱法及其应用Modernspectroscopy&itsapplicationinpharmaceuticalanalysisGC-FTIRGC-MSUPLC-MSHPLC-NMRHyphenatedTechniquesinChromatography现代联用技术及其应用HPLC-MSCE-MS++样品与溶剂脱离及电离EIESIAPCILC/MS接口离子源质量分析器检测离子HPLC数据系统质谱离子识别QuadrapoleTimeofFlightFourierTransform…+++++++离子检测++-++++++-+++第二节液质联用技术与应用2.1离子化方式2.2离子分离与测定模式Full-ScanMassSpectrometry•Advantage–ProvidesMWInformationFull-ScanMSofBuspironeNNNNNOOBuspirone(丁螺环酮)C21H31N5O2MW=385150200250300350400450500m/z255075100RelativeAbundance386408(M+H)+(M+Na)+SingleIonMonitoring(SIM)•Advantages–TargetedAnalyteMonitoring–HighDutyCycle–Simple•Disadvantages–Cansufferfrominterferences–NotassensitiveorselectiveasSRM(seebelow)Fixedm/zPassAllPassAllProductIonScanning:ATandemMSMethod•Advantage–ProvidesStructuralInformation•Disadvantage–LowdutycycleFixedm/zPassAllScanningProductIonSpectrumQ3Q2Q1ProductIonSpectrumofBuspironeNHNNNOONHNOO100150200250300350400m/z255075100RelativeAbundance122386222150265180NNNNHNOO(M+H)+PrecursorIonScanning•Advantage–IDcompoundsproducingspecificfragmention(e.g.,PO3−forphosphopeptides)•Disadvantage–LowdutycycleFixedm/zPassAllScanningPrecursorIonSpectrumQ3Q2Q1PrecursorIonScanModeforBuspironeMetabolitesPrecursorIonScan:Q3settom/z122NNNNNOOOH100200300400500m/zRelativeAbundance402386910111213141516Time(min)255075100RelativeAbundance11.6213.8413.1614.4012.1310.4515.45NNNNNOONHNNNeutralLossScanning•Advantage–Screenforcompoundsproducingspecificneutralloss(e.g.,lossof176forglucuronideconjugates)•Disadvantage–LowdutycycleScanningPassAllScanningNeutralLossSpectrumLinkedQ3Q2Q1NeutralLossScanofBuspironeMetabolitesNeutralLossScan:Q1/Q3differencesetto121Da100200300400500m/zRelativeAbundance402386910111213141516Time(min)255075100RelativeAbundance13.9211.6913.2115.5010.58NNNNNOONNNNNOOOHSelectedReactionMonitoring(SRM)•Advantages–TargetedAnalyteMonitoring–HighDutyCycle–“Simultaneous”MonitoringofMultipleTransitions•Disadvantage–No“advanced”structuralinformationFixedm/zPassAllFixedm/zQ1Q2Q3MS/MSSelectivityinComplexMatrices息斯敏——阿斯咪唑(astemizole)•Chlroamphenicol(氯霉素，CAP)残留测定•黄杨生物碱成分鉴定•苯甲酸利扎曲普坦人体药代动力学研究2.3药物分析中的典型应用OHOHNHHHOClClO2NC11H12Cl2N2O5FMW=323.13【类别】酰胺醇类抗生素【适应症】本品是治疗伤寒、副伤寒的首选药物，外用可治疗沙眼。因脑脊液浓度高，故常用于治疗细菌性脑膜炎和脑脓肿。此外，尚可外用治疗痤疮、酒糟鼻、脂溢性皮炎等。被农业养殖滥用！肉食品中严格检查。2.3.1Chlroamphenicol(氯霉素，CAP)残留测定HPLCanalysiswasperformedontheFinniganSurveyorHPLCmodulewithMSPumpandAutosampler–Column:ThermoHypersilGoldC18(100×2.1mm,5µ)–MobilePhase:A:Water;B:Acetonitrile–ColumnTemperature:40oC–GradientProgram:0.25mL/min–Injection:20uLwithloopTime(min)%A%B080202.520803.020803.180205.08020OperationConditionsforCAPIonsource:ESIIonpolarity:NegativeSprayvoltage:4000VSheathgaspressure:45Auxiliarygaspressure:15Iontransfercapillarytemperature:300oCSourceCID:8VScanType:SRM,3transitionsof[M-H]-(m/z:321)(321152,321194and321257)Q1peakwidth0.7DainSRMor0.2DainH-SRMQ3peakwidth0.7DaCollisionPressure:Arat1.3mTorrOHOHNHHHOClClO2NQ1peakwidthandH-SRMexperimentEnablingtheH-SRMexperimentHighlySelectiveSelectedReactionMonitoring(H-SRM)Reduces“isobaric”chemicalnoiseIncreasesconfidenceofanalysis&improvedLOQQ1peakwidth0.7DainSRMor0.2DainH-SRMQ3peakwidth0.7DaOHOHNHHOClClO2NONHHNOClClOHONHHHOClClO2NOHO2NOHCO2NOHHm/z321m/z257m/z321m/z194m/z152CAPSRMResult:CAPStandardQ1peakwidth=0.7DaRT:0.00-5.000.00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.44.64.8Time(min)020406080100020406080100020406080100RelativeAbundance020406080100RT:2.83AA:60868SN:15803.843.254.652.341.030.802.473.561.530.324.523.113.431.731.880.172.064.872.644.170.644.311.230.471.402.20RT:2.83AA:23577SN:16694.653.201.032.133.793.574.213.392.373.970.114.421.400.834.901.692.541.890.680.310.461.241.53RT:2.83AA:13035SN:1644RT:2.83AA:24218SN:6393.843.252.341.030.802.474.593.564.761.530.323.113.431.734.431.880.172.062.644.174.311.230.541.402.20NL:1.82E4TICF:MSICIS1221C03NL:7.07E3BasePeakm/z=151.50-152.50F:MSICIS1221C03NL:4.48E3BasePeakm/z=193.50-194.50F:MSICIS1221C03NL:6.77E3BasePeakm/z=256.50-257.50F:MSICIS1221C03TIC321-152321-194321-257CAPPeakAreaCounts=2.4E4CAPSRMResult:KidneyBlankRT:0.00-5.000.00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.44.64.8Time(min)020406080100020406080100020406080100RelativeAbundance0204060801001.281.481.751.892.052.612.231.032.832.462.953.073.223.783.480.694.603.624.324.060.364.870.184.454.720.512.772.052.231.851.641.522.421.772.572.953.253.351.313.544.321.034.163.974.870.420.930.224.723.824.463.690.811.180.662.152.682.991.651.852.293.212.831.372.392.033.524.504.013.673.451.124.610.194.