Solubility of drugs

Khalifa M.Asif Yunus
M.Pharm (Pharmaceutics)
J I I U ’ S
Ali-Allana College of Pharmacy Akkalkuwa
NBAAccredited
Asst. Prof.
Pharmaceutics Department
Ali-Allana college of pharmacy Akkalkuwa
E-mail: khalifa4517@gmail.com Mob. No. +91 9925064346

By: Khalifa M Asif Y Asst. Professor Pharmaceutics Dept. AACOP Akkalkuwa
Solubility of drugs: Solubility expressions, mechanisms of solute solvent
interactions, ideal solubility parameters, solvation & association,
quantitative approach to the factors influencing solubility of drugs,
diffusion principles in biological systems. Solubility of gas in liquids,
solubility of liquids in liquids, (Binary solutions, ideal solutions) Raoult’s law,
real solutions. Partially miscible liquids, Critical solution temperature and
applications. Distribution law, its limitations and applications

Importance of studying the phenomenon of solubility
Understanding the phenomenon of solubility helps the pharmacist to:
1. Select the best solvent for a drug or a mixture of drugs.
2. Overcome problems arising during preparation of pharmaceutical solutions.
3. Have information about the structure and intermolecular forces of the drug.
4. Optimize bioavailability of drug molecules.

A solution is a homogeneous mixture of two or more substances on
molecular level.
Solution
Solute:
The component of the mixture present in a
smaller amount is called the Solute.
Solvent:
The component of the mixture present in a
larger amount is called the Solvent.

Solubility
In a quantitative way:
it is the concentration of solute in a saturated solution at a certain
temperature
Or
The solubility is defined as the concentration of the solute in
solution when it is in equilibrium with the solid substance at a particular
temperature
In a qualitative way:
it is the spontaneous interaction of two or more substances (solute
& solvent) to form a homogeneous molecular dispersion

Concentration of a Solution
The concentration of a solution is defined as the amount of solute present in
a given amount of solution.
 Concentration is generally expressed as the quantity of solute in a unit
volume of solution.
“A solution containing a relatively low concentration of solute is called Dilute
solution.”
“A solution of high solute concentration is called Concentrated solution.”

An unsaturated solution contains just below the maximum quantity of
solute that dissolves at a given temperature in a specific amount of solvent.
A saturated solution contains the maximum quantity of solute that dissolves
at that temperature for a given quantity of solvent.
Super saturated solutions contain more solute than is possible for a given
quantity of solvent and are unstable.

Types And Examples Of Solutions

Solubility Expressions
1. Quantitative Expressions
2. Pharmacopoeial Expressions
3. Pharmaceutical compendia

1. Quantitative Expression
a. Percent Concentration
b. Molarity
c. Molality
d. Mole fraction

Percent (%) Concentrations
Percent concentrations are mass of solute to solution relationships.
(Weight/weight) x 100 = (w/w)%
(Weight/volume) x 100 = (w/v)%
(Volume/volume) x 100 = (v/v)%
Examples:
4.0 (w/v)% has 4.0 grams of solute in 100.0 mL of solution.
8.5 (v/v)% has 8.5 mL of solute in 100.0 mL of solution.
12.0 (w/w)% has 12.0 grams of solute in 100.0 grams of solution.

solutionofliters
soluteofmoles
)M(Molarity 
glycolethyleneM10.0solutionL0.2
glycolethylenemol20.0

Molarity
The molarity of a solution is the moles of solute in a liter of solution.
For example, 0.20 mol of ethylene glycol dissolved in enough water to
give 2.0 L of solution has a molarity of

For example, 0.20 mol of ethylene glycol dissolved in 2.0 x 103 g (= 2.0 kg)
of water has a molality of
solventofkilograms
soluteofmoles
)(molality m
glycolethylene10.0solventkg0.2
glycolethylenemol20.0
m
Molality
The molality of a solution is the moles of solute per kilogram of solvent.

solutionofmolestotal
Asubstanceofmoles
A 
Mole Fraction
The mole fraction of a component “A” (A) in a solution is defined as the
moles of the component substance divided by the total moles of solution
(that is, moles of solute and solvent).
For example, 1 mol ethylene glycol in 9 mol water gives a mole fraction for
the ethylene glycol of 1/10 = 0.10.

