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PHARMACEUTICALPHARMACEUTICAL
ANALYSIS ll ANALYSIS ll
LIQUID-LIQUID EXTRACTION
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LIQUID-LIQUID EXTRACTION
ØØ DEFINATIONDEFINATION LiquidLiquid--liquid extraction is aliquid extraction is a
versatile and dependable separationversatile and dependable separation
technique where in an aqueous solution istechnique where in an aqueous solution is
usually brought into contact with anotherusually brought into contact with anotherorganic solvent, exclusively immiscibleorganic solvent, exclusively immiscible
with the former, so as to affect a legitimatewith the former, so as to affect a legitimate
and actual transfer of either one or moreand actual transfer of either one or more
solute into the latter.solute into the latter.
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separation technique is superior separation technique is superior
BecauseBecause
Ø Ease of use
Ø Faster extraction times
Ø Decreased volumes of solvent
Ø Their superior ability to concentrate the
analytes.
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USING METARIALSUSING METARIALS
ØØ Separations may be performed by shaking theSeparations may be performed by shaking thetwo liquids in atwo liquids in a SEPARATORYSEPARATORY FUNNELFUNNEL for afor a
few minutes, and may be extended either tofew minutes, and may be extended either tolarge quantities of pharmaceutical substances orlarge quantities of pharmaceutical substances ortrace levels.trace levels.
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SHOWING BY FLOW CHARTSHOWING BY FLOW CHART
Two liquids placed in separatory funnelTwo liquids placed in separatory funnel
shaken to increase surfaceshaken to increase surface
areaarea
keep some timekeep some time
two phase systemtwo phase system
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FOR ORGANIC &INORGANICFOR ORGANIC &INORGANIC SOLUTESOLUTE
In case of organic soluteIn case of organic solute Two immiscible
organic solvents (e.g; alcohol& ether) are
used instead of aquous organic type of
extraction.In case of inorganic soluteIn case of inorganic solute one aquous
solvent & one organic solvent are
used.But if the component are water
sensitive then we have to form Chelates.
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PRINCIPLESPRINCIPLES
Feed phase
FEED PHASE CONTAINING
SOLUTEThis should be extracted
ADDITION OF SOLVENTIMMICIBLE WITH FEED PHASE
SOME SOLUTESARE TRNSFERED FROM
FEED PHASE TO
SOLVENT PHASE
(1)FEED PHASE
(2)SOLVENT PHASE
After extraction
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AFTER EXTRACTIONAFTER EXTRACTION
THESE TWO PHASES ARE CALLED
These two phases can be separated by
DISTILLATION for their IMMISCIBILITY.liquid-liquid extraction is also applicable
for an organic phase by adding aquous phase
FEED PHASE
RAFFINATE PHASE
OR
R
SOLVENT PHASE
EXTRACT PHASE
E
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THEORYTHEORY
ØØ TheThe NearstNearstDistribution Law!Distribution Law!states that at constantstates that at constanttemperature, a solutetemperature, a solutedistributes itselfdistributes itself
between two immisiblebetween two immisiblesolvents only in asolvents only in aparticular ratio.particular ratio.
KKp = Co/Caqp = Co/CaqKKp=partition coefficientp=partition coefficient
Co=Conc. of the analyte(orgCo=Conc. of the analyte(org))Caq=Conc.of the analyte(aq)Caq=Conc.of the analyte(aq)
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LIMITATIONS
ØØ It is not thermodynamically rigorous. ThatIt is not thermodynamically rigorous. That
means it is solely applicable to very dilutemeans it is solely applicable to very dilute
solutions.solutions.
ØØ It does not hold good when the distributingIt does not hold good when the distributingsubstance encounters association orsubstance encounters association or
distribution in either phases.distribution in either phases.
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TWO ASPECTS OF LIQUIDTWO ASPECTS OF LIQUID--
LIQUID EXTRACTIONLIQUID EXTRACTION
Ø Error due to the volume change
Ø Effectiveness of an extraction
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1. Error due to the volume change: if two
immiscible solvent is under extraction
process, then the volume of the two individualphases will be different comparison to the
initial volumes.
To avoid error of volume change, the
Procedure we adopted is:
Ø Measure the volume of the phase employed
for the analysis and incorporate this volume inthe calculations.
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ØSeparate the phase quantitatively and
subsequently dilute to known volume.ØSeparate the phase quantitatively and make use
of the entire volume in the remaining steps of the
analysis.
ØCarry a maker substance through the extractionto automatically compensate for volume changes.
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INDUSTRIALY EXTRACTIONINDUSTRIALY EXTRACTION
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22.. Effectiveness of an extractionEffectiveness of an extraction:: Based on theBased on the
appropriate partition coefficient of an immiscibleappropriate partition coefficient of an immiscible
solvent pair it is possible to calculate thesolvent pair it is possible to calculate the
effectiveness of an extraction!effectiveness of an extraction!..
