Solubility, Solubility Expressions, BCS Classification, Solute solvent interaction, Classification of solvents, Types of solutions, solubility of gases in liquids, liquids in liquid, Raoult's law, Ideal and Non-ideal solutions, association and solvation

1. Solubility of Drugs
Ms. Punam Dilip Bagad
Assistant Professor, Dept. of Pharmaceutics
GES’s Sir Dr. M. S. Gosavi College of Pharm. Edu. & Research,
Nashik-422005, INDIA

2.  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).
 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.
 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
INTRODUCTION

3. INTRODUCTION
 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.
 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

4.  Solubility, the phenomenon of dissolution of solute in solvent to give a
homogenous system, is one of the important parameters to achieve desired
concentration of drug in systemic circulation for desired pharmacological
response.
 Low aqueous solubility is the major problem encountered with formulation
development of new chemical entities as well as for the generic
development.
 More than 40% NCEs (new chemical entities) developed in
pharmaceutical industry are practically insoluble in water. Solubility is a
major challenge for formulation scientist.
 Any drug to be absorbed must be present in the form of solution at the site
of absorption.
INTRODUCTION

5. Various techniques are used for the enhancement of the solubility of
poorly soluble drugs which include physical and chemical
modifications of drug and other methods like particle size reduction,
crystal engineering, salt formation, solid dispersion, use of
surfactant, complexation, and so forth.
Selection of solubility improving method depends on drug property,
site of absorption, and required dosage form characteristics.
Solubility is the property of a solid, liquid, or gaseous chemical
substance called solute to dissolve in a solid, liquid, or gaseous
solvent to form a homogeneous solution of the solute in the solvent.
INTRODUCTION

6.  Understanding the phenomenon of solubility helps the pharmacist to:
a. Select the best solvent for a drug or a mixture of drugs.
b. Overcome problems arising during preparation of pharmaceutical solutions.
c. Have information about the structure and intermolecular forces of the drug.
d. Many drugs are formulated as solutions, or added as powder or solution forms
to liquids.
e. Drugs with low aqueous solubility often present problems related to their
formulation and bioavailability.
Importance of solubility

7. SOLUBILITY EXPRESSIONS

8. SOLUBILITY EXPRESSIONS
Expression Symbol Definition
Molarity M
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

9. Biopharmaceutical Classification
System (BCS)

10. SOLUTE SOLVENT INTERACTIONS
Three types of interaction in the solution process:
a. Solvent- solvent interaction
b. Solute –solute interaction
c. Solvent- solute interaction

11. 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.

12. Solvent - Solute Interactions
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) hydrogen
bonds.
Alcohol Dissolves in Water:
 The -OH group on alcohol is polar and mixes with the polar water through the
formation of hydrogen bonds.
 A wide variety of solutions are in this category such as sugar in water, alcohol
in water, acetic and hydrochloric acids.

13. Solvent - Solute Interactions
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:
 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.
 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.
 If A-B >> A-A or B-B, or the three forces are equal The solute will Form a
solution. Example: NaCl in water.

14. Classification of solvents & their mechanism of action
1. Polar solvents
2. Non polar solvents
3. Semi polar solvents

15. 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.

16. Polar solvents
 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.

17. 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.

18. Polar solvents
 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.

19. 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

20. 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

21. Polarityas Dielectric Constantof Solvent, ε
decrease, the solubilityalso decrease

22. 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 are classified as semipolar.

23. Types of solutions
 Solutions are homogeneous mixtures of two or more than two components.
Homogeneous mixture means its composition and properties are uniform
throughout the mixture. Solution of pharmaceutical importance comprise:
 Gases in liquids
 Liquids in liquids
 Solids in liquids

24. Type of Solution Solute Solvent Common Examples
Gaseous Solutions
Gas Gas Mixture of oxygen and nitrogen gases
Liquid Gas Chloroform mixed with nitrogen gas
Solid Gas Camphor in nitrogen gas
Liquid Solutions
Gas Liquid Oxygen dissolved in water
Liquid Liquid Ethanol dissolved in water
Solid Liquid Glucose dissolved in water
Solid Solutions
Gas Solid Solution of hydrogen in palladium
Liquid Solid Amalgam of mercury with sodium
Solid Solid Copper dissolved in gold

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

26. Solubility of gases in liquids

27. 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.

28. 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
 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.

29. RAOULT’S LAW
The partial pressure (Pi) of each component in a solution is equal to the mole fraction of
the component & the vapour pressure of the pure component”
Pi = xP
Or
P = pAxA + pBxB

30. IDEAL SOLUTIONS
 Solutions which obey Raoult’s law in all the solute composition in a solvent.

31. Non IDEAL SOLUTIONS
 Solutions which do not obey Raoult’s law over entire range of composition

33. Solubility of solids in liquids
 The solubility depends on the physical form of the solid, the nature and composition of solvent
medium as well as temperature and pressure of system.
 Factors affecting to solubility of solids in liquids:
1. Particle size (surface area) of drug particles
2. Molecular size
3. The boiling point of liquids and the melting point of solids
4. Effect of substituent
5. Temperature
6. Crystal properties-polymorphic crystals and amorphous forms
7. pH
8. Polarity
9. Presence of multiple solutes

34. IDEAL SOLUBILITY PARAMETERS
 ‘Ability of a liquid to act as a solvent’
1) Hildebrand solubility parameter (δ)
“ square root of cohesive energy density”
δ= √△Hv- RT/ Vm
2) Hansen solubility parameter (δt)
δt= δd + δp + δh

35. Solvation / Dissolution
 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

36. Association
 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

37. Ionic
surfactant
• Span
• tween
• Myrj
cationic noionic