 The USP lists the solubility of drugs as: the number of ml of solvent in
which 1g of solute will dissolve.
E.g. 1g of boric acid dissolves in 18 mL of water, and in 4 mL of glycerin
2. Pharmacopoeial Expressions

 Substances whose solubility values are not known are described by the
following terms:
Very soluble Less than 1 part
Freely soluble 1 to 10 parts
Soluble 10 to 30 parts
Sparingly soluble 30 to 100 parts
Slightly soluble 100 to 1000 parts
Very slightly soluble 1000 to 10 000 parts
Practically insoluble More than 10 000 parts
Parts of solvent required to dissolve 1 part of solute
3. Pharmaceutical compendia

Solute-Solvent interactions
 Solubility depends on chemical, electrical & structural effects that
lead to mutual interactions between the solute and the solvent.
 selection of the most suitable solvent is based on the principle of
“like dissolves like”. That is, a solute dissolve best in a solvent with
similar chemical properties. i.e.
 Polar solutes dissolve in polar solvents. E.g. salts & sugar
dissolve in water.
 Non polar solutes dissolve in non polar solvents. E.g. naphtalene
dissolves in benzene.

Step-1
Breaking of the solute-solute
bond to permit removal of solute
molecules from the solid state
Step-2
Formation of void within the
solvent to accumulate the
separated solute molecule.
Step-3
insertion of the displaced solute
in the solvent void, resulting in
solvation of solute

1. Polar solvents: These are made-up of strong dipolar molecules and
having hydrogen bonding.
E.g. water, hydrogen peroxide
1. Polar solvents
2. Non polar solvents
3. Semi polar solvents
Classification of solvents & their mechanism of action

1. Dielectric constant:
 Due to their high dielectric constant, polar solvents reduce the force
of attraction between oppositely charged ions in crystals.
Example:
 Water possessing a high dielectric constant-80 can dissolve NaCl.
 Chloroform-5 & benzene-2 cannot dissolve NaCl. Ionic compounds are
practically insoluble in these 2 solvents.
Polar solvents acts as a solvent according to the following mechanisms:

2. Breaking covalent bond & Hydrogen bond formation:
 Polar solvents break covalent bonds of potentially strong electrolytes by
acid-base reactions because these solvents are amphiprotic.
E.g. water brings about the ionization of HCI as follows:
HCl + H2O → H3O+ + Cl -
 Weak organic acids are not ionized appreciably by water; their partial
solubility is attributed instead to the hydrogen bond formation with
water.

3. Solvation through dipole interaction:
 Polar solvents are capable of solvating molecules & ions through dipole
interaction forces. The solute must be polar to compete for the bonds of
the already associated solvent molecules.
E.g. Ion-dipole interaction between sodium salt of oleic acid & water
Water dissolves phenols, alcohols and other oxygen & nitrogen containing
compounds that can form hydrogen bonds with water.
C17-H33-----C-----O- Na+ + n + H2O - Na+
C17-H33-----C-----O-
+

Consider the forces of attraction between solute and solvent molecules.
If the solvent is A & the solute is B, and the forces of attraction are
represented by A-A, B-B and A-B, one of the following conditions will occur:
1. If A-A >> A-B: The solvent molecules will be attracted to each other
& the solute will be excluded.
E.g. Benzene & water, where benzene molecules are unable to
penetrate the closely bound water aggregates.

2. If B-B >> A-A: The solvent will not be able to break the binding
forces between solute molecules;
E.g. NaCl in benzene, where the NaCl crystal is held by strong
electrovalent forces which cannot be broken by benzene.
3. If A-B >> A-A or B-B or the three forces are equal: The solute will
disperse & form a solution.
E.g. NaCl in water

The 4 OH groups make the molecule
highly polar, and it will also H bond
to water.
Vitamin C is water soluble.
The 2 C=O groups are polar, but
their geometric symmetry suggests
their pulls will cancel and the
molecule will be Non-polar.
Vitamin K3 is fat soluble.
Which Is Soluble in Water?

