Chapter 3

SOLUBILITY AND
DISTRIBUTION PHENOMENA

Pharm3 1
Outline

Introduction

Definition

Solvent-Solute Interaction

Solubility of Gases in Liquids

Solubility of Liquids in Liquids

Solubility of Solids in Liquids

Distribution of Solutes Between Immiscible Solvents

Pharm3 2
 Introduction

Importance:
 Permits the pharmacist to choose the best
solvent medium for a drug or combination of
drugs
 Helps in overcoming certain difficulties that
arise in the preparation of pharmaceutical
solutions
 Can serve as standard or test of purity

Pharm3 3
 Introduction

 Solubility of compound depends on the

physical & chemical properties of solute and
the solvent
 Temperature
 Pressure
 pH of the solution

Pharm3 4
 Definition

SOLUBILITY

 Defined in quantitative terms as the

concentration of solute in a saturated solution
at certain temperature, and in qualitative way,
 the spontaneous interaction of two or more
substances to form homogenous molecular
dispersion

Pharm3 5
Solutions Definition

Saturated Solution

One in which the solvent is in equilibrium with

the solute
A solution in which maximum amount of solute
has been dissolved

Pharm3 6
Solutions Definition

Unsaturated/ Subsaturated Solution

One containing the dissolved solute in a

concentration below that necessary for
complete saturation a definite temperature

Pharm3 7
Solutions Definition
Supersaturated Solutions

 One that contains more of the dissolve solute

than it would normally contain
 Solution that is more concentrated than a
saturated solution
 Some salts can be dissolved in large amounts at
elevated temperature, and upon cooling, fail to
crystallize from the solution
 Can be converted to saturated solution by
seeding the solution with crystals of the solute

Pharm3 8
Gibb’s Phase Rule

Solubility may be describe in a concise manner by

the use of Gibb’s Phase Rule

F=C–P+2
Where:
F – number of degrees of freedom
- least number of variables
C – smallest number of components that are
adequate to describe the chemical composition of
each phase
P- number of phases

Pharm3 9
Gibb’s Phase Rule

Example:
1. Given mass of gas
Water vapor confined to a particular volume
2. Liquid and gas
Liquid water and water vapor
3. Liquid water, ice, water vapor

Pharm3 10
Phase Diagram

11
Pharm3
Solubility Expressions (USP/NF)

Term Parts of solvent required

for 1 part of solute
Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble
Very slightly soluble
Practically insoluble / insoluble
Pharm3 12
 Solvent-Solute Interaction

Water  salts, sugars & similar compounds

Mineral Oil and benzene  substances that are

slightly soluble in water

“like dissolves like”

Pharm3 13
Polar Solvents

 Dissolves ionic solutes & other polar substances

 Water dissolves :
 phenol
 alcohols
 aldehydes
 ketones
 amines
 other O & N containing compounds that can form
hydrogen bonds with water

Pharm3 14
Polar Solvents

 Solubility of substances depends on:

 structural features
 length of non-polar chain of aliphatic alcohol
 = solubility 
 straight chain monohydroxyl alcohols,
aldehydes, ketones and acids with < 4/5
carbons cannot enter into the hydrogen-
bonded structures of water = slightly soluble
 branching of the carbon chains  non-polar
effects =  water solubility
Pharm3 15
Polar Solvents

 Polar solvents act following these

mechanisms:
1. High dielectric constant (water = 80)
- Reduce the force of attraction between
oppositely charged ions in crystals
2. Break covalent bonds of potentially strong
electrolytes by acid-base reactions
3. Polar solvents are capable of solvating
molecules and ions through dipole interaction
forces
Pharm3 16
Non Polar Solvents

 Like hydrocarbons are unable to reduce the

attraction between the ions of strong and
weak electrolytes because of the solvents low
dielectric constants
 Non polar compounds can dissolve nonpolar
solutes with similar internal pressures through
induced dipole interactions

Pharm3 17
Semi Polar Solvents

 Like ketones and alcohols can induce a

certain level of polarity in non polar solvent
molecules
 Semi polar compounds may act as
intermediate solvents to bring about miscibility
of polar and non polar liquids
 Acetone  solubility of ether in water
 Alcohol on water-castor oil mixture
 Propylene glycol  solubility of water-peppermint oil
and water-benzyl benzoate mixture

