LIQUID - LIQUID EXTRACTION

Liquid–liquid extraction (LLE), also known as solvent extraction and partitioning, is a method to
separate compounds or metal complexes, based on their relative solubility in two different
immiscible liquids, usually water (polar) and an organic solvent (non-polar).

Extraction is a process that separates components based upon chemical differences rather than
differences in physical properties.

Example:-
a. The separation of penicillin from the broth (the liquid phase obtained from biological
processes).
b. The separation of aromatic-ring hydrocarbons (e.g., benzene, toluene) from paraffin’s
using sulpholane.

LIQUID – LIQUID EXTRACTION

SOME IMPORTANT TERMINOLOGIES:-

1. FEED PHASE:-
a) Feed Phase is the initial solution containing the Target compound or Solute (A) and
Solvent (B).
b) In the feed phase, the solvent (C) added to perform the extraction.
c) So, 𝐅𝐞𝐞𝐝 𝐏𝐡𝐚𝐬𝐞 = 𝐒𝐨𝐥𝐮𝐭𝐞 + 𝐒𝐨𝐥𝐯𝐞𝐧𝐭 𝟏

2. EXTRACTANT AND EXTRACT:-

a) Extractant is the Solvent C that is added to the Feed Phase for extraction.
b) After extraction, the Extractant is called Extract (B+C) which contains the target
compound.
c) The Extract is evaporated to collect and measure the amount of the solute.
d) So, Before extraction, 𝐄𝐱𝐭𝐫𝐚𝐜𝐭𝐚𝐧𝐭 = 𝐒𝐨𝐥𝐯𝐞𝐧𝐭 𝟐

And, after extraction, 𝐄𝐱𝐭𝐫𝐚𝐜𝐭𝐚𝐧𝐭 = 𝐄𝐱𝐭𝐫𝐚𝐜𝐭 = 𝐒𝐨𝐥𝐯𝐞𝐧𝐭 𝟐 + 𝐒𝐨𝐥𝐮𝐭𝐞

3. RAFFINATE:-
a) Raffinate is generally, termed for the Feed Phase after extraction.
b) And if the extraction process is repeated, the Raffinate becomes the feed phase to which
the Solvent 2 is added again.
c) So, 𝐑𝐚𝐟𝐟𝐢𝐧𝐚𝐭𝐞 = 𝐅𝐞𝐞𝐝 𝐩𝐡𝐚𝐬𝐞 𝐚𝐟𝐭𝐞𝐫 𝐄𝐱𝐭𝐫𝐚𝐜𝐭𝐢𝐨𝐧 = 𝐒𝐨𝐥𝐯𝐞𝐧𝐭 𝟏 +
𝐑𝐞𝐦𝐚𝐢𝐧𝐢𝐧𝐠 𝐒𝐨𝐥𝐮𝐭𝐞
And, if the extraction process is repeated, then
𝐑𝐚𝐟𝐟𝐢𝐧𝐚𝐭𝐞 = 𝐅𝐞𝐞𝐝 𝐏𝐡𝐚𝐬𝐞 = 𝐒𝐨𝐥𝐯𝐞𝐧𝐭 𝟏 + 𝐑𝐞𝐦𝐚𝐢𝐧𝐢𝐧𝐠 𝐒𝐨𝐥𝐮𝐭𝐞.

PRINCIPLE OF LIQUID – LIQUID EXTRACTION:-

1. The basic principle behind extraction involves “the contacting of a solution with
another solvent that is immiscible with the original.”
2. The solvent is also soluble with a specific solute contained in the solution.
3. Two phases are formed after the addition of the solvent, due to the differences in densities.
4. The solvent is chosen so that the solute in the solution has more affinity toward the added
solvent. Therefore mass transfer of the solute from the solution to the solvent occurs.
Further separation of the extracted solute and the solvent will be necessary. However, these
separation costs may be desirable in contrast to distillation and other separation processes for
situations where extraction is applicable.