Non polar solvents
 Non polar solvents are unable to reduce the attraction between
the ions due to their low dielectric constants.
 They are unable to form hydrogen bonds with non electrolytes.
 Non polar solvents can dissolve non polar solutes through weak
vander-waals forces
Example: solutions of oils & fats in carbon tetrachloride or benzene.

Semi polar solvents
 Semi polar solvents, such as ketones can induce a certain
degree of polarity in non polar solvent molecules.
 They can act as intermediate solvents to bring about
miscibility of polar & non polar liquids.
Example: acetone increases solubility of ether in water.

Solvation
 The process of solvation is sometimes called dissolution. Solvation is a
kinetic process and is quantified by its rate.
 It is the attraction and association of molecules of a solvent with
molecules or ions of a solute.
 When a solute is soluble in a certain solvent, the solute's molecules or
ions spreads out and became surrounded by solvent molecules.
 A complex formed of molecule or ion of solute in a solvent is known as a
solvation complex.

“ Solvation is the process of rearranging solvent and solute molecules into
solvation complexes to distribute solute molecules evenly within the
solvent.”
 Solvation of a solute by water is called hydration.

Association
“Association or ion association is a chemical reaction wherein ions of opposite
electrical charge come together in solution to form a distinct chemical entity.”
 Ion associates are classified, according to the number of ions that associate
with each other, as ion pairs, ion triplets etc.
 Ion pairs are also classified according to the nature of the interaction as
contact solvent-shared or solvent-separated.
 Ion associates have been characterized by means of vibrational spectroscopy.

There are three distinct types of ion pairs depending on the nature of the
interaction
When both ions have a complete primary solvation
sphere, the ion pair may be termed fully solvated.
When there is about one solvent molecule between
cation and anion, the ion pair may be termed solvent-
shared.
When the ions are in contact with each other, the ion
pair is termed a contact ion pair.

Diffusion is defined as a process of mass transfer of individual molecules of
a substance.
 Diffusion is Migration of solute molecules from higher concentration to
lower concentration (i.e. Concentration gradient) to achieve equilibrium.
 In absence of external forces (such as agitation), the migration of solute
molecules measures the escaping tendency of solute.
 In case of osmosis escaping tendency of solvent molecules is
measured.
 In case of diffusion escaping tendency of solute molecule is measured.
Diffusion

 In pharmacy diffusion through natural barrier or polymeric barrier is
important.
The term barrier is applied to region or regions that offer resistance to
the passage of materials.
 Membrane is film separating the phases which may be porous, channeled
or non porous.
 The material that undergoes the transport is known as Diffusant or
permeant or penetrant.

Application
1. The release of drugs from dosage forms is diffusion controlled.
2. Molecular weight of polymer can be estimated.
3. Transport of drug from GIT, skin, etc., can be understood & predicted
through diffusion studies.
4. Diffusion of drugs into tissue and their excretion through kidneys can be
predicted.
5. The processes such as dialysis, microfiltration, ultrafiltration, hemodialysis,
osmosis, etc., use the principle of diffusion.

Transport cell
Diffusion of molecules is estimated by using transport cell.
Membrane
High conc. Low conc.
Donor
compartment
Receptor
compartment
Transport cell is used to study the diffusion Which consists of donor and
receptor compartment separated by membrane. Permeant dissolved in solvent
and placed in donor compartment. Vehicle is placed in receptor compartment.
The permeant get transported in to receptor comportment through membrane

timeareaatomsJ //
 In diffusion, molecules (mass) get transported from one compartment
to another over a period of time i.e. Rate of mass transfer (dM/dt)
 Rate of mass transfer (dM/dt) expressed as flux(J)
 Flux (J) is the rate of mass transfer across a unit surface area of a
barrier.
 Mathematically expressed as:
Fick’s first law
Flux

 Units for flux are g.cm -2sec -1 OR kg .meter -2sec -1
 Flux is always positive quantity because it increases continuously during process
)1...(..........
1
dt
dM
S
J 
dM = Change in mass of material, g
S = Surface area.cm2
dt = Change in time. sec

dx
dc
J   2..............
dx
dc
DJ 
gradientconctimeareaatomsJ .// 
Fick’s first law states that the flux is directly proportional to the concentration
gradient
Negative sign indicates a decrease in concentration But flux is positive quantity
dc = Change in conc. of material g/cm3.
D = Diffusion coefficient of a penetrant, cm/sec2.
dx = Change in the distance, cm.
Fick’s first law

