ANALISISFARMASI ANALISIS FARMASI ANORGANIK

FA 2101 FA2101
Dr.TutusGusdinar PharmacochemistryResearchGroup SchoolofPharmacy INSTITUTTEKNOLOGIBANDUNG

Thesyllabus y
Generalaspectsofpharmaceuticalanalysis:concentrationofelectrolyteand molecularspeciation,pHandbuffersystem,associationdissociationand equilibriumconstant;Acidimetryalcalimetry:monoprotic,polyprotic, amphiproticacidbase;buffercapacity;titrationcurve,indicativereaction, sampleanalysis;Precipitationandprecipitatometry:factorsthatinfluence sample analysis; Precipitation and precipitatometry : factors that influence precipitateformationandproperties(nucleation,crystallgrowth,aging), colloidstabilityandproperties;titrationcurve,indicativereaction,sample analysis;Complexcompoundandcomplexometry:typesofchelateandnon analysis; Complex compound and complexometry : types of chelate and non chelatecomplex,EDTA;titrationcurve,indicativereaction,sampleanalysis, Oxidimetryreductometry :redoxsystem,redoxequilibriumconstant; titrationcurve,indicativereaction,sampleanalysis;Gravimetricanalysis: titration curve indicative reaction sample analysis; Gravimetric analysis : gravimetricanalyticaltechniqueandseparation;Technicalapplicationon pharmaceuticalsubstancesandpreparation :titrimetrictypology,titration feasibility,calculationandresponsemeasurement,indicativereactions; Separationandmeasurementtechniquesandanalyticalerrors:separation techniquesandapplicationofreactionsinpharmaceuticalanalysis;statistics andanalyticalerrors.

MetodeAnalisisKlasik Metode Analisis Klasik

Metodekimiaanalisisuntukmenentukankadar y g senyawaterdiriatasgravimetridan titrimetri. Keduametodetersebut menghasilkanhargaabsolutyangdinyatakan menghasilkan harga absolut yang dinyatakan dalamsatuaninternasional(SIunits). Metodeklasikdigunakanuntukmenentukan kl k k k k kadardalamukuranbesar(1100%), sedangkanuntukukurankadaryang<1% digunakanmetodeinstrumen. digunakan metode instrumen.

 Classical analysishashadalonganddistinguishedhistory. Thecrudeclassicalanalysesofthepasthavebeen The cr de classical anal ses of the past ha e been improvedasbettervaluesforatomicmassesbecame available,astheprinciplesofphysicalchemistrywere applied,asorganic reagentswereintroduced,andas li d i i d d d instrumentaltechniquesbecameavailableforthe evaluationofthesystematicerrorsinherentinboth y gravimetry andtitrimetry. E i ti i t Existingisotopedilutionmassspectrometryandnewhigh dil ti t t d hi h performanceinductivelycoupledplasma opticalemission spectrometry,bothofwhicharemassratiobased,rivalor evenexceedclassicalanalysisinprecision,accuracy,and speed. Nevertheless,gravimetry andtitrimetry willendureas accurate,directlySItraceable,primarymethods,provided thattheir systematicerrorsareproperlyevaluatedusing h h i i l l d i thebestinstrumentaltechniquesavailable.

GRAVIMETRY
Gravimetriadalahpenentuankadarunsurataupunspesi Gravimetri adalah penentuan kadar unsur ataupun spesi kimiadengancaramengukurberathasilreaksikimia tidaklarutyangdiketahuidenganpasti. Hasilreaksiyangtidaklarutbisaberupagasyang berasaldarisuatularutanatauresidupadatyang berasal dari suatu larutan atau residu padat yang tidakmenguap,baikberasaldaripenguapanpada suhurendahmaupundaripemijaranpadasuhu tinggi.Padaumumnyayangdimaksudsenyawatidak larutadalahendapanyangterbentukdidalamsuatu larutandalamair. larutan dalam air. Gravimetri merupakan metode yang sudah dikenal sejak Gravimetrimerupakanmetodeyangsudahdikenalsejak abadke16.

TITRIMETRY
Titrimetriadalahmetodepenentuankadarunsuratau spesikimiadengancaramengukurjumlahsenyawa kimiayangsecarapastidiketahuibereaksisecara sempurnaberasaldariunsuratauspesiyangakan sempurna berasal dari unsur atau spesi yang akan ditentukantersebut. Massakimiatersebutdiukurdarisejumlahvolumelarutan standar(baku)dengancaratitrasi.Ada4metode titrimetri:titrasiasambasa,titrasipengendapan,titrasi titrimetri : titrasi asam basa titrasi pengendapan titrasi kompleksometri,antitrasioksidasireduksi.Titikakhir titrasisecaraklasikditentukandenganmengamati perubahanwarnaindikator,ataudenganmengamati perubahan warna indikator atau dengan mengamati selisihpotensialpadaelektroda,ataumengamati perubahankonduktivitaslarutan.

