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Pharmaceutical Analysis II; PHRM 309

What is liquid-liquid extraction?

• a useful method to separate components (compounds) of a

mixture.
• an aqueous solution is usually brought into contact with
another organic solvent.
• exclusively immiscible with one another.
•  Transfer of solute/solutes from one liquid into another
liquid phase. 
• also known as solvent extraction and partitioning.
Liquid-liquid extraction (LLE) (Contd.)
Why LLE is superior to others ?
• ease of use,
• faster extraction
• decreased volumes of solvent, and
• their superior ability to concentrate the
analytes.
 How do you do liquid-liquid extraction?
• Liquids are placed in the
separating funnel
• Moderate shaking (moderately)
• Increase the surface area
between the phases
• After completing extraction
-liquids are allowed to separate
• Denser phase settling to the
bottom of the separating funnel
Why do you shake it?
• Shaking allows greater area of contact between the two
immiscible liquids,
• resulting in faster equilibration of the solute
substance(s) between the two liquids.
LLE (Contd.)
• The mixture is brought into contact
with a solvent in which
– the substance of interest is
soluble, but
– the other substances present are
insoluble.
• Solute in the solution has more
affinity toward the added solvent.
Proportion of liquids in LLE

• Feed solution/phase:
– Initial solution containing one (or more) solute(s)
– Solute(s)+Solvent 1
• Solvent 2 is added in feed phase to perform extraction
• Extract
• Solvent that is enriched in solute(s) is called extract.
• Extract is evaporated to collect and measure the amount of the solute
• Solvent 2+Solute(s)
• Raffinate:
• The feed solution that is depleted in solute(s)
• If the extraction process is repeated, the Raffinate becomes the feed
phase.
LLE (Contd.)
• success depends on the difference
in solubility of a compound in
various solvents. 
• For a given compound, solubility
differences between solvents is
quantified as the "distribution
coefficient“.
Distribution coefficient “K”
• Most organic compounds are
more soluble in organic
solvents
• Some organic compounds
are more soluble in water.
Universal rule?
• At a certain temperature, the ratio of concentrations of a solute in each
solvent is always constant.
• This ratio is distribution coefficient, K.

• Sol 1 and Sol 2 are immiscible liquids.

Example:
• Suppose compd has K=2 between Sol 1 and Sol 2

• Fig1:
• 30 particles of are distributed between 100 mL volume of Sol 1 and Sol
2.
Example (Contd.)
• Fig 2:
• 300 particles of are distributed between 100 mL volume of Sol 1 and
Sol 2.