 3.....
dx
dc
DS
dt
dM

dx
dc
D
dt
dM
S
J 
1
D is effected by temperature, pressure etc. hence it is not constant it is
coefficient
Combining Equation (1) & (2),
OR
Equation 3 explains Rate of mass transfer as per Fick's first law

dx
dc
DS
dt
dM

No. of atoms
crossing area A
per unit time
Cross-sectional area
Concentration gradient
Mass transport is down the concentration gradient
Diffusion coefficient/ diffusivity
Diffusion coefficient: The quantity of a substance that is diffusing from one
region to another passes through each unit of cross section per unit of time
with respect to concentration gradient called also diffusivity

Application of Fick's first law
 Used to explain drug diffusion across biomembranes with desirable
parameters
 Applied in the design of sustained and controlled release systems

 It explains the change in concentration with time at a definite location
with respect to x, y and z axes(or direction)
Fick’s second law states that the change in concentration with time in a
particular region is proportional to the change in the concentration
gradient at that point of time
X
Z
Y Jy
Jx
Jz
Fick’s second law


















2
2
2
2
2
2
z
C
y
C
x
C
D
t
C
Fick’s second law refers to change in concentration of Diffusant with time at
any distance, x, i.e. non steady state flow.

Types of solutions
Solutions of pharmaceutical importance include:
1. Gases in liquids
2. Liquids in liquids
3. Solids in liquids

The solubility of a gas in a liquid is expressed as concentration of the
dissolved gas, when it is in equilibrium with the pure gas above the
solution.
Solubility of Gases in Liquids
Applications
 Preparation of reagents
 Preparation of carbonated Beverages
 Solubility of oxygen in blood
 Transportation of Anaesthetics gas in blood

The solubility of a gas in a liquids depends on:
1. Pressure
2. Temperature
3. Presence of salts
4. Chemical interaction with the solvent
Factors influencing Solubility of Gases in Liquids

Watch this video for better understanding
https://www.youtube.com/watch?v=sGymNfFReeM

 The solubility of a gas in a solvent depends on the pressure and the
temperature. When a gas is enclosed over its saturated solution, the
following equilibrium exists.
Gas ⇋ Gas in solution
 If pressure is increased on the system, the equilibrium will move in the
direction which will reduce the pressure.
 The solubility or concentration of a gas in a given solvent is increased
with increase of pressure.
Effect of pressure

A kinetic molecular explanation of the effect of pressure on gas-solution
system is illustrated in Fig.

 Henry’s law is, in fact, a form of Distribution law.
 If a vessel containing a liquid and a gas is shaken, at equilibrium the gas will
distributed between the liquid (Phase A) and the space above (Phase B).
Henry’s Law

https://www.youtube.com/watch?v=3OJauU6DJik&t=35s

It may be stated as : “for a gas in contact with a solvent at constant
temperature, concentration of the gas that dissolves in the solvent is directly
proportional to the pressure of the gas.”
Henry’s Law
 Henry’s law expresses the relationship between pressure and solubility of
a gas in liquid.

a) CO2 gas at 4 atm in equilibrium with dissolved CO2 resulting in high solubility of CO2 ;
b) In opened bottle pressure is released to 1 atm and hence equilibrium shifted upward,
gas bubbles evolved causing effervescence;
c) Partial pressure of CO2 in air being 0.001 atm, practically the whole of CO2 is removed
from solution, leaving the soft drink flat as the equilibrium is established.
a b c

Mathematically, Henry’s Law may be expressed as
C ∝ P
or C = k P
Where;
P = pressure of the gas
C = concentration of the gas in solution
k = proportionality constant known as Henry’s Law Constant.

Limitations of Henry’s Law
It applies closely to gases with nearly ideal behaviour.
1. At moderate temperature and pressure.
2. If the solubility of the gas in the solvent is low.
3. The gas does not react with the solvent to form a new species. Thus
ammonia (or HCl) which react with water do not obey henry’s law.
4. The gas does not associate or dissociate on dissolving in the solvent.