Titrimetricmethodsofanalysisarecapableofrapidand Ti i i h d f l i bl f id d convenientanalytedeterminationswithhigh accuracyand precision.Titrimetricanalysisisbasedonthecompletereaction precision Titrimetric analysis is based on the complete reaction betweentheanalyteand areagent,thetitrant :

aA+tT aA + tT

products

whereAandTrepresenttheanalyteandtitrant,respectively,and aandtarethestoichiometric coefficients. Forvolumetrictitrations,theamount,nA,ofanalyteinthe samplecanbecalculatedusing l b l l t d i whereCT i th h C istheconcentrationofthetitrant,andVT i th t ti f th tit t d V isthevolume l oftitrantneededtoreachthe endpoint.

nA=a/t.CTVT

Penentuankadarsuatuanalitdidalamlarutanmemerlukan: P k d li di d l l l k 1) Reaksi stoikhiometri anatara analit dan penitrasi reaksi Reaksistoikhiometrianataraanalitdanpenitrasi,reaksi tersebutharuscepatdansempurna,dimanahargaadant diketahui. 2) Konsentrasilarutanpenitrasi,CT,harusdiketahuidengan pasti.Larutanpenitrasiharusdibakukandengansenyawa bakuprimerataudititrasidenganlarutanyangterbuatdari b k i t ditit i d l t t b td i senyawabakuprimer. 3) Volume titik akhir titrasi harus dapat diukur secara tepat Volumetitikakhirtitrasiharusdapatdiukursecaratepat menggunakanindikatorwarnaataudenganinstrumen.Jika menggunakaninstrumenyangdapatmengukursecara berkelanjutan,makaakandiperolehkurvatitrasi. Caraini biasadigunakanuntukmenentukankadarcampuranatau untukmendeteksiadanya gangguan(interferensi). t k d t ki d (i t f i)

Syaratkhususanalisistitrimetri:

Gunakanlarutanpenitrasiyangumumdanjenisanalit yangbereaksidenganpenitrasitersebut,metode pembakuanlarutanpenitrasi,kestabilanlarutan penitrasi,metodedeteksititikakhir,danhalhallainnya yangpenting.

Pustaka: GHJeffery,JBassett,JMendham,RCDenney,VogelsTextbook ofQuantitativeChemicalAnalysis,5thedition. of Quantitative Chemical Analysis, 5th edition. HALaitinen,WEHarris,ChemicalAnalysis,2ndedition.

TitrimetricMethods: Titrimetric Methods :

AcidBaseTitrations
Reaksitransferprotondidalamlarutanair berlangsungsangatcepat. Aqueousacidbasetitrationsarethus Aqueous acid base titrations are thus suitablefortheanalysisofanyBronstedacid orbase.Practically,thepKaorpKbofthe b i ll h b f h analyteshould belessthanabout10(i.e., pKaorpKb<10)foracompletereaction betweenanalyteandtitrant. between analyte and titrant.

Inorderforthetitrationreactiontogotocompletion,a strongacidorastrongbaseistheusualchoice fora titrantinacidbasetitrations.Thelevellingeffectin aqueoussolutionsshouldbekeptinmind, however : thestrongestacidthatcanexistatasubstantial concentrationisthehydroniumion,H3O+, sinceany strongacidHAwillreactcompletelywithwater:

HA H O HA +H2O

A +H3O+ H

Thus,titratingwithanystrongacidisequivalentto Thus, titrating with any strong acid is equivalent to titratingtheanalytewithhydroniumion. Similarly,the strongestbasethatcanexistinwateristhehydroxide strongest base that can exist in water is the hydroxide ion,OH.

Fortheanalysisofbases,themostcommonaqueous y , q
titrantisHCl;sometimesH2SO4 orHClO4 are alsoused.Anyof thesemaybestandardizedby tris(hydroxymethyl)aminomethane,(HOCH2)3CNH2, whichis sometimesreferredtosimplyasTris. Sodiumcarbonate,Na Sodium carbonate Na2CO3,canalsoserveasaprimary can also serve as a primary standard,butitislessdesirablethanTrisduetoitslower equivalentweight. equivalent weight. Titrationsofbasesare sometimescalledalkalimetrictitrations.

