This is a complete chapter of Solubility of Drugs.

1. SOLUBILITY OF
DRUGS
Presented by
Swati Mittal

2. Objectives of the Chapter
After completion of this chapter, the student should be
able to:
1. Understand the various types of pharmaceutical solutions.
2. Define solubility, saturated & unsaturated solutions and polar
& non polar solvents.
3. Understand the factors controlling the solubility of strong &
weak electrolytes.
4. Definepartition coefficient &its importance in pharmaceutical
systems.

3. 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
solutions.
pharmaceutical
3. Many drugs are formulated as solutions, or added as powder or solution forms to
liquids.
4. Drugs with low aqueous solubility often present problems related to their
formulation and bioavailability.

4. 4
Definitions
• Solute: a component which dissolved in the solvent,
present in less amount in the solution.
• Solvent: a component in which solute is dissolved,
present in more amount than solute.
• Solution: A system in which solutes are completely
dissolved in solvent & form a homogenous molecular
dispersion.
• Saturated solution: Solution in which the solute in
solution is in equilibrium with solid phase.
• Unsaturated solution: Solution containing dissolved
solute in concentration below that necessary for
complete saturation.
• Supersaturated solution: Solution containing more of
the dissolved solute than it would normally contain.

5. Solubility
 In a quantitative way: it is the concentration of solute in
a saturated solution at a certain temperature.
 In a qualitative way: it is the spontaneous interaction of
two or more substances (solute & solvent) to form a
homogeneous molecular dispersion

6. Degree of saturation
Unsaturated, Saturated or Supersaturated?
How much solute can be dissolved in a solution?

7. Solubility Curve
Any solution can be made saturated, unsaturated, or supersaturated by
changing the temperature.

8. Thermodynamic solubility of
drugs
The thermodynamic solubility of a drug in a solvent is the maximum
amount of the most stable crystalline form that remains in solution in
a given volume of the solvent at a given temperature and pressure
under equilibrium conditions.
The equilibrium involves a balance of the energy of three interactions
against each other:
(1) solvent with solvent
(2) solute with solute
(3) solvent and solute

9. Steps of solid going into solution.
1. Step 1: Hole open in the solvent
2. Step 2: One molecule of the solid breaks away from the bulk
3. Step 3: The solid molecule is enter into the hole in the solvent

10. Solubility process
A mechanistic perspective of solubilization process for
organic solute in water involves the
following steps:
1. Break up of solute-solute intermolecular bonds
2. Break up of solvent-solvent intermolecular bonds
3. Formation of cavity in solvent phase large
enough to accommodate solute molecule
4. Transfer of solute into the cavity of solvent phase
5. Formation of solute-solvent intermolecular bonds

11. Enthalpy
 The enthalpy change of solution refers to the overall amountof heat
which is released or absorbed during the dissolving process (at
constant pressure).
 The enthalpy of solution can either be positive (endothermic
reaction) or negative (exothermic reaction).
 The enthalpy of solution is commonly referred to asΔH
solution.

12. Expression Symbol Definition
Molarity M, c Moles (gram molecular weights) of solute in 1 liter
(1000 ml) of solution.
Molality m Moles of solute in 1000 gm of solvent.
Normality N Gram equivalent weights of solute in 1 liter of
solution
Mole Fraction x Ration of moles of solute to total moles of solute+
solvent
Percentage by
Weight
% w/w gm of solute in 100 gm of solution
Percentage by
Volume
%v/v ml of solute in 100 ml of solution
Percentage
Weight in Volume
% w/v gm of solute in 100 ml of solution
Solubility
expressions

13. Solubility expressions
 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.
 Substances whose solubility values are not known are described by
the following terms:
Term Parts of solvent required for 1
part of solute
Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble Very
slightly soluble
Practically insoluble
Less than 1 part 1
to 10 parts
10 to 30 parts
30 to 100 parts
100 to 1000 parts
1000 to 10 000 parts
More than 10 000 parts

14. Biopharmaceutics Classification
System (BCS)
 BCS is a scientific framework for classifying Drug substances
according to their aqueous solubility and their intestinal permeability.