Pharm3 18
 Solubility of Gases in Liquids

Solubility of a gas in a liquid depends on:

Pressure Temperature

Presence of Chemical
Salts Reactions

Pharm3 19
Effect of
Pressure
 The pressure of gas above the solution
changes the solubility of the dissolved gas
in equilibrium with it
 Henry’s Law
 states that in a very dilute solution at constant
temperature, the concentration of dissolved
gas is proportional to the partial pressure of the
gas above the solution at equilibrium
 C2 = p

Pharm3 20
 Effect of
Temperature

 Temperature  = solubility of most gases 

 owing to the greater tendency of gas to expand

Pharm3 21
Presence of
Solubility of gas in liquid
Salts/
salting
Salting out
Out
 Gases are liberated from solutions in which
they are dissolved by the introduction of an
electrolyte or non electrolyte

 Resultant escape in gas is due to the

attraction of the salt ions or highly polar
non electrolyte for the water molecule
which reduces the density of the aqueous
environment adjacent to the gas molecule
Pharm3 22
 Effect of
Chemical
Reactions
 Henry’s law apply strictly to gases that are
only slightly soluble in solution and do not
react in any way in the solvent
 Gases such as hydrogen chloride, ammonia
and carbon dioxide show deviations as
result of chemical reaction between gas
and solvent, usually with a resultant
increase in solubility

Pharm3 23
Solubility Calculations

Henry’s Law

C2 = P
C2 – concentration of gas
- Henry’s law constant/ solubility
coefficient
P – partial pressure

Pharm3 24
Solubility Calculations

Bunsen Absorption Coefficient

Defined as

Vol of gas (L) in STP

Vol of the sol’n = αP

Volume of gas (L) (0oC & 760mmHg pressure) that

dissolve in 1L of solvent under partial pressure of
1 atm of the gas at definite temperature
Pharm3 25
Solubility Calculations

Ideal Gas Law

PV = nRT

P- pressure
V- volume
n – moles
R – gas constant (0.08205)
T – temperature (K)
Pharm3 26
Solubility Calculations

Example:
0.0160g of oxygen is dissolved in 1L water at
25ºC at oxygen pressure at 300mmHg
calculate for  and Bunsen coefficient.

Pharm3 27
Solubility Calculations

How many grams of oxygen can be dissolved

in 250ml of water when the total pressure
above the mixture is 760mmHg and partial
pressure of oxygen in the solution is 0.263
atm and the temperature is 25ºC

Pharm3 28
 Solubility of Liquids in Liquids

Alcohol + water = hydroalcoholic solutions

Volatile oils + water = aromatic waters
Volatile oils + alcohol = spirits / elixirs
Ether + alcohol = collodions

Pharm3 29
Ideal and Real Solutions

Ideal solution
 One in which there is no change in the properties of the
components other than dilution, when they are mixed to
form the solution.
 No heat is evolved or absorbed during the mixing
process
 The final volume of the solution represents an additive
property of the individual components.
 Ideal solutions are formed by mixing substances with
similar properties

Pharm3 30
Ideal and Real Solutions

Example:
100ml methanol + 100ml ethanol = 200ml
No evolution of heat

__________solution

100ml of sulfuric acid + 100m water = 180ml

Considerable evolution of heat

___________solution

Pharm3 31
Liquid-Liquid Systems

Miscibility – refers to the mutual solubilities of

the components in liquid-liquid systems

2 categories of LLS:

Complete Partial
Miscibility Miscibility
Pharm3 32
Influence of Foreign Substance

Binary compound + another substance = ternary

system ( 3 components)
 added material is soluble in only one of the two
components or if the solubilities in the two liquids
are different, the mutual solubility of the liquid pair
is decreased
 when the third substance is soluble in both the
liquids to roughly the same extend, mutual
solubility of the liquid pair is increased

Pharm3 33
Influence of Foreign Substance

 Blending – increase in mutual solubility of two

partially miscible solvents by another agent

 Micellar Solubilization – when solubility in

water of a nonpolar liquid is increased by
micelle-forming surface-active agent

Pharm3 34
 Solubility of Solids in Liquids

 Systems of solids in liquids is the most important

type of pharmaceutical solutions
 The solubility of a solid in an ideal solution
depends on temperature, melting point of the
solid, and molar heat of fusion
 In ideal solution, the heat of the solution is equal
to the heat of the fusion
 Ideal solubility is not affected by the nature of the
solvent
 Nonideal solution – heat of solution has a (+)
absorbed or (-) revolved heat