THEORY OF LIQUID – LIQUID EXTRACTION OR NERNST DISTRIBUTION LAW:-

Liquid – Liquid extraction follows the theory of Nernst Distribution Law / Partition Co–
efficient Law which states that –

“At a Constant / Fixed temperature, the ratio of concentration of solute in both

immiscible phases is found to be a constant.”

The Law can be expressed as –

𝑪𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏 𝒐𝒇 𝑺𝒐𝒍𝒖𝒕𝒆 𝒊𝒏 𝑶𝒓𝒈𝒂𝒏𝒊𝒄 𝑺𝒐𝒍𝒗𝒆𝒏𝒕

𝑲𝒑 =
𝑪𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏 𝒐𝒇 𝑺𝒐𝒍𝒖𝒕𝒆 𝒊𝒏 𝑨𝒒𝒖𝒆𝒐𝒖𝒔 𝑺𝒐𝒍𝒗𝒆𝒏𝒕

𝑪𝑶𝒓𝒈𝒂𝒏𝒊𝒄 𝑺𝒐𝒍𝒗𝒆𝒏𝒕
𝑲𝒑 = Where, Kp = Partition Co – efficient.
𝑪𝑾𝒂𝒕𝒆𝒓 𝒐𝒓 𝑨𝒒𝒖𝒆𝒐𝒖𝒔 𝑺𝒐𝒍𝒗𝒆𝒏𝒕

Limitation: - The Nernst distribution Law comes with 2 limitations –

1. This law is only applicable for very dilute solutions.

2. The law does not hold good when the target compound or solute is freely soluble /
distributed in both solvents. That means, for this law to be applicable, the solutes must be
affined to either of the Solvent especially to the Solvent 2.

Based on the Appropriate Partition Coefficient of an immiscible solvent pair, it is possible

to calculate the ‘Effectiveness of Liquid – Liquid Extraction’:-

Let us assume that – An Initial Feed Phase Solution contains a Solute (Target Compound) of
X mole in an Aqueous Solvent, Aaq with a volume of V2.

A second Organic Solvent, Borg with a Volume of V1 is added to the Feed Phase for extraction
of the solute.
After 1st extraction, the amount of solute remaining in Aqueous Solvent, Aaq is Y mole. So, after
extraction, amount of solute transferred to the Organic Solvent, Borg is (X – Y) mole.

Now according to Nernst Distribution Law,

𝑪𝑶𝒓𝒈𝒂𝒏𝒊𝒄
𝑲𝒑 =
𝑪𝑨𝒒𝒖𝒆𝒐𝒖𝒔

Here, COrganic = Concentration of Solute in Organic Solvent, Borg

CAqueous = Concentration of Solute in Aqueous Solvent, Aaq

Kp = Partition Co – efficient

(𝑿 − 𝒀)
𝑽𝟏
𝑲𝒑 =
𝒀
𝑽𝟐

[Because, Concentration = Amount of Substance or Solute / Volume]

(𝑿−𝒀) 𝑽𝟐
 𝑲𝒑 = ×
𝑽𝟏 𝒀

𝑿 𝑽𝟐 𝒀 𝑽𝟐
 𝑲𝒑 = (𝑽 × ) − (𝑽 × )
𝟏 𝒀 𝟏 𝒀

𝑿 𝑽 𝑽
 𝑲𝒑 = (𝒀 × 𝑽𝟐 ) − 𝑽𝟐
𝟏 𝟏

𝑽𝟐 𝑿
 𝑲𝒑 = × (𝒀 − 𝟏)
𝑽𝟏

𝑽 𝑿
 𝑲𝒑 × 𝑽𝟏 = 𝒀 − 𝟏
𝟐

𝑿 𝑽
 = 𝑲𝒑 × 𝑽𝟏 + 𝟏
𝒀 𝟐

𝒀 𝑽
 = (𝑲𝒑 × 𝑽𝟏 + 𝟏)−𝟏 _______(1)
𝑿 𝟐
 Since, X mole is the total amount of solute in Solvent Aaq as Feed Phase and Y mole is the
remaining amount of solute in solvent Aaq as Raffinate then in Equation 1, value of Y/X
mole will be a fraction or less than 1 and it is the amount of solute remaining in the Raffinate
as the un extracted form.