15. Solubility expressions: BCS
High solubility
 The highest single unit dose is completely soluble in 250 ml or less
of aqueous solution at pH 1 -6.8 (37 °C)
Xanax (alprazolam)
anxiety disorder

16. Three types of interaction in the
solution process
1. solvent –solvent interaction
2. solute –solute interaction
3. solvent solute interaction
ΔH sol = ΔH 1 + ΔH 2 + ΔH 3

17. Solvent - Solute Interactions
 In pre - or early formulation, selection of the most suitable solvent is
based on the principle of
“like dissolves like”
 That is, a solute dissolves best in a solvent with similar chemical
properties. Or two substances with similar intermolecular forces are
likely to be soluble in each others
 Polar solutes dissolve in polar solvents. E.g salts & sugar dissolve in
water .
 Non polar solutes dissolve in non polar solvents. Eg. naphtalene
dissolves in benzene.

18. POLAR SOLUTE - POLAR
SOLVENT
Ammonia Dissolves in Water:
 Polar ammonia molecules dissolve in polar water molecules.
 These molecules mix readily because both types of molecules
engage in hydrogen bonding.
 Since the intermolecular attractions are roughly equal, the molecules
can break away from each other and form new solute (NH3), solvent
(H2O) hydrogenbonds.

19. Alcohol Dissolves in Water
 The -OH group on alcohol is polar and mixes with the polar
water through the formation of hydrogenbonds.
 A wide variety of solutions are in this category such as sugarin
water, alcohol in water, acetic and hydrochloric acids.

20. Solute-Solvent interactions
 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. Example: 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. Example 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 .
form a solution. Example: NaCl in water.

21. 2
1
CLASSIFICATION OF SOLVENT & THEIR
MECHANISM OF ACTION
“LIKE DISSOLVES LIKE”
Sr.
No
Nature of
Solvent
Mechanism of solubility Example
1. Polar a. High
dielectric
constant
b. H- bond formation
c. dipole interactions
Water+ ethanol
2. Non-polar weak van der waal’s
forces
Fats, oils,
alkaloidal bases +
CCL4, benzene
3. Semi-polar induce certain degree of
polarity
Acetone increase
solubility of ether in
water

22. Polar solvents
 The solubility of a drug is due in large measure to the polarity of the solvent,
that is, to its dipole moment. Polar solvents dissolve ionic solutes and other
polar substances.
 The ability of the solute to form hydrogen bonds is a far more significant
factor than is the polarity as reflected in a high dipole moment
Water dissolves phenols, alcohols and other oxygen & nitrogen containing
compounds that can form hydrogen bonds with water.

23.  The solubility of a substance also depends on structural features such
as the ratio of the polar to the nonpolar groups of the molecule.
 As the length of a nonpolar chain of an aliphatic alcohol increases, the
solubility of the compound in water decreases
 Straight-chain monohydroxy alcohols, aldehydes, ketones, and acids
with more than four or five carbons cannot enter into the hydrogen-
bonded structure of water and hence are only slightly soluble.
Polar solvents

24. Polar solvents
 When additional polar groups are present in the molecule, as found in
propylene glycol, glycerin, and tartaric acid, water solubility increases
greatly.
Branching of the carbon chain reduces the nonpolar effect and leads to increased
water solubility.
Tertiary butyl alcohol is miscible in all proportions with water, whereas n-butyl
alcohol
dissolves to the extent of about 8 g/100 mL of water at 20°C.
tert-Butanol n-Butanol

25. Hydrogen bonding is the attractive
interaction of a hydrogen atom with
an electronegative atom, such as
nitrogen, oxygen
Dipole-dipole forces are electrostatic interactions of
permanent dipoles in molecules.

26. Non polarsolvents
 Non-polar solvents are unable to reduce the attraction between the ions
of strong and weak electrolytes because of the solvents' low dielectric
constants.
 They are unable to form hydrogen bonds with non electrolytes.
 Non polar solvents can dissolve non polar solutes through weak van der
Waals forces
 Example: solutions of oils & fats in carbon tetrachloride or benzene.
Polyethylene glycol 400 , Castor oil

27. Semi polar solvents
 Semi polar solvents, such as ketones can induce a certain
degree of polarity in non polar solvent molecules. For
example, benzene, which is readily polarizable, becomes
soluble in alcohol
 They can act as intermediate solvents to bring about
miscibility of polar & non polar liquids.
Example: acetone increases solubility of ether in water.
Propylene glycol has been shown to increase the mutual
solubility of water and peppermint oil and of water and
benzyl benzoate

28. Solvation / Dissolution
2
8
“ Interaction of a solute with the solvent, which leads
to stabilization of solute species in the solution”
+ve solvation energy= endothermic dissolution
-ve solvation energy= exothermic dissolution