Fortheanalysisofacids,NaOHisusuallyused;KOH
orBa(OH)2 mayalsobeused.Anyofthese maybestandardized againstpotassiumhydrogenphthalate(KHP).Thehydrogen phthalateanionis shownbelow. Titrationsofacidsaresometimescalledacidimetrictitrations. Tit ti f id ti ll d idi t i tit ti

Anyalkalinesolutionwillabsorbsubstantialamountsofcarbon dioxidefromtheatmosphere, resultinginthefollowingnet reaction : CO2 +2OH CO32 +2H2O ExposureofaqueousNaOHorKOHtitranttotheatmosphere resultsincarbonateerror. l i b Solid hydroxidesaltsmayalsocontainsignificantamountsof carbonateimpuritiesduetoabsorptionof atmosphericCO A carbonate impurities due to absorption of atmospheric CO2.A NaOHtitrantsolutionisbestpreparedbydilutionfroma concentrated (approximately50w/w%)solution.Sodium ( pp y ) carbonateisinsolubleinthissolution.Thedilutedtitrant solutionsaresometimesboiledtodrivedissolvedCO2 outofthe solutionandthenprotectedfrom exposuretoair.Theabsorption l i d h df i Th b i processisfairlyslow,occurringoveraperiodofhoursanddays. Ideally,acidimetrictitrationsshouldbeperformedwithafreshly Ideally acidimetric titrations should be performed with a freshly preparedandstandardizedsolution ofNaOH.

Example:BufferingofNaturalWaters Example : Buffering of Natural Waters

TheabilityofanaqueoussolutiontoresistchangesinpHuponthe The ability of an aqueous solution to resist changes in pH upon the additionofacidorbaseistermed thebufferingcapabilityofthe solution.Theabilityofanaturalwaterbodytoresistadecreasein pH isveryimportantduetotheubiquitouspresenceofacidrain. Thealkalinityofawaterbodyis definedasthenumberofmolesof H+ needed to bring a 1 L sample to pH 4 5 neededtobringa1 LsampletopH=4.5. Thehighertheacid neutralizingcapacity(ANC)ofthewater,the The higher the acid neutralizing capacity (ANC) of the water, the moreacidmustbeaddedtothe1 Lsampletobringthe pHto4.5. AcidimetrictitrationtopH = 4.5(ratherthantoanendpoint)isthus widelyusedtocharacterizethe abilityofawaterbodytoresist acidification.Ifpotentiometricdetectionisnotused,bromcresol green (perhaps mixed with methyl red) is used as a chemical (perhapsmixedwithmethylred)isusedasachemical indicator;thecolorchangesignifiestheendof thetitration.

KJELDAHL apparatus

Kjeldahl Analysis of Organic Nitrogen

The Kjeldahl procedure is a method for the analysis of organic nitrogen in the 3 oxidation state. The sample is digested with sulfuric acid to convert the organic nitrogen g g g to ammonium, NH4+. The digested sample is then basified and ammonia is then distilled into acid. The ammonia may be distilled into excess standard HCl; the amount of HCl remaining after the distillation is determined by alkalimetric titration Alternately ammonia may be distilled into titration. Alternately, excess boric acid, H3BO3; the dihydrogen borate, H2BO3, formed by reaction with ammonia is determined by y y acidimetric titration. The total Kjeldahl nitrogen (TKN) content of a water sample is a measure of the total concentration of nitrogen in the 3 oxidation state in the f 3 sample: ammonia/ammonium plus organic nitrogen. Kjeldahl analysis is also widely used to determine the protein content of food samples.

TitrimetryMethods t et y et ods PrecipitationTitrations

Precipitationreactionsinaqueoussolutionrangefrom rapidtoslow,dependingontheidentityofthe id l d di h id i f h precipitant. Manyprecipitationsaresufficientlyrapidandcomplete toformthebasisofquantitation b i f h b i f i i bytitration. i Precipitationtitrimetryhasseveraladvantagesover P i i i i i h l d precipitationgravimetry,including speed,sensitivity,and convenience. i

ArgentometricTitrations
Mostprecipitationreactionsinvolvethesilvercation,Ag Silver Most precipitation reactions involve the silver cation Ag+.Silver precipitationsarerapidand quantitative,andsilvernitrate,AgNO3, isusedforthedirecttitrationofanumberofanionsthat precipitatesilver :allthehalidesexceptF;SCN,CNO,AsO43, PO43,CN,C2O42,CO32,S2,CrO42.
[Seetable71onpage167inHarrisformoredetail]. [S t bl 7 1 167 i H i f d t il]

TitrationsusingAgNO3 astitrantare termedargentometric g g g titrations.Sodiumchlorideissuitableasaprimarystandard,andis mostoftenusedforstandardizationofthe titrantinargentometric titrations.Solidsilvernitrateisalsoavailableinhighenoughpurity toserve asaprimarystandard,butitismoreexpensive. Silvernitratesolutionsarestableinthedark,andamberbottles Silver nitrate solutions are stable in the dark and amber bottles areusedforstorage.Exposuretolight cancausephotoreductionof thesilvercations,particularinthepresenceoftraceimpurities ,p p p thatmay catalyzethereaction.

