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,
sample analysis; Precipitation and precipitatometry : factors that influence
sampleanalysis;Precipitationandprecipitatometry:factorsthatinfluence
precipitateformationandproperties(nucleation,crystallgrowth,aging),
colloidstabilityandproperties;titrationcurve,indicativereaction,sample
analysis; Complex compound and complexometry : types of chelate and non
analysis;Complexcompoundandcomplexometry:typesofchelateandnon
chelatecomplex,EDTA;titrationcurve,indicativereaction,sampleanalysis,
Oxidimetryreductometry :redoxsystem,redoxequilibriumconstant;
titration curve indicative reaction sample analysis; Gravimetric analysis :
titrationcurve,indicativereaction,sampleanalysis;Gravimetricanalysis:
gravimetricanalyticaltechniqueandseparation;Technicalapplicationon
pharmaceuticalsubstancesandpreparation :titrimetrictypology,titration
feasibility,calculationandresponsemeasurement,indicativereactions;
Separationandmeasurementtechniquesandanalyticalerrors:separation
techniquesandapplicationofreactionsinpharmaceuticalanalysis;statistics
andanalyticalerrors.
 Metode Analisis Klasik
MetodeAnalisisKlasik
Metodekimiaanalisisuntukmenentukankadar
y g
senyawaterdiriatasgravimetridan
titrimetri. Keduametodetersebut
menghasilkan harga absolut yang dinyatakan
menghasilkanhargaabsolutyangdinyatakan
dalamsatuaninternasional(SIunits).
Metodeklasikdigunakanuntukmenentukan
kl k k k k
kadardalamukuranbesar(1100%),
sedangkanuntukukurankadaryang<1%
digunakan metode instrumen.
digunakanmetodeinstrumen.
 Classical analysishashadalonganddistinguishedhistory.
The cr de classical anal ses of the past ha e been
Thecrudeclassicalanalysesofthepasthavebeen
improvedasbettervaluesforatomicmassesbecame
available,astheprinciplesofphysicalchemistrywere
applied,asorganic
li d i reagentswereintroduced,andas
i d d d
instrumentaltechniquesbecameavailableforthe
evaluationofthesystematicerrorsinherentinboth
y
gravimetry andtitrimetry.

EExistingisotopedilutionmassspectrometryandnewhigh
i ti i t 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
h h i systematicerrorsareproperlyevaluatedusing
i l l d i
thebestinstrumentaltechniquesavailable.
 GRAVIMETRY
Gravimetriadalahpenentuankadarunsurataupunspesi
Gravimetri adalah penentuan kadar unsur ataupun spesi
kimiadengancaramengukurberathasilreaksikimia
tidaklarutyangdiketahuidenganpasti.

Hasilreaksiyangtidaklarutbisaberupagasyang
berasal dari suatu larutan atau residu padat yang
berasaldarisuatularutanatauresidupadatyang
tidakmenguap,baikberasaldaripenguapanpada
suhurendahmaupundaripemijaranpadasuhu
tinggi.Padaumumnyayangdimaksudsenyawatidak
larutadalahendapanyangterbentukdidalamsuatu
larutan dalam air.
larutandalamair.

Gravimetrimerupakanmetodeyangsudahdikenalsejak
Gravimetri merupakan metode yang sudah dikenal sejak
abadke16.
 TITRIMETRY
Titrimetriadalahmetodepenentuankadarunsuratau
spesikimiadengancaramengukurjumlahsenyawa
kimiayangsecarapastidiketahuibereaksisecara
sempurna berasal dari unsur atau spesi yang akan
sempurnaberasaldariunsuratauspesiyangakan
ditentukantersebut.

Massakimiatersebutdiukurdarisejumlahvolumelarutan
standar(baku)dengancaratitrasi.Ada4metode
titrimetri : titrasi asam basa titrasi pengendapan titrasi
titrimetri:titrasiasambasa,titrasipengendapan,titrasi
kompleksometri,antitrasioksidasireduksi.Titikakhir
titrasisecaraklasikditentukandenganmengamati
perubahan warna indikator atau dengan mengamati
perubahanwarnaindikator,ataudenganmengamati
selisihpotensialpadaelektroda,ataumengamati
perubahankonduktivitaslarutan.
Titrimetricmethodsofanalysisarecapableofrapidand
Ti i i h d f l i bl f id d
convenientanalytedeterminationswithhigh accuracyand
precision Titrimetric analysis is based on the complete reaction
precision.Titrimetricanalysisisbasedonthecompletereaction
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
nA=a/t.CTVT
whereC
h CT istheconcentrationofthetitrant,andV
i th t ti f th tit t d VT isthevolume
i th l
oftitrantneededtoreachthe endpoint.
P
Penentuankadarsuatuanalitdidalamlarutanmemerlukan:
k d li di d l l l k