29. Association
2
9
“ Chemical reaction in which the opposite electric
charge ions come together in solution & form a
distinct chemical entity”
Classification according to nature of interaction:
1. Contact
2. Solvent shared
3. Solvent separated

30. Types of solutions
Solutions of pharmaceutical importance include:
 Gases in liquids
 Liquids in liquids
 Solids in liquids

31. When the pressure above the
solution is released (decreases),
the solubility of the gas
decreases
As the temperature increases the
solubility of gases decreases
Solubility of gases in liquids

32. SOLUBILITY OF GASES IN LIQUIDS
Henry’s law:
‘Solubility is directly proportional to partial pressure of
gas at a constant temperature’.
S= KP
32

33. 33
SOLUBILITY OF LIQUIDS IN LIQUIDS
1. Completely miscible liquids:
E.g. Water+ ethanol, Glycerine+ Alcohol, benzene+
CCL4
2. Partially miscible liquids:
E.g. Phenol+ water.
3. Completely immiscible liquids:
E.g. Mercury+ water.

34. Solubility of liquids in liquids
 Preparation of pharmaceutical solutions involves mixing of 2 or more liquids
 Alcohol & water to form hydroalcoholic solutions
 volatile oils & water to form aromatic waters
 volatile oils & alcohols to form spirits , elixirs
Liquid-liquid systems may be divided into 2 categories:
1. Systems showing complete miscibility such as alcohol & water, glycerin &
alcohol, benzene & carbon tetrachloride.
2.
Systems showing Partial miscibility as phenol and water; two liquid layers are
formed each containing some of the other liquid in the dissolvedstate.
The term miscibility refers to the mutual solubility of the components in liquid
liquid system

35. Solubility of liquids inliquids
 Partial miscibility results when: Cohesive forces of the constituents of a mixture
are quite different, e.g. water (A) and hexane (B). A-A » B-B.
 When certain amounts of water and ether or water and phenol are mixed, two
liquid layers are formed, each containing some of the other liquid in the dissolved
state.
 The effect of temperature on the miscibility of two-component liquids is
expressed by phase diagrams.
 In the phase diagrams of two-component liquids, the mixture will have an upper
critical solution temperature, a lower critical solution temperature or both.

36. Raoult’slaw
• In ideal solutions partial vapor pressure of each
volatile constituent is equal to the vapor pressure of
the pure constituent multiplied by its mole fraction
in the solution.
• Thus, for two constituents A and B
• in which ƤA and ƤB are the partial vapor pressures of
the constituents over the solution when the mole
fraction concentrations are XA and XB respectively

37. Vapor
pressure-
composition
curve foran
idealsolution
(binary
mixture)

38. DeviationfromRaoult’sLaw
(Henry'slaw)
• Negative
• Positive

39. Positive deviationfrom
Raoult’sLaw
• When the interaction between A and B
molecules is less than that between
molecules of the pure constituents (A-A
or B-B), the presence of B molecules
reduces the interaction of the A-A
molecules correspondingly reduce the B- B
interaction.
• Accordingly, the dissimilarity of polarities
or internal pressures of the constituents
results in a greater escaping tendency of
both the A and the B molecules. The
partial vapor pressure of the constituents
is greater than that expected from
Raoult's law, and the system is said to be
positive deviation.
• E.g. Benzene + Ethyl Alcohol

40. Negative deviation from
Raoult’sLaw
• Negative deviation: When the
"adhesive" attractions
between molecules of
different species exceed the
"cohesive" attractions
between like molecules, the
vapor pressure of the
solution is less than that
expected from Raoult's ideal
solution law, and negative
deviation occurs
• E.g. Chloroform + Acetone

41. NegativedeviationfromRaoult’sLaw
• The vapor pressure-composition relationship of the
solute(Chloroform) cannot be expressed by
Raoult's law, but instead by an equation known as
Henry's law (Chloroform + Acetone)
•Ƥsolute = ksolute Xsolute
• Henry’s law applies to the solute and Raoult's
applies to the solvent in dilute solutions of real
liquid pairs