SulfateAnalysis Sulfate Analysis Thesulfatecontentofanaqueoussolutionmaybe determinedbytitrationwithaqueousbarium chloride, determined by titration with aqueous barium chloride BaCl2.Thetitrantisusuallystandardizedusingsodium sulfate. sulfate FluorideAnalysis Fluoride Analysis Fluoridecannotbeanalyzedbyargentometrictitration (AgFissoluble);instead,thesamplemaybe titrated (AgF is soluble); instead the sample may be titrated withlanthanumnitrate,La(NO3)3,orleadnitrate, Pb(NO3)2,sincebothLaF3 (pKsp = 16 2) and since both LaF (pKsp=16.2)and PbF2 (pKsp=7.57)areinsoluble.Sodiumfluorideisa suitableprimarystandard. suitable primary standard

EndpointDetection Avarietyofchemicalindicatorsareusedtoindicatethe endpointofargentometrictitrations : endpoint of argentometric titrations : The Fajans Volhard and Mohr methods are discussed in Fajans,Volhard,andMohr methodsarediscussedin somedetailinthelaboratory handoutTitrimetric AnalysisofChloride,andinyourtextbook(Harris Analysis of Chloride and in your textbook (Harris chapter7). Asilverwireorringisasufficientindicatorelectrodefor potentiometrictitrationsusingAgNO whileafluoride potentiometric titrations using AgNO3, while a fluoride ISEissuitableforpotentiometricendpointdetectionfor fluorideanalysisusingLa orPb2+titrantsolutions. fluoride analysis using La3+ or Pb2+ titrant solutions

Example:AnalysisofChlorideinSurfaceWaters

Chlorideisfrequentlyamajoranioninsurfaceand groundwater;certainlyisamajorconstituentof groundwater; certainly is a major constituent of seawater.Althoughchlorideinfreshwaterisusuallyof geologicalorigin,run offfromroadssalted duringthe geological origin run off from roads salted during the wintermaysignificantlyincreasethechloridecontentof surroundingstreams,riversand lakes.Ahigh chloride surrounding streams rivers and lakes A high chloride concentrationmayimpartanoticeablysaltytasteto potablewater,andcanalso damagemetallicpipesand potable water and can also damage metallic pipes and growingplants. Argentometrictitrationofwatersamplesisastandard Argentometric titration of water samples is a standard methodforchloridedetermination; concentrationsin thelowppmrangemaybedetectedusing the low ppm range may be detected using potentiometrictitration.

TitrimetricMethods:

RedoxTitrations
Redoxreactionsarethemostdiverseofthefourmain classesofinorganicaqueousreactions (acid base, classes of inorganic aqueous reactions (acidbase, precipitation,complexationandredox). Inprinciple,then,redoxtitrationscanbeusedto In principle, then, redox titrations can be used to analyze foranyoxidizingorreducingagent.However, manyredoxreactionsareeithertoosloworhave many redox reactions are either too slow or have inconsistentstoichiometry.Thestability oftitrantand analytesolutionscanalsobeaproblem. analyte solutions can also be a problem. Nevertheless,awidevarietyofanalytescanbe Nevertheless, a wide variety of analytes can be convenientlydeterminedbyredoxtitrations.

Consideragenericredoxhalfreaction(chargesomitted forclarity) : ox+ne red d Achemical(i.e.,oxinthisequation)thatpullselectrons fromanothersubstanceisanoxidizing agent,whilea chemical(red)thatforcesanothersubstancetoaccept electronsisareducingagent. Together,ox/redformaredoxcouple;redoxcouplesare analogoustoacid/baseconjugatepairs.And justlike acidbasereactions,theconjugateofastrongoxidizing agentisaweakreducingagent. Thestrengthofoxidizing/reducingagentscanbe deducedbythestandardreductionpotential:avery positivestandardpotentialindicatesastrongoxidizing agent,whilealowpositiveoranegative potentialis characteristicofastrongreducingagent.