 Temperature also influences the solubility of gas in a liquid. As the
temperature increases, the solubility of gases decreases.
 This is due to ;
 Tendency of gases to expand,
 Increases in the pressure at the elevated temperatures.
Effect of Temperature
Application
 Dissolved gases are removed by heating.
 Distilled water is maintained at 80ºC in order to
make it convenient for parenteral use.

 Addition of other substances lowers the solubility of gas in a liquid.
 E.g. when a small amount of salt is added to carbonated solution, the gas
escaped from the solution. This phenomenon is known as salting out.
 In the gaseous solution, attraction between the gas and solvent is
effective. When the electrolytes are added, they established greater
attraction with water molecules. Therefore, gas releases.
Effect of Salts
Application
 Importance to stabilize Aqueous solution of Vitamin-A.
 High sugar concentration decreases the solubility of oxygen so that
substances liable to oxidation are better protected.

 Gases such as HCl, NH3, and CO2 show deviation as a result of chemical
reaction between gas and solvent.
 For these systems henry’s law is not applicable.
 Due to chemical reaction, the solubility of gases is higher.
 Example; HCl is about 10,000 times more soluble in water than in liquid
oxygen.
Effect of Chemical Reaction
Application
 These principles are used for the preparation of a reagents such as
concentrated solutions namely HCl, H2SO4, HNO3

Solubility of liquid in liquid
 The solutions of liquids in liquids may be divided into three classes as
follows :

Ideal solutions
Ideal solution is defined as a solution in which there is no change in the
properties of the components other than dilution when they are mixed to form
the solution
 Molecules exhibit complete freedom of motion and randomness of
distribution in the solution.
Example:
Equal volume of methanol & Ethanol is mixed, the final volume is the sum of
volume of both
Ideal & Real solutions

Characteristics
 The volume change due to mixing of solute with solvent should be zero
 Final volume of the solution is simply sum of the volumes of its constituents
 There is no contraction or expansion when they are mixed.
 The enthalpy change due to mixing of solute in a solvent must be zero
 solute and solvent molecules having same type of intermolecular attraction.
 No heat is absorbed or evolved during mixing of the components.
 Solute molecules should neither dissociate nor associate in the solution.

Real solutions
Real solution is defined as a solution which shows change in the total volume
of solution upon mixing its different components together
Example:
At room temperature when 100ml of H2SO4 is mixed with 100ml of H2O, the
total volume becomes 180ml rather than 200ml.
 During mixing acid & water heat is evolved, causing reduction in total
volume of solution

Solubility of completely miscible liquids
 Liquids like alcohol and ether mix in all proportions and in this respect
they could be compared to gases.
 The properties of such solutions, however, are not strictly additive, and
therefore their study has not proved of much interest.
 Generally the volume decreases on mixing but in some cases it
increases. Sometimes heat is evolved when they are mixed while in
others it is absorbed.
 The separation of this type of solutions can be effected by fractional
distillation.

Solubility of partially miscible liquids
 A large number of liquids are known which dissolve in one another only to a
limited extent e.g., ether and water.
 Ether dissolves about 1.2% water; and water also dissolves about 6.5%
ether. Since their mutual solubilities are limited, they are only partially
miscible.
 When equal volumes of ether and water are shaken together, two layers are
formed, one of a saturated solution of ether in water and the other of a
saturated solution of water in ether.
 These two solutions are referred to as conjugate solutions.

 The left hand side of the parabolic
curve represents one of the two
conjugate solutions which depicts the
% of phenol dissolved in water at
various temperatures.
 The solubility of phenol increases
with temperature.
The curve in Fig. represents the miscibility of phenol and water.
Phenol-Water System
100
10050
50
0
Temperature(ºC)
% W/W of phenol in water

 The right hand side of the curve
represents the other conjugate
solution layer that gives the % of
water in phenol.
 The solubility of water in phenol
also increase with increase of
temperature.
The curve in Fig. represents the miscibility of phenol and water.
100
10050
50
0
Temperature(ºC)
% W/W of phenol in water

 The two solution curves meet at the maxima on the temperature-
composition curve of the system. This point here corresponds to
temperature 66°C and composition of phenol as 33%.
 Thus at a certain maximum temperature the two conjugate solutions
merge, become identical and only one layer results.
The temperature at which the two conjugate solutions (or layers) merge into
one another to from one layer, is called the Critical Solution Temperature (CST)
or Upper Consulate Temperature.
 The determination of critical solution temperature used for testing the
purity of phenol and other such substances.

