chp05 Analysis of Aromatic acid

CHAPTER5ANALYSISOFAROMATICCARBOXYLICACIDSGENERALCONSIDERATIONSInthischapterwewilllearntheanalysisofaromaticcarboxylicacids(toaromaticringconnectedwithcarboxylgroup)andtheirsalts,aromaticesters,andsubstitutedaromaticcarboxylicacidssuchas:acetyl-salicylicacid(Aspirin),sodiumpara-Aminosalicylatebenzoicacid,sodiumbenzoatebenorilate（贝诺酯）,etc.SalicylicacidssalicylicacidAspirinsodiumpara-aminosalicylateOHCOOH(Na)OCOCH3COOHCOOH(Na)OHNH2BenzoicacidsbenzoicacidsodiumbenzoateOtheraromaticacidsbenorilate（贝诺酯）COOHCOONaCOONHCOCH3OCOCH35.1.1Properties:1.alkalimetalsaltsofaromaticaciddissolveinwater,freearomaticacidsaresolubleinorganicsolvents(alcohol,chloroform,andether),butslightlyorhardlysolubleinwater2.aromaticacidswereclassifiedintothemildstrongacid(pKa=3~6)mineralacid(HCl,H2SO4)aromaticacidcarbonicacid(pKa6.3)phenols(pKa9.95)Section1AnalysisofSalicylicAcidsaromaticacidmaymakecarbonate,hydrocarbonateyieldcarbondioxidegas,butphenolsdonot.——todistinguisharomaticacidsandphenols——toidentifysaltofaromaticaciddrugsbymeltingpointofaromaticacids(decomposedproductunderthestrongacidsolution)AnalysisofSA3.aromaticestersmayhydrolysisespeciallyundertheexcessalkali.——assay:afteralkalinehydrolysis(excessalkalivolumetricsolution,VS),backtitrationwithacidvolumetricsolution,VS.AnalysisofSA4.substitutedaromaticacidshydroxylgrouponbenzenering——ferricchloride,suchascoloredferricsalicylicacidcomplexamino-grouponbenzenering——diazotisation(sodiumnitritetitration)maybeusedforassay——diazocouplingreaction(with-naphthol)maybeusedforidentificationAnalysisofSA5.1.2Identification:1.Thereactionwithferricchloride:——salicylicacidanditssalt(hydroxylgroup)+FeCl3→violetcomplex——theoptimumpHvalueis4～6COOHOH6+4FeCl3COO-O-2Fe3Fe+12HClAnalysisofSA2.Thereactionofhydrolyzedproducts:acetylsalicylicacid+Na2CO3→sodiumsalicylate+NaAc+CO2solution+acid→salicylicacid↓+aceticacid↑solution+H2SO4+CH3CH2OH→aceticether(specialodour)H2SO4CH3COOCH2CH3CH3COONa+CH3CH2OHAnalysisofSA3.Thediazo-couplingreaction:Thearomaticacidscontainingaromaticprimaryamine(orpotentialaromaticprimaryamine)maytakeplacethediazotisationreactionwithsodiumnitritetoproducethediazoniumsalt,thelattermaycouplewith-naphtholinthealkalinesolutiontoyieldanorangeredprecipitateAnalysisofSAAnalysisofSANaOOCHONH2+HClHOOCHONH2+NaClHOHOOCNH2+NaNO2+HClHOHOOCN2+Cl-+NaCl+2H2OHOHOOCN2+Cl-+HO+NaOHHOHOOCNNHO+H2O4.ThereactionwithBr2:AnalysisofSACOONaOHNH2BrBrBrNH2OH+3Br2+2HBr+NaBr+CO25.Characteristicultra-violetabsorptionspectra