Solubility Expression, Ideal Solubility Parameters, Solubility of Gas in Liquids, Solubility of Liquids in Liquids.

1. PREPARED BY – JUHI BHADORIA
DESSIGNATION – ASSITANT PROFESSOR
TOPIC- SOLUBILITY OF DRUGS
INDORE MAHAVIDHAYALA

2. SOLUBILITY OF DRUGS

3. +
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. Define partition coefficient & its importance in pharmaceutical
systems.

4. +
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. Have information about the structure and intermolecular forces of the
drug.
4. Many drugs are formulated as solutions, or added as powder or solution
forms to liquids.
5. Drugs with low aqueous solubility often present problems related to their
formulation and bioavailability.

5. +
DEFINITIONS
 Solution: is a mixture of two or more components that form a homogenous
mixture. The components are referred to the solute and/or solutes & the
solvent and/or solvents .
 Solute: is the dissolved agent . (less abundant part of the solution )
 Solvent : is the component in which the solute is dissolved (more abundant
part of the solution).
 A saturated solution: is one in which an equilibrium is established between
dissolved and undissolved solute at a definite temperature. Or A solution that
contains the maximum amount of solute at a definite temperature
 An unsaturated solution: or subsaturated solution is one containing the
dissolved solute in a concentration below that necessary for complete
saturation at a definite temperature.

6. +
SOLUBILITY
 A supersaturated solution: contains more of the dissolved solute
than it would normally contain in a saturated state at a definite
temperature.
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

7. +
DEGREE OF SATURATION
Unsaturated, Saturated or Supersaturated?
 How much solute can be dissolved in a solution?

8. +
SOLUBILITY CURVE
 Any solution can be made saturated, unsaturated, or supersaturated
by changing the temperature.

9. +
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

10. +
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

11. +
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

12. +
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

13. +
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

14. +
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

15. +
BIOPHARMACEUTICS CLASSIFICATION SYSTEM
(BCS)
 BCS is a scientific framework for classifying Drug substances
according to their aqueous solubility and their intestinal permeability

16. +
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

17. +
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.

18. +
CLASSIFICATION OF SOLVENTS & THEIR MECHANISM
OF ACTION:-
1. Polar solvents
2. Non polar solvents
3. Semi polar solvents

19. +
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.

20. +
 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

21. +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

22. +
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.

23. + NON POLAR SOLVENTS
 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

24. + 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

25. +
POLARITY AS DIELECTRIC CONSTANT OF SOLVENT,
Ε DECREASE , THE SOLUBILITY ALSO DECREASE

26. +

27. +
POLARITY
 The solubility of the drug substance is attributable in large part to the
polarity of the solvent, often expressed in terms of dipole moment,
related to the dielectric constant.
 Solvents with high dielectric constants dissolve ionic compounds
(polar drugs) readily because of ion–dipole interactions,
 Solvents with low dielectric constants dissolve hydrophobic
substances (non-polar drugs)
 polar solvents, with examples such as water and glycerin;
 non-polar solvents, with example such as oils.
 Solvents with intermediate dielectric constants
semipolar.
are classified as

28. + TYPES OF SOLUTIONS
Solutions of pharmaceutical importance include:
 Gases in liquids
 Liquids in liquids
 Solids in liquids

29. +
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

30. +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 dissolved state.
The term miscibility refers to the mutual solubility of the components in liquid-liquid
systems.

31. +SOLUBILITY OF LIQUIDS IN LIQUIDS
 Complete miscibility occurs when: The adhesive forces between
different molecules (A-B) >> cohesive forces between like molecules
(A-A or B-B).
 Polar and semipolar solvents, such as water and alcohol, glycerin
and alcohol, and alcohol and acetone, are said to be completely
miscible because they mix in all proportions.
 Nonpolar solvents such as benzene and carbon tetrachloride are
also completely miscible.

32. +
SOLUBILITY OF LIQUIDS IN LIQUIDS
 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.

33. +
SOLUBILITY OF SOLIDS
IN LIQUIDS

34. +
SOLUBILITY OF SOLIDS IN LIQUIDS
FACTORS INFLUENCING SOLUBILITY
1- Particle size (surface area) of drug particles
↓Particle size → ↑ surface area→ ↑Solubility

35. +
o So is the solubility of large
particles
o S is the solubility of fine
particles
o γ is the surface tension of the
particles
o V is molar volume
o T is the absolute temperature
o r is the radius of the fine particle
o R is the gas constant
SOLUBILITY OF SOLIDS IN LIQUIDS
FACTORS INFLUENCING SOLUBILITY

36. +
EXAMPLE
 A solid is to be comminuted so as to increase its solubility by 10%,
that is s/so is to become 1.10
 What must be the final particle size, assuming that the surface
tension of the solid is 100 dynes/cm and the volume per mile is 50
cm3? The temperature is 27oC
Answer: 0.042µm

37. + 2- Molecular size
 Molecular size will affect the solubility.
 The larger the molecule or the higher its molecular weight the less
soluble the substance.
 Larger molecules are more difficult to surround with solvent
molecules in order to solvate the substance.
 In the case of organic compounds the amount of carbon branching
will increase the solubility since more branching will reduce the size
(or volume) of the molecule and make it easier to solvate the
molecules with solvent

38. +3- The boiling point of liquids and the melting point of solids:
Both reflect the strengths of interactions between the molecules in
the pure liquid or the solid state.
In general, aqueous solubility decreases with increasing boiling
point and melting point.

39. + 4-The influence of substituents on the solubility of molecules
in water can be due to their effect on the properties of the solid
or liquid (for example, on its molecular cohesion, or to the
effect of the substituent on its interaction with water molecules.
Substituents can be classified as either hydrophobic or
hydrophilic, depending on their polarity

40. +
 Polar groups such as –OH capable of hydrogen
bonding with water molecules impart high
solubility
 Non-polar groups such as –CH3 and –Cl are
hydrophobic and impart low solubility.
 Ionization of the substituent increases
solubility, e.g. –COOH and –NH2 are slightly
hydrophilic whereas –COO– and –NH3 are very
hydrophilic.
INFLUENCE OF SUBSTITUENTS ON THE
SOLUBILITY

41. +
 The position of the substituent on the molecule can influence its effect on
solubility, for example the aqueous solubilities of o-, m- and p-
dihydroxybenzenes
INFLUENCE OF SUBSTITUENTS ON THE
SOLUBILITY

42. +
5-Temperature
 Temperature will affect solubility. If the solution process absorbs energy
then the solubility will be increased as the temperature is increased.
 If the solution process releases energy then the solubility will decrease
with increasing temperature.
 Generally, an increase in the temperature of the solution increases the
solubility of a solid solute.
 A few solid solutes are less soluble in warm solutions.
 For all gases, solubility decreases as the temperature of the solution
increases.

43. +
6-Crystal properties
Polymorphic Crystals, Solvates, Amorphous forms
Polymorphs have the same chemical structure but different physical properties,
such as solubility, density, hardness, and compression characteristics
A drug that exists as an amorphous form (non crystalline form) generally
dissolves more rapidly than the same drug in crystalline form

44. +
APPLICATION
 Extraction
 Preservative action of weak acids in o/w systems
 Drug absorption/distribution/action