• No matter how much solute there is, the distribution coefficient K

remains constant, equal to 2
• Calculation:
• Let the X amount will be extracted in Solvent 2. Total number is 300. Therefore,
300-X amount is in Solvent 1. Diff Coff is 2.
• Sol 1= 100 mL and Sol 2 = 100 mL
• K= (X/100)/(300-X)/100=2
• Or, X=2(300-X)
• Or, X=600-2X
• Or, 3X=600
• Or, X=200
• When you double the volume of solvent 2 (i.e., 200 mL of
solvent 2 and 100 mL of solvent 1)
• Calculation:
• Let the X amount will be extracted in Solvent 2. Total number is 300. Therefore,
300-X amount is in Solvent 1. Diff Coff is 2.
• Sol 1= 100 mL and Sol 2 = 200 mL
• K= (X/200)/(300-X)/100=2
• Or, X=2(300-X)X2
• Or, X=1200-4X
• Or, 5X=1200
• Or, X=240 in Sol 2 and (300-240=60) in Sol 1
 One extraction with 200 mL gave a TOTAL of 240 particles.
More solutes are extracted in larger amount of extraction solvent
Home Work!
• Problem!!!
• Solvent 2 = 300 mL
• Solvent 1= 100 mL
• Number of particles: 350
• Diffusion coefficient is 2
• Calculate the amount of particles extracted in Solvent 2.
Sequential Extraction
• Solvent 1 = 100 mL
• Solvent 2 = 100 mL
• Number of particles you have to extract is 300.
• Diffusion coefficient is 2
Extract twice with 100 mL of solvent 2. How many particles will be extracted
from TWO portions of Solvent 2?
If you extract twice with 100 mL of solvent 2?
• First 100 mL of solvent2 - extract 200 particles
• Still 100 mL of solvent1- contain 100 particles
• Add a second 100 mL volume of fresh solvent2
• According to the distribution coefficient K=2 - 67
more particles are extracted.
• Additional 67 particles are extracted with the
second portion solvent2
• Total no of particles = 267 using 2 portions of
solvent2 (100 ml each time)
• No of particles from single extraction is 240
using one 200 mL portion of solvent2
• More efficient to carry out two extractions with
1/2 volume of extraction solvent than one large
volume.
• Likewise, extraction three times with 1/3 the
volume is even more efficient.
• The greater the number of small extractions, the
greater the quantity of solute removed.
Example:
• Suppose that you have a mixture
of sugar in vegetable oil (it tastes
sweet!) and you want to separate
the sugar from the oil
• You observe that the sugar
particles are too tiny to filter and
you suspect that the sugar is
partially dissolved in the
vegetable oil.
• How about shaking the mixture with
water ?
• Will it separate the sugar from the
oil?
• Sugar is much more soluble in water
than in vegetable oil
• Adding water - The water phase is
the bottom layer
• oil phase is the top layer, because
water is denser than oil.
• By shaking the layers (phases) well, you
increase the contact area between the
two phases.
• The sugar will move to the phase in
which it is most soluble: the water layer.
• After waiting for a while, two clear
layers are formed again.
• Now the water phase tastes sweet,
because the sugar is moved to the
water phase upon shaking.
• In this example
– water was the extraction solvent
– the original oil-sugar mixture was
the solution to be extracted;
– sugar was the compound extracted
from one phase to another.
• What? The oil phase still
somewhat tastes sweet?
• not all of the sugar was
removed from the oil by one
extraction with water
• repeat the extraction with
water to remove more sugar
from the oil phase, until the
oil layer no longer tastes
sweet
Problem
• One gram of a compound requires the following quantities of solvent
to dissolve: 47 mL of water, 8.1 mL of chloroform, 370 mL of diethyl
ether, or 86 mL of benzene.
• Calculate the solubility of the compound in these four solvents (as
g/100 mL).
• Estimate the partition coefficient of the compound between
chloroform and water, ethyl ether and water, and benzene and water.
• Which solvent would you choose to extract the compound from an
aqueous solution?
Problem
• One gram of a compound requires the following quantities of solvent to
dissolve: 47 mL of water, 8.1 mL of chloroform, 370 mL of diethyl ether, or 86
mL of benzene.
• Calculate the solubility of the compound in these four solvents (as g/100 mL).
• 1 gm of compound dissolved in 47 ml of water
• 47 ml of water contains 1 gm of compound
• 100 ml of water will contain 100/47 gm of compound = 2.13 gm
• 100 ml of chloroform will contain 100/8.1 gm compound=12.34 gm
• 100 ml of diethylether will contain 100/370 gm = 0.3 gm
• 100 ml of benzene will contain 100/86 gm = 1.16 gm
• One gram of a compound requires the following quantities of solvent
to dissolve: 47 mL of water, 8.1 mL of chloroform, 370 mL of diethyl
ether, or 86 mL of benzene.
• Estimate the partition coefficient of the compound between
chloroform and water, ethyl ether and water, and benzene and water.
• 100 ml of water will contain 100/47 gm of compound = 2.13 gm
• 100 ml of chloroform will contain 100/8.1 gm compound=12.34 gm
• 100 ml of diethylether will contain 100/370 gm = 0.3 gm
• 100 ml of benzene will contain 100/86 gm = 1.16 gm
• KCHCl3/H2O=12.34/2.13 =5.79
• Kethylether/water=0.3/2.13= 0.14
• Kbenzene/water=1.16/2.13=0.54
• K is calculated from K = Corganic solvent/Cwater. Chloroform would be the
solvent of choice to extract the compound from an aqueous solution
because the partition coefficient for this pair of solvents is the highest.