 When a nonvolatile solute is dissolved in solution, the presence of
solute molecules in the surface blocks a fraction of the surface where
no evaporation can take place.
 This causes the lowering of the vapour pressure.
Lowering of vapour pressure

Raoult’s Law
The vapour pressure of a pure solvent is decreased when a non-volatile
solute is dissolved in it.
If p is the vapour pressure of the solvent and p that of the solution, the
lowering of vapour pressure is (p – ps).
This lowering of vapour pressure relative to the vapour pressure of the
pure solvent is termed the Relative lowering of Vapour pressure.
Thus, Relative Lowering of Vapour Pressure = (p – ps)/p

As a result of extensive experimentation, Raoult (1886) gave an empirical
relation connecting the relative lowering of vapour pressure and the
concentration of the solute in solution. This is now referred to as the
Raoult’s Law.
It states that : the relative lowering of the vapour pressure of a dilute
solution is equal to the mole fraction of the solute present in dilute
solution.

Ideal Solutions and Deviations from Raoult’s Law
A solution which obeys Raoult’s law strictly is called an Ideal solution.
A solution which shows deviations from Raoult’s law is called a Non-ideal
or Real solution.
 Suppose the molecules of the solvent and solute are represented by A
and B respectively.
 Now let γAB be the attractive force between A and B, and γAA between A
and A.

If γAB= γAA
 The solution will show the same vapour pressure as predicted by Raoult’s
law and it is an ideal solution.
If γAB> γAA
 Molecule ‘A’ will escape less readily and the vapour pressure will be less
than that predicted by Raoult’s law (Negative deviation).
if γAB< γAA
 Molecule ‘A’ will escape from the solution surface more readily and the
vapour pressure of the solution will be higher than predicted by Raoult’s
law (Positive deviation).

Solubility of Solids in liquid
Solubility of salts in water
Solubility of slightly soluble Electrolyte
Solubility of Weak Electrolytes.

Solubility of salts in water
 Solubility of salts in water is depend on temperature, a rise in
temperature increase the solubility of a solid that absorbs heat
(endothermic) when it dissolves.
 If the solution process is exothermic, i.e. if heat is evolve, the solubility
in this case decreases with elevation of the temperature.
 Most of the solids belongs to the class of compounds that absorb heat
when they dissolve.

100
100
75
7550
50
25
250
Na2So4. 10 H2O
Na2So4
KNo3
NaCl
Solubility(g/100gwater)
Temperature (ºC)

 Sodium sulphate exist in hydrate form, Na2So4. 10H2O, up to
temperature about 50ºC, the solution process (dissolution) is
endothermic, and solubility increase with increase in temperature.
 Above this point, the compound exist in Anhydrous salt Na2So4, the
dissolution is exothermic, and solubility decreases with increase in
temperature.
 Sodium chloride does not absorb or evolve heat when it dissolve in
water; thus solubility is not altered by a change of temperature.

 When an ionic solid substance dissolves in water, it dissociates to give
separate cations and anions.
 As the concentration of the ions in solution increases, they collide and
reform the solid phase.
 Ultimately, a dynamic equilibrium is established between the solid phase
and the cations and anions in solution.
 For example, for a sparingly soluble salt, AgCl, we can write the
equilibrium equations as follows :
Solubility of slightly soluble Electrolyte

At equilibrium the solute continues to dissolve at a rate that exactly matches
the reverse process, the return of solute from the solution. Now the solution
is said to be saturated.
The Solubility (S) of a substance in a solvent is the concentration in the
saturated solution.
Solubility of a solute may be represented in grams per 100 ml of solution. It
can also be expressed in moles per litre.

Applying the Law of Mass Action to the above equilibrium for AgCl, we have;
The amount of AgCl in contact with saturated solution does not change with
time and the factor [AgCl] remains the same. Thus the equilibrium
expression becomes
where [Ag]+ and [Cl]- are expressed in mol/L.
The equilibrium constant is called the Solubility Product Constant (or simply
the Solubility Product) and is denoted by K.