Let,Let,
x moles of solute in vx moles of solute in v22 volume when solvent is a!volume when solvent is a!
(x(x--y) moles solute in vy) moles solute in v11 volume when solvent is b!volume when solvent is b!(x(x--y)/ vy)/ v11
Kp=Kp=
y/y/ vv22
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or, Kp =(or, Kp =(x/x/ vv11--x/x/ vv11)) vv22/y/y
or, Kp =x/y.vor, Kp =x/y.v22/v/v11--vv22/v/v11or, Kp =vor, Kp =v22/v/v11(x/y(x/y--11))
or, Kp. vor, Kp. v22/v/v11=(x/y=(x/y--11))
or, x/y= (vor, x/y= (v22
/v/v11
. Kp +. Kp + 11))or, y/x= (vor, y/x= (v11/v/v22. Kp +. Kp + 11) " ) " ## After the total extraction, After the total extraction,
(v(v11/v/v22. Kp +. Kp + 11))f f nn ==
nn
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Here,Here,
KKp = partition coefficientp = partition coefficient
f f nn = fraction of extracted= fraction of extracted
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SOLVENT SELECTION CRITERIASOLVENT SELECTION CRITERIA
11)) MISCIBILITY:MISCIBILITY: Solvents defined as if theSolvents defined as if theTwo components can be mixed together inTwo components can be mixed together in
all proportions without forming two separateall proportions without forming two separate
phases.phases.
Solvent miscible with water in allproportions include Acetone, Acetonitrile,
Dimethyl acetamide, N,N-dimethylformamide,
Dimethyl sulfoxide, 1,4,-dioxane etc.
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22)) DENSITYDENSITY: If density difference is high then: If density difference is high thenimmiscibility will be high. On other hand if densityimmiscibility will be high. On other hand if density
difference is low it causes miscibility.difference is low it causes miscibility.
e.g; He.g; H22O & CHO & CH22ClCl
here the density of CHhere the density of CH22Cl is high.Cl is high.&& HH22O is low.O is low.
So, CHSo, CH22Cl will come down to theCl will come down to the
lower Portion of the separatorylower Portion of the separatory
Funnel &Funnel & HH22O will come up.O will come up.
HH22OO
CHCH22ClCl
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33)) SOLUBILITYSOLUBILITY:: Two immiscible solventTwo immiscible solvent
become totally mixed up under a certain amount.become totally mixed up under a certain amount.
e,g;e,g; HH22O & CHO & CH22ClCl2211..66%% CHCH22ClCl22 = soluable in= soluable in HH22OO
00..2424%% HH22O = soluable in CHO = soluable in CH22ClCl22
To overcome this problem we can use whichTo overcome this problem we can use whichsolubility is zero.Otherwise it would be moresolubility is zero.Otherwise it would be more
complex.complex.
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FACTORS INFLUENCE SOLVENTFACTORS INFLUENCE SOLVENT
EXTRACTIONEXTRACTION
ØØ Effect of temparatureEffect of temparature: Temparature must: Temparature must
be fixed through the process because itbe fixed through the process because it
depends on the solubility of the substancedepends on the solubility of the substance
in two respective solvevts.in two respective solvevts.
KKp = Sp = S11/S/S22
Solubility of solute in solventa!
Solubility of solute in solventa!
Solubility of solute in solvent b! Solubility of solute in solvent b!
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ØØ Effect of pH on extractionEffect of pH on extraction: It may be: It may be
observed that the pH for anobserved that the pH for an extraction system!extraction system!
must be selected in such a fashion so that themust be selected in such a fashion so that themaximum quantity of the analyte is present inmaximum quantity of the analyte is present in
the extractable form, that obviously suggeststhe extractable form, that obviously suggests
that the analyte should always be in the form ofthat the analyte should always be in the form of
either a free base or a free acid.either a free base or a free acid.
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EMULSIONEMULSION
EMULSIONEMULSION:: Emulsion may be defined as aEmulsion may be defined as a
dispersed system containing at least two Idispersed system containing at least two I
mmiscible liquid phases.mmiscible liquid phases.
The effectiveness and meaningful extractionThe effectiveness and meaningful extractionof a solute is rended almost impossibleof a solute is rended almost impossible
when there is an emulsion formation duringwhen there is an emulsion formation during
an extraction process. Emulsion formationan extraction process. Emulsion formation
makes the separation of the two phasesmakes the separation of the two phases
difficult.difficult.
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FACTORS CAUSES SLOWFACTORS CAUSES SLOW--
COALESCENCE EMULSIONCOALESCENCE EMULSION
The breaking of an emulsion could be a slow
process. There are a number of factors
which may be responsible for the slow-
coalescence of an emulsion, namely:1. Finely divided powders of albumin, gelatin
and natural gums have a tendency to coat
droplets formed in an emulsion which
ultimately prevent them from coalescing.
