16第十六章药品质量控制中的现代分析方法与技术.pptx
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1、药品质量控制中的药品质量控制中的现代分析方法与技术现代分析方法与技术Modern analytical methods & techniquesin quality control of drugs第十六章第十六章 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。手段与动力。色谱及其联用技术:色谱及其联用技术: 药学研究分子水平。药学研究分子水平。手性分析:手性分析: 毛细管电泳及手性色谱技术药物研究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。与质量控制提供了保障。现代光谱技术:现代光谱技术: 药物结构鉴定,药物结构鉴定
2、, 微量杂质检定。微量杂质检定。第一节 概况Capillary electrophoresis,CEModern chromatogr & its application药物现代色谱法及其应用药物现代色谱法及其应用UPLCUltraPerformance LC (UPLC ) technology starts with unique 1.7 m small-particle chemistries. Chromatographers no longer need to choose between speed and resolutionwith UPLC you get both.Mass
3、 spectroscopy MSNuclear magnetic resonance spectrometry NMRX-ray diffraction methodNear infrared spectrometry NIRS现代光谱法及其应用现代光谱法及其应用Modern spectroscopy & its application in pharmaceutical analysisGC-FTIRGC-MSUPLC-MSHPLC-NMRHyphenated Techniques in Chromatography 现代联用技术及其应用现代联用技术及其应用HPLC-MSCE-MS+样品与溶
4、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数据系统离子识别 Quadrapole Time of Flight Fourier Transform +离子检测+-+-+第二节第二节 液质联用技术与应用液质联用技术与应用2.1 离子化方式离子化方式2.2 离子分离与测定模式离子分离与测定模式Full-Scan Mass Spectrometry Advantage Provides MW InformationFull-Scan MS of BuspironeNNNNNOOBuspirone (丁螺环酮)C21H31N5O2MW = 38515020025
5、0300350400450500m/z255075100Relative Abundance386408(M+H)+(M+Na)+Single Ion Monitoring (SIM) Advantages Targeted Analyte Monitoring High Duty Cycle Simple Disadvantages Can suffer from interferences Not as sensitive or selective as SRM (see below)Fixed m/zPass AllPass AllProduct Ion Scanning: A Tand
6、em MS Method Advantage Provides Structural Information Disadvantage Low duty cycleFixed m/zPass AllScanningProduct Ion SpectrumQ3Q2Q1Product Ion Spectrum of BuspironeNHNNNOONHNOO100150200250300350400m/z255075100Relative Abundance122386222150265180NNNNHNOO(M+H)+Precursor Ion ScanningAdvantage ID comp
7、ounds producing specific fragment ion (e.g., PO3 for phosphopeptides)Disadvantage Low duty cycleFixed m/zPass AllScanningPrecursor Ion SpectrumQ3Q2Q1Precursor Ion Scan Mode for Buspirone MetabolitesPrecursor Ion Scan: Q3 set to m/z 122NNNNNOOOH100200300400500m/zRelative Abundance40238691011121314151
8、6Time (min)255075100Relative Abundance11.6213.8413.1614.4012.1310.4515.45NNNNNOONHNNNeutral Loss Scanning Advantage Screen for compounds producing specific neutral loss (e.g., loss of 176 for glucuronide conjugates) Disadvantage Low duty cycleScanningPass AllScanningNeutral Loss SpectrumLinkedQ3Q2Q1
9、Neutral Loss Scan of Buspirone MetabolitesNeutral Loss Scan: Q1/Q3 difference set to 121 Da100200300400500m/zRelative Abundance402386910111213141516Time (min)255075100Relative Abundance13.9211.6913.2115.5010.58NNNNNOONNNNNOOOHSelected Reaction Monitoring (SRM) Advantages Targeted Analyte Monitoring
10、High Duty Cycle “Simultaneous” Monitoring of Multiple Transitions Disadvantage No “advanced” structural informationFixed m/zPass AllFixed m/zQ1Q2Q3MS/MS Selectivity in Complex Matrices息斯敏阿斯咪唑(astemizole) Chlroamphenicol(氯霉素,氯霉素,CAP)残留测定残留测定 黄杨生物碱成分鉴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苯甲酸利扎曲普坦人体药代动力学研究2.3药物分
11、析中的典型应用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。2.3.1 Chlroamphenicol(氯霉素,氯霉素,CAP)残留测定残留测定HPLC analysis was performed on the Finnigan Surveyor HPLC module with MS Pump and AutosamplerC
12、olumn: Thermo Hypersil Gold C18 (1002.1 mm, 5)Mobile Phase: A: Water; B: AcetonitrileColumn Temperature: 40 oCGradient Program: 0.25 mL/minInjection: 20 uL with loopTime (min)% A% B080202.520803.020803.180205.08020Operation Conditions for CAPIon source:ESIIon polarity:NegativeSpray voltage:4000 VShe