42. Idealandrealsolutions
Ideal Solution
• Ideal Solution is one in
which there is no attraction
between solute and solvent
molecules.
• Ideal solution is one in
which there is no change
in the properties of the
components, other than
dilution.
• They obey Raoult’s law
Real Solutions
• In real solutions the
"cohesive“ force of attraction
between A for A exceeds the
"adhesive" force of attraction
existing between A and B.
• Alternatively, the attractive
forces between A and B may
be greater than those between
A and A or B and B. This
• may occur even though the
liquids form solution in all
proportions. Such mixtures
are real or non-ideal
• They do not obey Raoult's law

43. IDEAL SOLUTIONS
“ Solutions which obey Raoult’s law in all the
solute composition in a solvent”
43

44. REAL/ NON IDEAL SOLUTIONS
“Solutions which do not obey Raoult’s law over entire
range of composition”
Negative deviation
PA< Xa P
△H < 0
△V < 0
Positive deviation
PA> Xa P
△H > 0
△V > 0 14

45. Azeotropicbinarymixture
• It is the mixture of liquids that has a constant
boiling point because the vapour has the same
composition as the liquid mixture.
• The boiling point of an azeotropic mixture may
be higher or lower than that of any of its
components.
• The components of the solution cannot be
separated by simple distillation

46. AZEOTROPES
(Constant boiling mixtures)
MINIMUM
BOILING
AZEOTROPES
+ve deviation from Raoult’s law 46
MAXIMUM
BOILING
AZEOTROPES
-ve deviation from Raoult’s law

47. PartialMiscibility
Partiallymiscible liquids are influenced by the
temperature.The two conjugate phases changed to a
homogenous single phase at the critical solution
temperature
47
Some liquid pairs (e.g.
trimethylamine and
water) exhibit a
lower consolute
temperature, below
which the two
members are soluble
in all proportions
and above which two
separate layers form.

48. PartialMiscibility
Few mixtures (e.g. nicotine
and water) show both
an upper and a lower
consolute temp. with
an intermediate temp.
region in which the
two liquids are only
partially miscible.
A final type exhibits no
critical solution
temperature (e.g. ethyl
ether and water shows
partial miscibility over
the entire temperature
range at which the
mixture exists.
48

49. FACTORS INFLUENCING SOLUBILITY OF
SOLID IN LIQUID
1. Temperature
2. Nature of solvent ( like dissolves
like)
3. Pressure
4. pH
5. Particle size
6. Crystal structure
7. Molecular structure
8. Solute- solvent interactions
9. Addition of substituent
10. Common ion effect
11.Solubilizingagent 9

50. Temperature
• Most solids dissolve with absorption of heat and the
solubility of such solids increases as the temperature
increases, e.g., solubility of NaCl, NaNO3, KNO3in
water increases with temperature.
• For solids which dissolve with the evolution of heat,
increase in temperature causes a decrease in
•
solubility, e.g., solubility of Ca(OH)2 in water.
Effect of temperature on the solubility of soilds can be
represented by the use of ‘solubility curve’.

51. Particle size
• The particle size of the solids also affects
its solubility in a given solvent. Generally, a
decrease in the particle size causes an
increase in the solubility. This is because a
decrease in particle size results in increase
in surface area and surface free energy
which increases solubility.

52. Molecular structure
modifications
• Slight modification in the molecular structure of solids
may lead to marked changes in their solubility in the
given solvent. For example, if a weak acid ( CH3COOH
→weak electrolyte, poor soluble) is
converted into its salt (CH3COONa), its ionic dissociation
in water increases markedly leading to an increase in the
interaction between the solute and
the solvent which ultimately leads to an increase in the
solubility.

53. • Solubility can also be decreased by modifications such as
esterification.
ESTERIFICATION
•
•
Chloramphenicol (antibiotic) ------------------
-----→
Soluble
Chloramphenicol palmitate
Poor Soluble
• Such a decrease in solubility is sometimes beneficial in pharmaceutical
practice since this decrease in solubility helps in taste masking of
certain drugs such as chloramphenicol (very bitter) to chloramphenicol
palmitate (tasteless).

54. Common ion effect
• “The process in which solubility of a weak
electrolyte is reduced by the addition of a
strong electrolyte which has common ion to
that of weak electrolyte”.
• Ionization of sodium chloride in water can
be represented by equilibrium constant
expression as:

55. NaCl (
S
O
L
I
D
)↔ Na+ (
a
q) + Cl -
(a
q
)
Kc = [Na+] [Cl-] / [NaCl]
HCl ionizes in water as: HCl
↔
H+(aq)+ Cl-
(aq)
•On passing HCl gas through aqueous solution of NaCl
, concentration of Cl- ions is increased, therefore some
of the NaCl is precipitated out to maintain the constant
value of the equilibrium constant. This is called as
common ion effect which reduces solubility.