The Ksp expression may be stated as :
the product of the concentration of ions (mol/l) in the saturated
solution at a given temperature is constant.

The Solubility of silver chloride in water at 20ºC is 1.34 x 10-5 mole/liter.
Sliver chloride is strong electrolyte, it completely dissociated.
Solubility product of this salt is
Ksp = (1.34 x 10-5) x (1.34 x 10-5)
= 1.8 x 10-10
If an ion in common with AgCl, that is Ag+ or Cl-, is added to solution of
silver chloride, the equilibrium is altered.
The addition of sodium chloride increase the concentration of chloride
ions so that [Ag+] [Cl-] > Ksp
And some of the AgCl precipitates from the solution until the equilibrium
[Ag+] [Cl-] = Ksp is re-established.

 Hence, addition of common ions is to reduce the solubility of slightly
soluble electrolyte.
 If the common ion forms a complex with salt the net solubility may be
increased.
 Salt having no ion in common with the slightly soluble electrolyte produce
an effect opposite to that of common ions.
 E.g. the solubility of silver chloride in 0.1M solution of ammonium
sulphate is 1.6 x 10-5 moles/liter

 To prevent precipitation of slightly soluble salt in water, some substance
can be added that will tie up & reduces the concentration of one of the
ion.
 More of the salt will then pass from undissolved to dissolve state until
the solubility product constant is reach and equilibrium is re-established.
E.g.
If the ferric ion in a solution of slightly soluble base, Fe(OH)3, can be
combined by complex formation with sodium citrate, more Fe+3 will pass
in to solution so as to keep Ksp constant. In this manner the solubility of
iron compounds is increased by citrates.
Application

Solubility of Weak Electrolytes.
 Many important drugs belongs to the class of weak acids and bases.
 They react with strong acids & bases and within definite range of pH,
exist as ions that are ordinarily soluble in water.
 Carboxylic acids containing more then 5 carbons are relatively insoluble
In water, they react with dilute sodium hydroxide, carbonates and
bicarbonates to form soluble salts.

 The fatty acids containing more then 10 carbon atoms forms soluble
soaps with alkali metals & insoluble soap with other metal ions. They
are soluble in solvents having low dielectric constant;
e.g. oleic acid (C17H33COOH) is insoluble in water but is soluble in
alcohol & ether.
 Hydroxy acids, such as tartaric acid & citric acids, are quit soluble in
water since they are solvates through their hydroxyl groups.

 Phenol is weakly acidic and only slightly soluble in water but quit
soluble in dilute sodium hydroxide solution.
 Many organic compound containing basic nitrogen e.g. alkaloids,
local anaesthetics, antihistamines are not very soluble in water but
are soluble in dilute solution of acid.
𝑪 𝟔 𝑯 𝟓 𝑶𝑯 + 𝑵𝒂𝑶𝑯 = 𝑪 𝟔 𝑯 𝟓
−
+ 𝑵𝒂+
+ 𝑯 𝟐 𝑶

Factors affecting solubility of weak electrolyte
1. Influence of pH
2. Effect of solvent on solubility of drug
3. Combined effects of pH and solvents
4. Effects of surfactants

Influence of pH
 The solubility of weak electrolytes is strongly Influenced by pH of the
solution.
E.g.
 1% Solution of phenobarbital sodium is soluble at pH values high
in alkaline range.
 Below pH 8.3 the soluble ionic form is converted in to molecular
phenobarbital.
 In order to ensure a clear homogenous solution & maximum
therapeutic effectiveness, the preparation should be adjusted to an
optimum pH.

Effect of solvent on solubility of drug
 A solute is more soluble in a mixture of solvents than in one Solution
alone. This phenomenon is known as Cosolvancy.
 The solvents that, in combination, increase the solubility of solute are
called cosolvent.
 1g of Phenobarbitol is soluble in 1000 ml water, in 10 ml alcohol, in 40
ml of chloroform, and in 15 ml of ether.