Thestrengthofanoxidizingorreducingagentisvery oftendependentonpH.Thereisageneralrule ofthumb : often dependent on pH There is a general rule of thumb : acidicconditionstendtomakeoxidizingagentsmore powerfulandrenderreducingagents lessreactive.Some powerful and render reducing agents less reactive Some fewredoxreagentsarerelativelyinsensitivetopH,which canbeanadvantage. can be an advantage MostredoxreagentsarestableonlywithinacertainpH range. range Sampletreatmentisoftennecessarytoadjustthe oxidationstateoftheanalyte.Theanalyteiseither oxidation state of the analyte The analyte is either pre reducedorpreoxidized.Forprereductionoftheanalyte, manymetals(manyofwhicharestrong reducingagents) many metals (many of which are strong reducing agents) canbeused.Itiscommontouseareductor,whichisa columnofgranulatedmetal throughwhichthesample column of granulated metal through which the sample solutionispoured.

Twocommonreductorsare :theJonesReductor,which usesamalgamatedzinc(ZnHg)granules,andtheWalden g ( g) g Reductor,whichusessilvergranules (chlorideisadded tothesample,usuallyasHCl).TheWaldenReductoris p y ) moreselective(i.e.,aless powerfulreducingagent)than theJonesReductor. Preoxidationisnotascommonasprereduction,since theanalyteisusuallydesiredinareduced formfor titrationwithanoxidizingagent.However,whenpre oxidationisnecessary,sodium bismuthate,NaBiO3, ammoniumperoxydisulfate,(NH4)2S2O8,orhydrogen peroxidemaybeused.

TitrimetricMethods:

ComplexometricEDTATitrations
Complexometrictitrationsarebasedonthereaction betweenLewisacids(usuallymetalcations)and ( y ) Lewisbases.M+:LM:L Lewisacidsandbasesreacttoformacomplex.The base Lewis acids and bases react to form a complex The base donatestwoelectronstoformabondwith theacid.Since theproton,H is a good Lewis acid by definition any the proton H+,isagoodLewisacid,bydefinitionany BronstedbasewillbeaLewis base.Lewisbaseswill possessatleastasinglelonepairofelectronsthatitwill possess at least a single lone pair of electrons that it will donatetotheLewis acid.Lewisbasesarealsosometimes calledligands,andtheatomscontainingthelonepairis called ligands and the atoms containing the lone pair is the ligandbindingsite.

Aspecialsubsetofligandsarethosethatcontainmore thanonebindingsiteonthemolecule;these arecalled than one binding site on the molecule; these are called chelatingagents.Chelatingagentsformparticularly strongcomplexes calledchelates withLewisacids. strong complexes called chelates with Lewis acids Byfarthemostcommoncomplexometrictitrantis ethylenediaminetetraaceticacid, EDTA.Thisisa ethylenediaminetetraacetic acid EDTA This is a hexadentatechelatingligand,meaningthattherearesix ligandbindingsiteson EDTAmolecule. ligand binding sites on EDTA molecule EDTAtitrationsareveryversatile:theycanbeusedfor theanalysisofallthemetal cationsexceptthealkali the analysis of all the metal cations except the alkali metals,andcanevenbeused(throughbacktitration andsimilarmethods) fortheanalysisofmanyanions. and similar methods) for the analysis of many anions EDTAtitrationsarealsofairlysensitive,capableof detecting concentrations of some metals at levels of concentrationsofsomemetalsatlevelsof approximately10ppm(i.e.,10mg/L).

AdvantagesofEDTAasaComplexingTitrant
Complexationofmetalcationswithunidentateligandsisnot usefulasthebasisforaquantitative titration.Let simaginethat useful as the basis for a quantitative titration. Lets imagine that wehaveasolutionofCu2+ tobeanalyzedbycomplexometric titration. Wecanuseatitrantsuchasaqueousammonia,aunidentate ligand.Thefollowingequationsshowthe stepwiseformationof complexesbetweenthemetalandtheligand: l b t th t l d th li d Cu2++ NH3 +NH CuNH32+ +NH3 Cu(NH3)22+ +NH3 Cu(NH3)32++NH3 CuNH32+ logK 3.99 logK =3.99 Cu(NH3)22+ logK=3.34 Cu(NH3)32+logK=2.73 Cu(NH3)42+logK=1.97

SincethecoordinationnumberofCu ideally we would observe Since the coordination number of Cu2+,ideallywewouldobserve fourdistinctendpointsduringthe titrationwithNH3.