Pharm3 35
Solubility of Strong Electrolytes

  temp -  solubility of a solid that absorbs

heat

Pharm3 36
Solubility of Slightly Soluble Electrolytes

 When slightly soluble electrolytes are

dissolved to form saturated solutions, it is
described as a special constant – solubility
product, Ksp

Pharm3 37
Solubility of Weak Electrolytes

 Most drugs are weak acids and bases

 react with strong acids and bases, with definite
ranges of pH and exists in ions that is soluble in
water
Examples:
 Carboxylic acids with more than 5 carbons
 insoluble in water
 react with dilute NaOH, CO3-2, HCO3- to form salts

Pharm3 38
Solubility of Weak Electrolytes

 Fatty acids containing more than 10 carbons:

 form soluble soaps with alkali metals
 forms insoluble soaps with other metal ions
 Hydroxy acid (tartaric acid and citric acid)
 quite soluble in water
 ammonium and potassium bitartrates are not very
soluble in water

Pharm3 39
Solubility of Weak Electrolytes

 Aromatic acids
 react with dilute alkalies to form water-soluble salts
 precipitated as the free acids if stronger acidic
substances are added to the solution
 Alkaloids, sympathomimetic amines,
antihistamines, local anesthetics
 not very water soluble but soluble in dilute solutions of
acids (atropine sulfate, tetracaine hydrochloride)
 addition of alkali to solution of salt of these
compounds precipitates the free base from solution

Pharm3 40
Solubility of Weak Electrolytes

 Sulfonamides (aliphatic nitrogen)

 slightly soluble weak acid
 form water-soluble salts in alkali solutions
 sodium salts are precipitated from solution by
addition of strong acid or salt of a strong acid and
weak base
 Barbiturates (weak acids)
 soluble in alkali
 precipitated as free acids when stronger acid is
added and the pH of the solution is lowered

Pharm3 41
Influence of Solvents on the Solubility of Drugs

strong
electrolyte

weak electrolytes
may behave like:

non-
electrolytes

Pharm3
42
Influence of Solvents on the Solubility of Drugs

pH adjusted that
no effect in
made drug in
solubility
ionic form
Weak
Electrolytes
pH adjusted that
precipitation
made drug un-
occurs
ionized

Pharm3
43
Influence of Solvents on the Solubility of Drugs

 Cosolvency – solute is more soluble in a

mixture of solvents in ONE solvent alone
 Cosolvents – solvents that increase the
solubility of solute

Pharm3
44
Influence of Surfactants

 Weakly acidic and basic drugs may be brought

into solution by the solubilizing action of
surface-active agents

Pharm3 45
Effect of Complexation in Multicomponent System

 Many liquid preparations consist of more than

a single drug in solution
 several drugs with pharmaceutical adjuncts
interact in solution to form insoluble complexes

Pharm3 46
Influence of Other Factors on the Solubility of
Solids
  solubility -  particle size

s = solubility of fine particles

so= solubility of the solids consisting of large particles
= surface tension of the particles for solids
V = molar volume (cm3/mole)
r = final radius of the particles in cm
R = gas constant ( 8.314 x 107 erg/deg mole)
T = absolute temp

Pharm3 47
 Distribution of Solutes Between
Immiscible Solvents
 If an excess of liquid or solid is added to a
mixture of two immiscible liquids, it will
distribute itself between the two phases so
that each becomes saturated.
 If the substance is added to the immiscible
solvents in an amount insufficient to saturate
the solutions, it will still become distributed
between the two layers in a definite
concentration ratio

Pharm3 48
Distribution Law:

C1 and C2 are the equilibrium concentration of

the substances in solvent1 and solvent2
K = distribution ratio/ distribution coefficient/
partition coefficient

*** applicable only in dilute solutions

Pharm3 49
Importance of Partition to the Pharmacist

1. Preservation of oil-water systems

2. Drug action at nonspecific sites
3. Absorption and distribution of drugs
throughout the body

Pharm3 50
THANK YOU!

Pharm3 51