Solvent Given Conc g/100 mL K

Water 1g/47 mL 2.1 -

Chloroform 1g/8.1 mL 12.3 5.9

Diethyl Ether 1g/370 mL 0.27 0.13

Benzene 1 g/86 mL 1.2 0.57
Summary
• Liquid-liquid extraction is based on the transfer of a solute substance
from one liquid phase into another liquid phase according to the
solubility.
• Extraction becomes a very useful tool if you choose a suitable extraction
solvent.
• You can use extraction to separate a substance selectively from a mixture,
or to remove unwanted impurities from a solution.
• In the practical use, usually one phase is a water or water-based
(aqueous) solution and the other an organic solvent which is immiscible
with water.
Problems!!!
• Five grams of Compound A is dissolved in 90 mL of
water. The distribution coefficient for Compound A
between hexanes and water is 5 (in other words,
KCompound A(hexanes/water) = 5)
1.How much of Compound A will be in the hexanes if
you extract it from the water one time with 90 mL of
hexanes?
2.How much of Compound A will be in the hexanes if
you extract it from the water with three sequential
extractions using 30 mL of hexanes each time, and
then combine the hexanes extracts?
Theory of liquid-liquid extraction:
• Behavioral pattern of two immiscible solvents is
essentially non-ideal with respect to one another.
• If a third substance is made to dissolve in a two-phase
mixture of the solvents, it may behave ideally in either
phases provided its concentration in each individual
phase is approximately small.
• Therefore, under these prevailing experimental
parameters the ratio of the mole fractions of the solute
in the two respective immiscible phases (‘a’ and ‘b’) is
found to be a constant which is absolutely independent
of the quantity of solute present.
• It is termed as the Nernst Distribution Law or the
Partition Law and may be expressed as follows:
Theory of liquid-liquid extraction:
• Nernst Distribution Law
• “At constant temperature, a solute distributes itself
between two immiscible solvents only in a
particular ratio”
• This statement is a Nernst Distribution Law –
i.e.  the law that determines the relative
distribution of a component that is soluble in two
liquids, these liquids being immiscible or miscible
to a limited extent.
• This law is one of the laws applying to ideal dilute
solutions. 
•  It was discovered by W. Nernst in 1890.
• The Nernst distribution law states that, at
equilibrium, the ratio of the concentrations of a
third component in two liquid phases is
constant. The law may be expressed in the
form:

•The constant (Kp) is also known as distribution

coefficient or the partition coefficient.
•Partition Law offers Two limitations:

•(a) It is solely applicable to very dilute solutions in

which case the ratio of the activities almost
approaches unity, and

•(b) It does not hold good when the distributing

substances encounters association or distribution in
either phases (i.e., ‘a’ and ‘b’).
• There are two general types of liquid-liquid
extractions:
• 1. an organic solvent extraction, in which an
organic solvent with a high affinity for the
desired compound is used to extract the
compound from another solution, and
• 2. an acid-base extraction, in which an organic
acid or base is extracted from an organic
solvent by using an aqueous solution of an
inorganic base or acid, respectively. A
neutralization occurs which converts the
compound into an ionic, water-soluble salt,
causing it to transfer from the organic phase to
the aqueous phase.
• Extraction with organic solvents
• Liquid-liquid extractions usually involve water and an organic
solvent. Most common organic solvents (diethyl ether, ethyl
acetate, toluene, methylene chloride) are immiscible in water. If
you place 50 mL of ethyl acetate and 50 mL of water in a flask and
stir the solution to mix it, you will not obtain a homogeneous
solution. Rather, if the solution is allowed to stand after stirring,
two distinct liquid phases will form in the flask: the more dense
solvent as the lower layer and the less dense solvent as the upper
layer.
• Most organic solvents are much less polar than water. A general
rule of thumb for solubility states that like dissolves like. Polar
compounds are more soluble in polar solvents than in nonpolar
solvents, and vice versa. The selective solubility of different
compounds in polar versus nonpolar solvents allows the separation
of the compounds in a mixture by liquid-liquid extraction.
• For example, at 25 oC, the solubility of benzoic acid in water
is 3.4 g per liter while the solubility of benzoic acid in
chloroform (CHCl3) is 222 g per liter. Water and chloroform
are immiscible solvents. If a solution of 1 g of benzoic acid in
400 mL of water is extracted with 400 mL of chloroform, we
would expect most of the benzoic acid to be transferred to
the chloroform layer in which it is more soluble. The benzoic
acid will distribute itself between the two solvents in the
ratio of the solubilities in each solvent:

• No matter how much benzoic acid is present in the system, it

will always be distributed between the chloroform and water
so that the ratio of the concentration in each solvent is 65.3.
• From this estimate of the distribution coefficient, we can calculate how
much benzoic acid is present in the chloroform and water layers after
the extraction. Let x = grams of benzoic acid in the water layer and y =
grams of benzoic acid in the chloroform layer. Since we started with 1 g
of benzoic acid,
x + y = 1 . Using this equation along with the value for the distribution
coefficient calculated above, we can determine the concentration of
benzoic acid in each layer:

• Or, since the vols of both solvents used are the same:

• The total amount of benzoic acid present is (x + y) = 1. Rearranging

this equation and substituting for x in the previous equation gives

• Solving this equation for y gives 0.015 g (15 mg) of benzoic acid in the
water layer, and, since the total amount of benzoic acid is 1 g, there is
0.985 g (985 mg) of benzoic acid in the chloroform layer.
 Apparatus and Techniques:

• Separatory Funnel extractions are

performed to extract compounds either into or
from an aqueous layer.

• A separatory funnel is a useful apparatus for

LLE.

• Mix and separate two immiscible liquids in

this glassware.
Mixing two layers
Step 1 Sep funnel in a ring clamp
• Set up the sep funnel
• Place the sep funnel in a ring
clamp on a ringstand
• Check to see that the stopcock is
closed.
 Mixing two layers (Contd.)
Step 2 Separatory funnel

• Place a stemmed funnel in the neck of

the separatory funnel. 
• Add the liquid to be extracted, then add
the extraction solvent. 
• The total volume in the separatory
funnel should not be greater than three-
quarters of the funnel volume.
Mixing two layers (Contd.)
Step 3 Insert stopper

• Insert the stopper in

the neck of the
separatory funnel.
Mixing two layers (Contd.)
Step 4 Insert, invert and rock gently
• Pick up the separatory funnel
• Before inserting the stopper, swirl the
sep funnel gently to release any gas
formed upon mixing.
• Insert the stopper.
• While holding the stopper in place,
invert the sep funnel and rock it once
gently.
 Mixing two layers (Contd.)
Step 5
• Point the stem up and slowly open the stopcock to
release excess pressure.
• Close the stopcock, and while holding the stopper
and stopcock firmly, shake the sep funnel several
times.
• Vent the funnel as before, then shake the sep
funnel again.
• Vent and repeat the shaking and venting
process several times.
• Shake the funnel vigorously for a few
seconds.
• Release the pressure, then again shake
vigorously.
• About 30 sec total vigorous shaking is
usually sufficient to allow solutes to come to
equilibrium between the two solvents.
• Vent frequently to prevent pressure buildup,
which can cause the stopcock and perhaps
hazardous chemicals from blowing out.
• Take special care when washing acidic
solutions with bicarbonate or carbonate
since this produces a large vol of CO2 gas.
• Put the funnel back into the ring
and let it rest undisturbed until
the layers are clearly separated.
•
• While waiting, remove the stopper
and place a beaker or flask under
the sep funnel.
• Carefully open the stopcock
and allow the lower layer to
drain into the flask.