13、ath gas pressure:45Auxiliary gas pressure:15Ion transfer capillary temperature:300 oCSource CID:8 VScan Type:SRM, 3 transitions of M-H-(m/z: 321)(321152, 321 194 and 321 257)Q1 peak width0.7 Da in SRM or 0.2 Da in H-SRMQ3 peak width0.7 DaCollision Pressure:Ar at 1.3 mTorrOHOHNHHHOClClO2NQ1 peak widt
14、h and H-SRM experiment Enabling the H-SRM experiment Highly Selective Selected Reaction Monitoring (H-SRM) Reduces “isobaric” chemical noise Increases confidence of analysis & improved LOQQ1 peak width0.7 Da in SRM or 0.2 Da in H-SRMQ3 peak width0.7 DaOHOHNHHOClClO2NONHHNOClClOHONHHHOClClO2NOHO2NOHC
15、O2NOHHm/z 321m/z 257m/z 321m/z 194m/z 152CAP SRM Result: CAP Standard Q1 peak width = 0.7 DaRT: 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)020406080100020406080100020406080100Relative Abundance020406080100RT: 2.83AA: 60868SN: 15803.843.254.652.341
16、.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: 6393.843.252.341.030.802.474.593.564.761.530.323.1
17、13.431.734.431.880.172.062.644.174.311.230.541.402.20NL:1.82E4TIC F: MS ICIS 1221C03NL:7.07E3Base Peak m/z= 151.50-152.50 F: MS ICIS 1221C03NL:4.48E3Base Peak m/z= 193.50-194.50 F: MS ICIS 1221C03NL:6.77E3Base Peak m/z= 256.50-257.50 F: MS ICIS 1221C03TIC321-152321-194321-257CAPPeak Area Counts = 2.
18、4E4CAP SRM Result: Kidney Blank RT: 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)020406080100020406080100020406080100Relative Abundance0204060801001.281.481.751.892.052.612.231.032.832.462.953.073.223.783.480.694.603.624.324.060.364.870.184.454.720.
19、512.772.052.231.851.641.522.421.772.572.953.253.351.313.544.321.034.163.974.870.420.930.224.723.824.463.690.811.180.662.152.682.991.651.852.293.212.831.372.392.033.524.504.013.673.451.124.610.194.924.324.200.940.420.820.691.281.481.751.892.612.052.231.032.462.833.073.293.783.490.694.603.624.060.364.
20、374.214.830.180.51NL:5.30E4TIC F: MS 1221D05NL:1.79E3Base Peak m/z= 151.50-152.50 F: MS 1221D05NL:4.69E2Base Peak m/z= 193.50-194.50 F: MS 1221D05NL:5.27E4Base Peak m/z= 256.50-257.50 F: MS 1221D05TIC321-152321-194321-257CAP SRM Result: Kidney Spiked (0.5ng/g)RT: 0.00 - 5.000.00.20.40.60.81.01.21.41
21、.61.82.02.22.42.62.83.03.23.43.63.84.04.24.44.64.8Time (min)020406080100020406080100020406080100Relative Abundance0204060801001.292.061.482.881.842.262.421.082.762.623.033.343.483.973.624.943.784.814.390.580.130.464.240.280.774.104.66RT: 2.88AA: 13715SN: 30RMS2.231.572.111.452.451.821.283.342.593.48
22、3.933.191.124.163.710.694.390.434.710.190.870.554.864.54RT: 2.88MA: 6787SN: 17RMS2.511.882.661.661.081.261.972.261.473.820.950.724.123.033.204.673.654.403.374.854.543.980.550.330.134.26RT: 2.87MA: 14653SN: INF1.292.061.481.842.291.002.422.613.033.253.393.973.624.943.784.814.390.580.130.464.240.280.7
23、74.104.66NL:4.68E4TIC F: MS 1221D08NL:3.47E3Base Peak m/z= 151.50-152.50 F: MS ICIS 1221D08NL:2.26E3Base Peak m/z= 193.50-194.50 F: MS 1221D08NL:4.63E4Base Peak m/z= 256.50-257.50 F: MS 1221D08TIC321-152321-194321-257CAPNot accurate for confirmationCAP detectedCAP H-SRM Result: CAP Standard Q1 peak
24、width = 0.2 DaRT: 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)020406080100020406080100020406080100Relative Abundance020406080100RT: 2.89AA: 16306SN: 1762RMS1.661.780.221.153.864.324.893.462.031.010.551.512.302.614.593.311.320.773.083.680.363.994.20
25、2.732.444.724.442.15RT: 2.89AA: 7313SN: 24498RMS3.423.083.854.384.831.073.980.151.331.532.061.763.673.301.932.560.362.200.492.694.120.690.884.592.36RT: 2.91AA: 1841SN: 273RMSRT: 2.89AA: 7129SN: 768RMS1.661.780.221.154.323.863.461.012.030.552.301.512.614.593.311.324.870.773.680.364.202.444.003.074.72
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