56. Effect of surfactants
(solubilising agent):
• Solubility of poor soluble drugs may be enhanced
by a technique known as micellar solubilisation,
which involves the use of surfactants for
increasing the solubility.
• When a surfactant having a hydro-philic (water
loving) and a lipo-philic (or hydrophobic
→water hating) portion is added to a liquid, it re-
arranges itself to from a spherical aggregate known
as micelle

57. • In aqueous medium, the surfactant
molecule orientate in such a manner that
their hydrophilic portion faces the water
and the lipophilic portion (hydro- phobic)
resides in the micellar interior. An insoluble
compound added to the surfactant liquid,
enters the micelle interior and gets
solubilised.

59. • Similarly, In non- aqueous medium (e.g.
oil), the surfactant molecule orientate in
such a manner that their hydrophobic
portion faces the non-aqueous liquid and
the hydrophilic portion resides in the
micellar interior. An insoluble compound (
such as water) added to the surfactant
liquid, enters the micelle interior and gets
solubilised.

62. 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 representsconcentration,
we can write the distribution law as
C1/C2 = S1/S2 = KD
where S1 and S2 are the solubilities of the solute in the two solvents.
Hence knowing the value of the Distribution coefficient (KD) and the solubility of
solute in one of the solvents, the solubility of solute in the second solvent can be
calculated.

65. APPLICATION OF DISTRIBUTION LAW
 There are numerous applications of distribution law in the
laboratory as well as in industry
(1) Solvent Extraction-
This is the process used for the separation of organic
substances from aqueous solutions. The aqueous solution is
shaken with an immiscible organic solvent such as ether (or
benzene) in a separatory funnel. The distribution ratio being in
favour of ether, most of the organic substance passes into the
ethereal layer. The ethereal layer is separated and ether distilled
off. Organic substance is left behind.

66. 2) Partition Chromatography
A paste of the mixture is applied at the top of a column of
silica soaked in water. Another immiscible solvent ( hexane)
is allowed to flow down the column. Each component of the
mixture is partitioned between the stationary liquid phase
(water) and the mobile liquid phase (hexane). The various
components of the mixture are extracted by hexane in order
of their distribution coefficients.

67. (3) Desilverization of Lead (Parke’s Process)
When molten zinc is added to molten lead containing silver
(argentiferous lead), zinc and lead form immiscible layers and
silver is distributed between them. Since the distribution ratio
is about 300 in favour of zinc at 800º C, most of silver passes
into the zinc layer. On cooling the zinc layer, an alloy of silver
and zinc separates. The Ag-Zn alloy is distilled in a retort
when zinc passes over leaving silver behind. The lead layer
still contains unextracted silver. This is treated with fresh
quantities of molten zinc to recover most of the silver

68. (4) Confirmatory Test for Bromide and Iodide
The salt solution is treated with chlorine water. Small quantity
of bromine or iodine is thus liberated. The solution is then
shaken with chloroform. On standing chloroform forms the
lower layer. The free bromine or iodine being more soluble in
chloroform concentrates into the lower layer, making it red for
bromine and violet for iodine.

69. 5)Determination of Association
When a substance is associated (or polymerized) in solvent A
and exists as simple molecules in solvent B, the Distribution law
is modified as
n√Ca/Cb = k
when n is the number of molecules which combine to form an
associated molecule.

70. (6) Determination of Dissociation
Suppose a substance X is dissociated in aqueous layer and exists assingle
molecules in ether.
If x is the degree of dissociation (or ionisation), the distribution law is modified
as
C1 /C2 )(1-x) = K
where C1 = concentration of X in benzene
C2 = concentration of X in aqueous layer
The value of x can be determined from conductivity measurements, while C1
and C2 are found experimentally. Thus the value of K can be calculated. Using
this value of K, the value of x for any other concentrations of X can be
determined.

71. (7) Determination of Solubility
Suppose the solubility of iodine in benzene is to be determined.
Iodine is shaken with water and benzene. At equilibrium
concentrations of iodine in benzene (Cb) and water (Cw) are
found experimentally and the value of distribution coefficient
calculated.
Cb / Cw = Kd
Sb/ Sw = Kd
where Sb = solubility in benzene; and Sw = solubility in water.

72. 72
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