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

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

Pustaka:
GHJeffery,JBassett,JMendham,RCDenney,VogelsTextbook
of Quantitative Chemical Analysis, 5th edition.
ofQuantitativeChemicalAnalysis,5thedition.
HALaitinen,WEHarris,ChemicalAnalysis,2ndedition.
 Titrimetric Methods :
TitrimetricMethods:
AcidBaseTitrations
Reaksitransferprotondidalamlarutanair
berlangsungsangatcepat.
Aqueous acid base titrations are thus
Aqueousacidbasetitrationsarethus
suitablefortheanalysisofanyBronstedacid
orbase.Practically,thepKaorpKbofthe
b i ll h b f h
analyteshould belessthanabout10(i.e.,
pKaorpKb<10)foracompletereaction
between analyte and titrant.
betweenanalyteandtitrant.
Inorderforthetitrationreactiontogotocompletion,a
strongacidorastrongbaseistheusualchoice fora
titrantinacidbasetitrations.Thelevellingeffectin
aqueoussolutionsshouldbekeptinmind, however :
thestrongestacidthatcanexistatasubstantial
concentrationisthehydroniumion,H3O+, sinceany
strongacidHAwillreactcompletelywithwater:

HA +H
HA H2O
O A +H
H3O+
Thus,titratingwithanystrongacidisequivalentto
Thus, titrating with any strong acid is equivalent to
titratingtheanalytewithhydroniumion. Similarly,the
strongest base that can exist in water is the hydroxide
strongestbasethatcanexistinwateristhehydroxide
ion,OH.
Fortheanalysisofbases
y ,,themostcommonaqueous
q
titrantisHCl;sometimesH2SO4 orHClO4 are alsoused.Anyof
thesemaybestandardizedby
tris(hydroxymethyl)aminomethane,(HOCH2)3CNH2, whichis
sometimesreferredtosimplyasTris.
Sodium carbonate Na2CO3,canalsoserveasaprimary
Sodiumcarbonate,Na can also serve as a primary
standard,butitislessdesirablethanTrisduetoitslower
equivalent weight.
equivalentweight.
Titrationsofbasesare sometimescalledalkalimetrictitrations.

Fortheanalysisofacids,NaOHisusuallyused;KOH
orBa(OH)2 mayalsobeused.Anyofthese maybestandardized
againstpotassiumhydrogenphthalate(KHP).Thehydrogen
phthalateanionis shownbelow.
Tit ti
Titrationsofacidsaresometimescalledacidimetrictitrations.
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
carbonate impurities due to absorption of atmosphericCO
carbonateimpuritiesduetoabsorptionof atmospheric CO2.A
A
NaOHtitrantsolutionisbestpreparedbydilutionfroma
concentrated (approximately50w/w%)solution.Sodium
( pp y )
carbonateisinsolubleinthissolution.Thedilutedtitrant
solutionsaresometimesboiledtodrivedissolvedCO2 outofthe
solutionandthenprotectedfrom
l i d h df exposuretoair.Theabsorption
i Th b i
processisfairlyslow,occurringoveraperiodofhoursanddays.
Ideally acidimetric titrations should be performed with a freshly
Ideally,acidimetrictitrationsshouldbeperformedwithafreshly
preparedandstandardizedsolution ofNaOH.
Example : Buffering of Natural Waters
Example:BufferingofNaturalWaters
TheabilityofanaqueoussolutiontoresistchangesinpHuponthe
The ability of an aqueous solution to resist changes in pH upon the
additionofacidorbaseistermed thebufferingcapabilityofthe
solution.Theabilityofanaturalwaterbodytoresistadecreasein
pH isveryimportantduetotheubiquitouspresenceofacidrain.
Thealkalinityofawaterbodyis definedasthenumberofmolesof
H+ neededtobringa1
needed to bring a 1 LsampletopH=4.5.
L sample to pH 4 5