Solubility of phenobarbital in water-alcohol-glycerin mixtures

 The solubility of Phenobarbitol in water-alcohol-glycerin mixtures is
plotted on semi logarithmic graph.
 By drawing lines parallel to abscissa in fig. at hight equivalent to the
required phenobarbital concentration, it is simply calculated the relative
amounts of various combinations of alcohol, glycerin & water needed to
achieve Solution.
 E.g. at 22% alcohol, 40% glycerin, and the remainder water (38%), 1.5%
w/v of phenobarbital is dissolved.

Combined effects of pH and solvents
The solvents affect the solubility of weak electrolytes in a buffered solution in
two ways
 The addition of alcohol in buffered solution of weak electrolytes
increases the solubility of unionized species by adjusting the polarity of
solvent to a more favorable value.
 Being less polar than water, alcohol decrease the dissociation of weak
electrolytes, and the solubility of the drug goes down as the
dissociation constant is decrease.

Example:
 The pKa of phenobarbital, 7.41, is raised to 7.92 in hydrochloric
solution containing 30% by volume of alcohol.
 The solubility of unionized phenobarbital is increase from 0.12g/100
water to 0.19g/100 30% alcohol.

Effects of surfactants
 surface active agents enhance the solubility of poorly water soluble
drugs due to micelles. This phenomenon is known as Micellar
Solubilization.
Example;
Solubility of procaine is enhanced by 25% in aqueous buffer, owning to
the formation of surfactants micelles.

https://www.youtube.com/watch?v=tTIIBch_zhE&t=84s
Distribution Law

Distribution Law
 If we take two immiscible solvents A and B in a beaker, they form separate
layers.
 When a solute X which is soluble in both solvents is added, it gets
distributed or partitioned between them.
 Molecules of X will pass from solvent A to B and from solvent B to A.
Finally a dynamic equilibrium is set up.
 At equilibrium, the rate, at which molecules of X pass from one solvent to
the other is balanced.

Distribution of solute X between solvent A and B.

Statement of Nernst's distribution law
 Nernst (1891) studied the distribution of several solutes between
different appropriate pairs of solvents.
 He gave a generalization which governs the distribution of a solute
between two non-miscible solvents. This is called Nernst’s Distribution
law (or Nernst’s Partition law) or simply Distribution law or Partition
law.
“ If a solute X distributes itself between two immiscible solvents ‘A’
and ‘B’ at constant temperature and X is in the same molecular condition
in both solvents;
Concentration of X in A
Concentration of X in B
= KD

 If C1 denotes the concentration of the solute in solvent A and C2 the
concentration in solvent B,
Nernst’s Distribution law can be expressed as
C1
C2
= KD
 The constant KD (or simply K) is called the Distribution coefficient or
Partition coefficient or Distribution ratio.

Solubilities And Distribution Law
 When a solute is shaken with two non-miscible solvents, at
equilibrium both the solvents are saturated with the solute. Since the
solubility also represents concentration, we can write the distribution
law as
 where S1 and S2 are the solubilities of the solute in the two solvents.

Applications
 knowing the value of the Distribution coefficient (K) and the solubility of
solute in one of the solvents, the solubility of solute in the second
solvent can be calculated.
 Helps to predict stability of oil water system i.e. emulsion.
 Used to check and determine the association and dissociation of solute in
the solvents.
 In pharmaceutical development; to determination of types of delivery
system for newly developed drugs based on partition coefficient.
 It is a measure of a drugs hydrophobicity and an indication of its ability to
cross cell membrane.

Limitations
 Temperature and pressure can affect the solubility, hence should be
maintained constant.
 Solubility of solute should be good in both solvents.
 Mutual solubility of solute should be same in both phases.
 Mutual solubility of solvents should not altered after addition of solute.
 Applicable only for solutes which must not undergo any chemical
changes during partition.
 Applicable only for dilute solution.

Partition coefficient of Benzoic acid
https://www.youtube.com/watch?v=8hT3HW0Odxk&t=19s
Determination of Partition coefficient of Iodine
https://www.youtube.com/watch?v=TRnkyxfkGf0&t=241s
https://www.youtube.com/watch?v=Mu8B0Chj4-I&t=21s
Solubility determination by volumetric analysis
Practicals Videos

Solubility of drugs

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