1)max:benorilate（贝诺酯）absolutealcoholsol.max=240nm=730～7602)Amax/Amin:sodiump-aminosalicylatephosphatebuff(pH7.0)sol.A265±2nm/A295±2mn=1.50～1.566.Infra-redabsorptionspectra7.TLCAnalysisofSA%11cmE1.Aspirin①ClarityofsolutionaspirinissolubleinNa2CO3TS,butimpuritiesinsoluble5.1.3Testofspecificimpurities:AnalysisofSAOCOCH3OHCOOOCOCH3COOOH(CH3CO)2,COOHOHCOOHOCOCH3,AnalysisofSACOOHOH[O]COOHOHHO[O]OOCOOHCOOHOHOCOOHOHOCOOH-OO+OCOOH②FreeSalicylicacid——Ferricchloridecolorimetry2.Sodiumpara-aminosalicylatemeta-aminophenolAnalysisofSACOONaNH2OHH2O-CO2OHNH2[O]OHOH2NOOHNH2[O]OHOHOOOHOH——Doublephasetitrationmeta-aminophenolissolubleinether,butSodiumpara-aminosalicylateisnot.titratetheetherlayerusinghydrogenchlorideVS(0.02mol/L)AnalysisofSAp-SANam-APH2OC2H5OC2H5m-PAH2OHClm-PAHCl——ion-pairedHPLCchromatographiccondition:column:ODS(C18)mobilephase:phosphatebuff-methanolcounterion:tetrabutylammoniumhydroxideion-paired:AnalysisofSANH2OH+(C4H9)4N+OH-pH5~7NH2O-(C4H9)4N++H2OCounterIontetra-alkylammonium(hydroxide,bromide)——acidsubstances:-COOH,-SO3H,-OH——tetrabutylammoniumhydroxide——pH5~7,0.005mol/Lalkylsulfonate(sodium)——alkalinesubstances:=NH,-NH2——C5~8——pH3~5,0.005mol/LAnalysisofSAcalculation(P101)(m-aminophenol)percentagecontent(%)P(%)=10(C/W)(Ru/Rs)C——theconc.ofm-aminophenol(g/ml)W——thequantityofdrug(mg)RuandRs——theratioofareasAnalysisofSA100)()()/(100)()((%)mgWmlDmlgCRsRupWDmetaCRsRuP10100)(1000)(100)/(WCRsRugWmlmlgCRsRu1.NeutralizationMethod①DirecttitrationASAKa=3.27×10-4maybetitratedwithsodiumhydroxideVS(0.1mol/L)5.1.4Assay:AnalysisofSACOOHOCOCH3+NaOHCOONaOCOCH3+H2OtoprotectfromhydrolysisofASA:——neutralizedalcoholdissolvesample——temperatureisbelow20℃——rapidtitration——continuouslystirAnalysisofSA②Backtitration（USP）ASAesterstructuremaybehydrolyzed,first,addexcessivesodiumhydroxideVS,heattohydrolyzeASAthen,titratetheexcessofsodiumhydroxideVSwithhydrochloricacidVSAnalysisofSACOOHOCOCH3+2NaOHCOONaOH+CH3COONa+H2O2NaOH+H2SO4Na2SO4+H2O③TwostepstitrationASAtabletscontaininghydrolyzed(SAandHAc)andprotectives(citricacid,tartaricacid)neutrlization——dissolvethesampleinneutralizedalcohol,usingphenothalinasindicator,NaOHVStitrationtopinkhydrolysisandtitration——addexcessiveNaOHVStohydrolysis,backtitratetheexcessNaOHVSusingH2SO4VSAnalysisofSACOOHOCOCH3+NaOHCOONaOCOCH3+H2OCOOHOCOCH3+2NaOHCOONaOH+CH3COONa+H2O2NaOH+H2SO4Na2SO4+H2OCHOCH2COOHCOOHCH2COOH+3NaOHCCH2COONaCH2COONaCOONaHO+3H2OAnalysisofSA2.SodiumNitriteTitration(thismethodwillbediscussedinnextchapter)3.HPLC4.LC-UVAnalysisof