• Drain just to the point that the

upper liquid barely reaches
the stopcock.
• If the upper layer is to be removed from
the funnel, remove it by pouring it out of
the top of the funnel.
• Often repeated extractions with fresh
solvent are needed.
• Leave the upper layer in the separatory
funnel if this layer contains the compound
of interest.
• If the compound of interest is in the lower
layer, the upper layer must be removed
from the separatory funnel.
• Remember to store the stopper separately
from the funnel.
 Separating the two layers
• Once the two immiscible liquids have been thoroughly
shaken together - ready to separate the two liquids
• Drain the bottom layer
• Make sure that the stopper has been removed from the top of
the sep funnel.
• (If air cannot come in from the top, draining won't be
smooth.)
• Carefully open the stopcock to drain the lower layer into a
clean Erlenmeyer flask
• Step 6.
• For repeating the extraction, place
the solution to be extracted in the sep
funnel, then add fresh extracting
solvent.
• (A) If the UPPER layer is the solution
to be extracted further:
• The sep funnel still contains the
upper layer. Leave it there.
• Add fresh extraction solvent. Repeat
the extraction process.
• (B) If the BOTTOM layer is the solution to
be extracted further:
• Remove the upper layer remaining in the sep
funnel first.
• Drain the layer into a clean Erlenmeyer flask
and label the flask.
• Then return the bottom layer to the sep
funnel (Remember to use a fluted funnel
when transferring liquids!).
• Add fresh extracting solvent and repeat the
extraction process.
• Reminder:
• The TOP layer is always poured out FROM THE TOP of the
sep funnel,
• whereas the BOTTOM layer is always drained FROM THE
BOTTOM.
 SOLVENT SELECTION CRITERIA
•Miscibility:
•Solvents defined as miscible if the two components can be mixed together in all
proportions without forming two separate phases.

•Solvents miscible with water in all proportions include acetone, acetonitrile,

dimethyl acetamide, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane,
ethyl alcohol, isopropyl alcohol, methanol, 2-methoxyethanol, N-methylpyrrolidone,
n-propyl alcohol, pyridine, tetrahydrofuran, and trifluoroacetic acid.

•- Solvents should be immiscible

•Density:
•Another consideration when selecting an extraction solvent is its density.

•Solvents that are more dense than water will form the lower layer of the
pair when mixed together, while solvents that are less dense than water will
form the upper layer or ‘‘float’’ on water.
Ethyl ether (0.7133 g/mL)

Water (0.9982 g/mL)

Water (0.9982 g/mL)

Chloroform (1.4892 g/mL)

•Ethyl ether has a density of 0.7133 g/mL at 20oC and would constitute the
upper phase when combined with water, which has a density of 0.9982 g/mL
at that temperature.

•On the other hand, the density of chloroform is 1.4892 g/mL at 20oC.
Therefore, water would form the top layer in a water–chloroform solvent
pair.
 •Should have high density difference

•Water (0.9982 g/mL) and Hexane (0.6548 g/mL) They are less
prone to emulsion problems.

•Water (0.9982 g/mL) and Benzene (0.8765 g/mL) Should not be

used in the extraction process.
•Solubility:
•Although immiscible solvents may form two visibly distinct phases when mixed together, they
are often somewhat soluble in each other and will, in fact, become mutually saturated when
mixed with each other.

•For example, 1.6% of the dichloromethane (solvent) is soluble in water. Conversely, water is
0.24% soluble in dichloromethane.

•- Should be insoluble to each other.

•When the phases are separated for recovery of the extracted analyte, the organic solvent layer
will contain water.

•Similarly, after extraction the depleted aqueous phase will be saturated with organic solvent and
may pose a disposal problem.
FACTORS INFLUENCING SOLVENT EXTRACTION

• A number of factors exert a positive influence on the

phenomenon of solvent extraction, namely:
– (a) Effect of temperature and inert solutes,
– (b) Effect of pH on extraction,
– (c) Effect of ion-pair formation, and
– (d) Effect of synergistic extraction.
Emulsion Problem encountered in LLE

•  Emulsion can be defined as a dispersed system where one

liquid phase is dispersed as droplets into another immiscible
liquid phase and the dispersion is stabilized by using an
appropriate emulsifying agent.
•  In Liquid – Liquid Extraction, the phases are dispersed in
each other through moderate shaking so that they can come in
each other’s contact for solute transfer.
•  But, they must not form emulsion and after shaking they
must form separate layers again.
Factors Influencing Emulsion Stability