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2. Usually surfactants decrease the interfacial
tension between the two immiscible liquids which
help in stabilizing an emulsion.
3. Ionic species may get absorbed at the interface
of two immiscible layers resulting in the formation
Of a net charge on the droplets. Because all
droplets shall essentially bear the similar charge,
naturally they will repel one another thereby
preventing coalescence.
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In fact,there are many natural and syntheticIn fact,there are many natural and synthetic
substances that are profusely incorporated in thesubstances that are profusely incorporated in the
formulation of drugs which are found to stabilizeformulation of drugs which are found to stabilize
emulsions either by coating the droplets or byemulsions either by coating the droplets or by
minimizing the interfacial tension.Eg;minimizing the interfacial tension.Eg;
((11)Coating the droplets)Coating the droplets:: Starch, Acacia, Gelatin,Starch, Acacia, Gelatin,Silica, Finely divided talc.Silica, Finely divided talc.
((22))Minimizing the interfacial tensionMinimizing the interfacial tension:: Mono & DiMono & Di--Glycerides, Stearates, Sorbitan monoleate.Glycerides, Stearates, Sorbitan monoleate.
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PREVENTION OF EMULSIONPREVENTION OF EMULSION
FORMATIONFORMATION
It has been obsered that once an emultionIt has been obsered that once an emultion
formed it is difficult to break the emusion.In orderformed it is difficult to break the emusion.In order
to avoid forming emulsions in the course of anto avoid forming emulsions in the course of an
extraction process:extraction process:
11)) Very cautious & gentle agitation and employingVery cautious & gentle agitation and employing
a sufficiently large liquida sufficiently large liquid--liquid interface providesliquid interface provides
a reasonably good extraction. Vigorous ora reasonably good extraction. Vigorous or
thorough shaking of the two phases is notthorough shaking of the two phases is not
required at all.required at all.
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22)) The removal of insoluable materials in a liquidThe removal of insoluable materials in a liquid
phase must be done by filtration before carryingphase must be done by filtration before carrying
out the extraction process.out the extraction process.
33)) Always prefer & use such solvent pairs that Always prefer & use such solvent pairs that
have a large density difference & high interfacialhave a large density difference & high interfacial
tension.tension.
44)) When performing extraction from water alwaysWhen performing extraction from water alwaysensure not to work at pH extremes.ensure not to work at pH extremes.
55)) In acute emulsion problems substance likeIn acute emulsion problems substance like
alumina or silica are used to resolve the problemalumina or silica are used to resolve the problem
by adsorption of emulsifying agents.by adsorption of emulsifying agents.
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PROCESS OF BREAKING OF ANPROCESS OF BREAKING OF AN
EMULSIONEMULSION
ØØ Mechanical meansMechanical means:: Coalescence may beCoalescence may be
achieved by mechanically creatingachieved by mechanically creating
turbulence on the surfaces of the droplets byturbulence on the surfaces of the droplets by
stirring with the help of a glassstirring with the help of a glass--rod.rod.
ØØ CentrifugationCentrifugation:: Where the densities of theWhere the densities of the
two liquids are appreciably differenttwo liquids are appreciably different
coalescence may be achieved bycoalescence may be achieved by
centrifugation.centrifugation.
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Ø Addition of mono & di-valent ions: Simple
emulsions are broken by adding mono-valent
salts like NaCl. Charge stabilized emulsions are
sensitive to the di-valent ions like CaCl2, MgCl2.
ØEthanol or higher alcohol: Addition of small
quantities of either ethanol or a higher alcohol aidin coalescing and emulsion.
ØSilicone-defoaming agent: A few drops of the
silicone de-foaming agent sometimes help in
breaking of an emusion.
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ØSudden cooling of emulsion: Sudden temp. drop
or freezing of an emulsion enhances the
interfacial tension between two immiscible
phases thereby causing coalescence.
Ø Altering the ratio of solvents: Coalescence may
also be achieved by altering the ratio of the
prevailing dispersed phase or by partialeveporation of the solvent.
ØThin-bed of an adsorbent: Passing of an
emulsion through a thin-bed of an adsorbent
helps in achieving coalescence.The analyte mustnot be adsorbed from either solvent.
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Prepared ByPrepared By::
Mst. Sifat LailaMst. Sifat Laila $ $ 20072007--11--7070--021021
Samina MostafaSamina Mostafa $ $
20072007--11--7070--013013Israq Binte EshaqueIsraq Binte Eshaque $ $ 20072007--11--7070--009009
Tahmina KhanomTahmina Khanom $ $ 20052005--22--7070--006006
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THANK YOUTHANK YOU