Thehighertheacid
The higher the acid neutralizingcapacity(ANC)ofthewater,the
neutralizing capacity (ANC) of the water, the
moreacidmustbeaddedtothe1 Lsampletobringthe pHto4.5.
AcidimetrictitrationtopH = 4.5(ratherthantoanendpoint)isthus
widelyusedtocharacterizethe abilityofawaterbodytoresist
acidification.Ifpotentiometricdetectionisnotused,bromcresol
green (perhapsmixedwithmethylred)isusedasachemical
(perhaps mixed with methyl red) is used as a chemical
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
g with sulfuric acid to convert the organic
g nitrogen
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 alkali-
metric titration
titration. Alternately
Alternately, ammonia may be distilled into
excess boric acid, H3BO3; the dihydrogen borate, H2BO3,
formed by y reaction with ammonia is determined by y
acidimetric titration. The total Kjeldahl nitrogen (TKN)
content of a water sample is a measure of the total
concentration off nitrogen in the 33 oxidation state in the
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
f h b i f i i bytitration.
b i i

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

TitrationsusingAgNO
g g 3 astitrantare termedargentometric
g
titrations.Sodiumchlorideissuitableasaprimarystandard,andis
mostoftenusedforstandardizationofthe titrantinargentometric
titrations.Solidsilvernitrateisalsoavailableinhighenoughpurity
toserve asaprimarystandard,butitismoreexpensive.
Silver nitrate solutions are stable in the dark and amber bottles
Silvernitratesolutionsarestableinthedark,andamberbottles
areusedforstorage.Exposuretolight cancausephotoreductionof
thesilvercations,particularinthepresenceoftraceimpurities
,p p p
thatmay catalyzethereaction.
SulfateAnalysis
Sulfate Analysis
Thesulfatecontentofanaqueoussolutionmaybe
determined by titration with aqueous barium chloride,
determinedbytitrationwithaqueousbarium chloride
BaCl2.Thetitrantisusuallystandardizedusingsodium
sulfate.
sulfate

FluorideAnalysis
Fluoride Analysis
Fluoridecannotbeanalyzedbyargentometrictitration
(AgF is soluble); instead the sample may be titrated
(AgFissoluble);instead,thesamplemaybe titrated
withlanthanumnitrate,La(NO3)3,orleadnitrate,
Pb(NO3)2,sincebothLaF
since both LaF3 (pKsp=16.2)and
(pKsp = 16 2) and
PbF2 (pKsp=7.57)areinsoluble.Sodiumfluorideisa
suitable primary standard
suitableprimarystandard.
EndpointDetection

Avarietyofchemicalindicatorsareusedtoindicatethe
endpoint of argentometric titrations :
endpointofargentometrictitrations :

The Fajans,Volhard,andMohr
Fajans Volhard and Mohr methodsarediscussedin
methods are discussed in
somedetailinthelaboratory handoutTitrimetric
Analysis of Chloride and in your textbook (Harris
AnalysisofChloride,andinyourtextbook(Harris
chapter7).

Asilverwireorringisasufficientindicatorelectrodefor
potentiometric titrations using AgNO3, whileafluoride
potentiometrictitrationsusingAgNO while a fluoride
ISEissuitableforpotentiometricendpointdetectionfor
fluoride analysis using La3+ orPb
fluorideanalysisusingLa or Pb2+
2+ titrantsolutions.
titrant solutions
Example:AnalysisofChlorideinSurfaceWaters

Chlorideisfrequentlyamajoranioninsurfaceand
groundwater; certainly is a major constituent of
groundwater;certainlyisamajorconstituentof
seawater.Althoughchlorideinfreshwaterisusuallyof
geological origin run offfromroadssalted
geologicalorigin,run off from roads salted duringthe
during the
wintermaysignificantlyincreasethechloridecontentof
surrounding streams rivers and lakes.Ahigh
surroundingstreams,riversand lakes A high chloride
chloride
concentrationmayimpartanoticeablysaltytasteto
potable water and can also damagemetallicpipesand
potablewater,andcanalso damage metallic pipes and
growingplants.
Argentometric titration of water samples is a standard
Argentometrictitrationofwatersamplesisastandard
methodforchloridedetermination; concentrationsin
the low ppm range may be detected using
thelowppmrangemaybedetectedusing
potentiometrictitration.
 TitrimetricMethods:
RedoxTitrations
Redoxreactionsarethemostdiverseofthefourmain
classes of inorganic aqueous reactions (acid
classesofinorganicaqueousreactions (acidbase,
base,
precipitation,complexationandredox).
In principle, then, redox titrations can be used to
Inprinciple,then,redoxtitrationscanbeusedto
analyze foranyoxidizingorreducingagent.However,
many redox reactions are either too slow or have
manyredoxreactionsareeithertoosloworhave
inconsistentstoichiometry.Thestability oftitrantand
analyte solutions can also be a problem.
analytesolutionscanalsobeaproblem.