Emulsion formation is a problem when dealing with the

extraction of drugs from biological or pharmaceutical
formulations which tend to emulsify even upon moderate
shaking due to presence of emulsion stabilizers in the
formulation.
These Emulsion Stabilizers are –
– Finely Divided Powders
– Surfactant
– Ionic Species
• Finely Divided Powders
• Finely Divided Powders have a
tendency to coat the droplets formed in
an emulsion which ultimately prevent
them from forming coalescence.
• They are used as emulsifying agents
and as binders in pharmaceutical liquid
and solid dosage forms respectively.
• Such examples are –
•Albumin
•Gelatin
•Natural Gums (Such as Acacia)
• Surfactants
• Surfactants are used to increase H2O
solubility of a compound which can
either be solid / liquid.
• Presence of such surfactants is very
frequent in pharmaceutical
formulations which prevent
coalescence by surrounding the
droplets formed.
• Examples of such surfactants are –
• •Cetosteryl alcohol
• •Glyceryl Monooleate
• Ionic Species
•  Ionic Species get absorbed
at the interface of the droplets
resulting in a net charge on the
droplets.
•  Because all droplets
essentially bear the similar
charge, they will repel one
another thereby preventing
coalescence.
• Prevention of Emulsion Formation
• It has been observed that once an emulsion is formed it is rather
difficult to break it. Therefore, it is absolutely necessary to adhere
to the guidelines, as far as possible, in order to avoid forming
emulsions in the course of an extraction process.
• Moderate Shaking
– The solvents must be shaken moderately, so that the
phases are dispersed in each other for solute transfer but
then again forms separate layers.
– Always affect very cautious and gentle agitation besides
employing a sufficiently large liquid-liquid interface to
obtain a reasonably good extraction. Especially when the
two-liquid layers have a large contact surface in an
extraction process, vigorous or thorough shaking of the
two phases is not required at all,
– It is because vigorous shaking can form emulsion.
• High Density Difference
– Density Difference between the
solvents chosen must be high so
that they do not form emulsion
upon dispersion.
– E.g. –
– Density of Water, Benzene and n –
hexane are 0.9982 gm / ml, 0.8765
gm / ml and 0.6548 gm / ml
respectively.
High Density Difference (Cont.)

– In case of Water – benzene system there is a very low density

difference (0.1217 gm / ml); so the system is very susceptible
to emulsion formation even upon moderate shaking.
– But, in case of H2O – n-hexane system, there is a high density
difference (0.3434 gm / ml); so there is less chance of
emulsion formation.
– But, in case of H2O – n-hexane system, there is a high density
difference (0.3434 gm / ml); so there is less chance of
emulsion formation.
• Removal of Finely Divided Solids
– Finely divided Solids tend to stabilize the emulsion Formation by
coating the droplets.
– So, before extraction these solids must be removed from feed phase by
filtration.

• Avoiding High pH Range

– Since, Emulsification occurs more frequently and easily in Extreme pH
range (i.e. below 4 – Extremely Acidic and above 9 – Extremely Basic);
these ranges should be avoided and kept between 4 to 9.

• Removal of Surfactant by Using Adsorbents

– To remove Surfactants, a thin bed of adsorbents (E.g. Alumina, Silica
Gel) can be used through which the feed phase can be passed through.
– However, use of such adsorbents must be avoided which can adsorb the
solute.
Processes of Breaking Emulsion

• Mechanical Means
• In case of simple emulsion,
coalescence can be achieved
by mechanically creating
turbulence on the surface of
the droplets by stirring with
a glass rod.
• Centrifugation
– Centrifugation is a process of separation by the application of
Centrifugal Force based on the density difference between the
phases.
– So, when the density difference between the phases / solvents is
considerably high, centrifugation can be applied to break the
emulsion.