 Since, value of Kp is a constant for a particular solvent pair and Volume of solvents V1 and
V2 are also known then it is possible to find out value of Y / X even before performing the
extraction. Thus, it is possible to find out the Effectiveness of the Solvent Pair used in the
Liquid – Liquid Extraction.

 If the extraction process is repeated a second time by using the same solvents in the same
volume, then equation 1 can be –

𝒀 𝑽
= (𝑲𝒑 × 𝑽𝟏 + 𝟏)−𝟐 _____ (2)
𝑿 𝟐

 And, for n number of extractions the equation can be –

𝒀 𝑽
= (𝑲𝒑 × 𝑽𝟏 + 𝟏)−𝒏 _____ (3)
𝑿 𝟐
CRITERIAS OF SOLVENT SELECTION:-
PROPERTIES OF SOLUTE:-

Solutes / Target Compounds can be –

1. Organic Solute :-
a) Most Organic Solutes are soluble in Organic solvents, which can be extracted with
any organic solvents (E.g. Extraction Caffeine by Chloroform).
b) However, for both pharmaceutical and therapeutical purpose, some organic solutes
are introduced as salts in order to increase their solubility in Water, (E.g.
Promethazine hydrochloride, a hydrochloric salt of Promethazine).
c) So, before performing liquid – liquid extraction of such organic solutes, they are
converted into their original organic forms by means of a chemical reaction, so that
they can be extracted by any organic solvents (E.g. Promethazine Hydrochloride is
 converted into Promethazine before they are extracted with organic solvents like n –
hexane or Chloroform).
d) However, it is to say that upon chemical reaction the concentration of original
compound does not changes.

2. Inorganic Solute :-

a) Inorganic solutes are frequently encountered in aqueous solvents either as Impurities

or as Pharmaceutical Ingredients.
b) And before their extraction, it is absolutely necessary to form ion – association
complexes or metal – chelates (by using organic – ligands), so that they may be
extracted by an appropriate organic solvent.
c) For example, Cu (II) can be extracted by acetyl acetone by forming Cu (II) – acetyl
acetone complex.

FACTORS INFLUENCING LIQUID – LIQUID EXTRACTION:-

1. Effect of Temperature :-

a) Solubility of a compound changes according to the changes in the temperature.

b) Solubility of a Solute increases with increasing temperature.

c) In case of Liquid – Liquid Extraction, this is crucial because, differences in

temperature at any sequence of the extraction process may change the solubility of
solute in the both aqueous and organic phases.

d) And if the solubility of the solute decreases in Organic Phase but increases in
Aqueous Phase due to change in temperature change then, it will be disastrous,
because for the extraction process to be effective, the solute must have higher
solubility towards Organic Solvent.

e) So, temperature must be kept fixed during the extraction process.

2. Effect of Ph :-

a) pH is a measurement of concentration of proton present in a solution.

b) It determines whether the solution is basic, acidic or neutral.
c) The higher the pH value of a solution the fewer protons are present in it and the less
acidic or more basic it is, and vice – versa.
d) pH value of neutral solution is 7.
e) pH is expressed as the negative logarithm of Concentration of Proton.
 𝒑𝑯 = −𝑳𝒐𝒈 [𝑯+ ]
f) pH is important in Liquid – Liquid Extraction because, most drugs to be extracted are
either weak acids or weak bases which donate or accept protons respectively.
g) Since, the solvent for extraction is organic, the solute / Target Compound must be in
their extractable form (A neutral or unionized form of the solute regardless whether
the solute is a weak base or a weak acid).
h) So, pH of the Feed Phase must be adjusted by using a suitable buffer, so that the
solute remains in their neutral / unionized form.