Nevertheless,awidevarietyofanalytescanbe
Nevertheless, a wide variety of analytes can be
convenientlydeterminedbyredoxtitrations.
Consideragenericredoxhalfreaction(chargesomitted
forclarity) : ox+ne redd
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
often dependent on pH There is a general rule ofthumb
oftendependentonpH.Thereisageneralrule of thumb :
:
acidicconditionstendtomakeoxidizingagentsmore
powerful and render reducing agents lessreactive.Some
powerfulandrenderreducingagents less reactive Some
fewredoxreagentsarerelativelyinsensitivetopH,which
can be an advantage
canbeanadvantage.
MostredoxreagentsarestableonlywithinacertainpH
range.
range
Sampletreatmentisoftennecessarytoadjustthe
oxidation state of the analyte The analyte is either pre
oxidationstateoftheanalyte.Theanalyteiseither
reducedorpreoxidized.Forprereductionoftheanalyte,
many metals (many of which are strong reducingagents)
manymetals(manyofwhicharestrong reducing agents)
canbeused.Itiscommontouseareductor,whichisa
column of granulated metal throughwhichthesample
columnofgranulatedmetal 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
Lewis acids and bases react to form a complex The base
Lewisacidsandbasesreacttoformacomplex.The base
donatestwoelectronstoformabondwith theacid.Since
the proton H+,isagoodLewisacid,bydefinitionany
theproton,H is a good Lewis acid by definition any
BronstedbasewillbeaLewis base.Lewisbaseswill
possess at least a single lone pair of electrons that it will
possessatleastasinglelonepairofelectronsthatitwill
donatetotheLewis acid.Lewisbasesarealsosometimes
called ligands and the atoms containing the lone pair is
calledligands,andtheatomscontainingthelonepairis
the ligandbindingsite.
Aspecialsubsetofligandsarethosethatcontainmore
than one binding site on the molecule; these arecalled
thanonebindingsiteonthemolecule;these are called
chelatingagents.Chelatingagentsformparticularly
strong complexes calledchelates
strongcomplexes called chelates withLewisacids.
with Lewis acids
Byfarthemostcommoncomplexometrictitrantis
ethylenediaminetetraacetic acid EDTA.Thisisa
ethylenediaminetetraaceticacid, EDTA This is a
hexadentatechelatingligand,meaningthattherearesix
ligand binding sites on EDTAmolecule.
ligandbindingsiteson EDTA molecule
EDTAtitrationsareveryversatile:theycanbeusedfor
the analysis of all the metal cationsexceptthealkali
theanalysisofallthemetal cations except the alkali
metals,andcanevenbeused(throughbacktitration
and similar methods) fortheanalysisofmanyanions.
andsimilarmethods) for the analysis of many anions
EDTAtitrationsarealsofairlysensitive,capableof
detecting concentrationsofsomemetalsatlevelsof
concentrations of some metals at levels of
approximately10ppm(i.e.,10mg/L).
AdvantagesofEDTAasaComplexingTitrant
Complexationofmetalcationswithunidentateligandsisnot
useful as the basis for a quantitative titration.Let
usefulasthebasisforaquantitative titration. Letssimaginethat
imagine that
wehaveasolutionofCu2+ tobeanalyzedbycomplexometric
titration.
Wecanuseatitrantsuchasaqueousammonia,aunidentate
ligand.Thefollowingequationsshowthe stepwiseformationof
complexesbetweenthemetalandtheligand:
l b t th t l d th li d

Cu2++NH
+ NH3 CuNH32+ logK =3.99
logK 3.99
CuNH32+ +NH3 Cu(NH3)22+ logK=3.34
Cu(NH3)22+ +NH3 Cu(NH3)32+logK=2.73
Cu(NH3)32++NH3 Cu(NH3)42+logK=1.97

Since the coordination number of Cu2+,ideallywewouldobserve

SincethecoordinationnumberofCu ideally we would observe
fourdistinctendpointsduringthe titrationwithNH3.