• Addition of Mono – or Di – valent Cations

– Saturated Solution of Mono – valent or Di – valent Salts (E.g. NaCl
or CaCl2) can be added to break down the emulsion by increasing
the ionic strength of Water / Aqueous Phase / Feed Phase.
– Upon increasing the ionic strength of Feed Phase, solubility of
organic solute or Complex / Chelate of inorganic solute in aqueous
phase / Feed Phase decreases and they will return to their own
more soluble organic phase.
• Addition of Ethanol or Higher Alcohol
– Addition of Ethanol or higher alcohol increases coalescence in
emulsion by increasing the interfacial tension between phases.

• Silicone – Defoaming Agent

– Addition of Silicone Defoaming Agent helps in breaking the
emulsion.

• Sudden Cooling or Thermal Shock

– Sudden temperature drop or freezing (i.e. giving a thermal shock)
of emulsion mostly enhances the interfacial tension between the
two immiscible phases thereby causing coalescence.
• Alteration of Solvent Ratio
– Coalescence of an emulsion can be achieved by altering the ratio of
solvents prevailing in the dispersed phase.
– It can be done by slowly adding solvents.

• Thin – Bed of Adsorbent

– A thin bed of adsorbents (E.g. Alumina, Silica Gel) can be used
through which the feed phase can be passed through to break the
emulsion.
Liquid-Liquid Washing

• Liquid – Liquid Washing is a process of separation of

impurities from the extract or reaction medium
containing the target solute and also the impurities.
• The process can be used to remove impurities from a
reaction medium.
• Type of impurities removed in Liquid-Liquid Washing
• Impurities to be removed via Liquid – Liquid Washing can
be of 2 type –
– Byproduct
– Catalyst
• For example, all of A and B reacts to form C and D which is
catalyzed by X. So, here the impurities are
– byproduct D and catalyst X.
Steps of Liquid-Liquid Washing

• Steps involved in the Liquid – Liquid Washing are –

– Reaction Work–up
– Separation of Target Solute from the Reaction medium
by adding Organic Solvent
– Removal of Impurities
• Reaction Work-up
– Reaction of Phenol and Acetic anhydride results in the
formation of Phenol acetate and Acetic Acid which is
catalysed by Triethylamine.

Phenol acetate is the product or target compound

• Separation of target solute from the reaction medium
– Before performing the separation, it must be considered that
solubility of the target compound in organic solvent must be
higher than the solubility of impurities.
– So, solvent should be selected in such a way.
– In case of this reaction, the target compound Phenol acetate
is insoluble in water and soluble in Ether which is higher
than that of both Acetic Acid and Triethylamine.
– So, Ether can be the organic solvent of choice to separate
Target Solute from the Reaction medium.
• Removal of impurities
– Selection of Solvents to remove impurities depends on the properties of
impurities.
– Impurities of acidic nature can be removed by adding saturated
aqueous solution of a Strong Base in the organic extract. E.g. Acetic
Acid (A Weak Acid) can be removed by adding saturated aqueous
solution of NaHCO3 in Ether extract of Phenol acetate.
– As a result, Sodium acetate will be formed which is salt of Acetic Acid
and soluble in water from the saturated aqueous solution of NaHCO3.
• Impurities of basic nature can be removed by adding dilute
solution of Strong Acids in the organic extract. E.g.
Triethylamine (A base) can be removed by adding 10% HCl
aqueous solution in Ether extract of Phenol acetate. As a result,
Triethylamine hydrochloride will be formed which is salt of
Triethylamine and soluble in water.
Difference between LLE and LLW
Topic Liquid – Liquid Extraction Liquid – Liquid Washing
Target Compound Extracted by Organic Solvent Remains in the Organic Solvent

Solvent Evaporation Performed to collect and measure the Target solute Not required because Impurities are removed

Solubility of Target Solubility of the target compound in organic solvent Solubility of the target compound in organic
Solute must be higher than in aqueous solvent solvent must be higher than the solubility of
impurities

Selection of Solvents Depends on Miscibility, Solubility and Density of the Depends on the properties of impurities
solvent pair

Contents in the Only Target Solute Target Solute + Impurities (Byproduct +

extract Catalyst)