Solubility and Partition

Phenomena
Contents

I. General Principles
II. Solvent-Solute Interactions
III. Solubility of Gases in Liquids
IV. Solubility of Liquids in Liquids
V. Solubility of Solids in Liquids
VI. Partition Phenomena
 Ⅰ. General Principles

1. Definitions
2. Solubility Expressions
3. Factors Affecting Solubility
Definitions
 Solution : a liquid in which a solid substance has been
dissolved.
• Solute : a solid substance that is dissolved in a liquid.
• Solvent : a liquid that can dissolve other substances.
 Solubility :
• the concentration of solute in a saturated solution at
equilibrium at a given temperature
• given as per weight or volume of solvent
g (solute) / 100g (solvent)
1g (solute) / volume (ml) of solvent
 Saturated Solution
the solute is in equilibrium with the solid phase

 Unsaturated or Subsaturated Solution

one containing the dissolved solute in a concentration that
necessary for complete saturation at a definite temperature

 Supersaturated Solution
one that contains more of the dissolved solute than it would
normally contain at a definite temperature
 Miscible
the solute when it is a liquid and will form a solution with a
solvent over any concentration range

 The Phase Rule

F=C–P+2
 Solubility Expressions
USP Chart of Descriptive terms 대한약전 제 8개정
Term Parts solvent to 1 part
solute 

Very soluble Less than 1

  

Freely soluble 1-10 (3-10%)

 

Soluble 10-30


Sparingly soluble 30-100

 

Slightly soluble 100-1000

  

Very slightly soluble 1000-10,000

   

Practically insoluble, More than 10,000

 
insoluble
 Factors Affecting Solubility
 Temperature
 H so ln S(T2 ) H soln T2  T1
log  ( )
S e RT S(T1 ) 2.303R T2T1
 Pressure
C2 = σp
 pH
 Chemical Structures
- Dipole moment
- Dielectric properties
- Hydrogen bonding
Ⅱ. Solvent – Solute Interactions

1. Polar Solvents
2. Nonpolar Solvents
3. Semipolar Solvents

“Like Dissolves Like”

Polar Solvents (dissolve ionic solutes and other polar substances)

 Influential Factors
• Dipole moment
• Hydrogen bonds
• Acidic and basic character of constituents
• Structural features
 Mechanism
• High dielectric constant
• Amphiprotic
• Dipole interaction force
 Water
Non-polar Solvents (dissolve nonpolar solutes)

 Influential Factors
• Induced dipole interactions
• Weak van der Waals-London type forces

 Hydrocarbons
Semi-polar Solvents(Intermediate solvents)

 Influential Factors
• Induce a certain degree of polarity in non-polar solvent molecules

 Ketones and alcohols

Ⅲ. Solubility of Gases in Liquids

1. Effect of Pressure
2. Effect of Temperature
3. Salting Out
4. Effect of Chemical Reaction
5. Solubility Calculations
Effect of Pressure

 Henry’s Law

C2 = σp

C2 = concentration of the dissolve gas (g/l)

p = partial pressure (mm of the undissolve gas)
σ = inverse of the Henry’s law constant, K

in a dilute solution at constant temperature, the concentration

of dissolved gas is proportional to the partial pressure of the
gas above the solution at equilibrium
Effect of Temperature

 As the temperature increases, the solubility of most gases

decreases, owing to the greater tendency of the gas to expand
Salting Out

 Gases are often liberated from solutions in which they are

dissolved by the introduction of an electrolytes and sometimes by a
nonelectrolyte

NaCl gases
sucrose carbonated
solution
Effect of Chemical Reaction

 Gases (HCl, NH3, CO2) + Solvent

→ Chemical reaction
→ Increase solubility
Solubility Calculations

 Inverse Henry’s law constant, 

C2 =  P

 Bunsen absorption coefficient, 

Vgas. STP
= P
Vsoln.
 : 일정 온도, gas의 partial pressure 1 기압하에 solvent 1L
에 녹 는 gas의 volume (L)
Satuated condition : 0℃, 760mmHg
Ⅳ Solubility of Liquids in Liquids

1. Ideal and Real Solutions

2. Complete Miscibility vs Partial Miscibility
3. Influence of Foreign Substances
4. Influence of Solvents on Solubility
Ideal and Real Solutions

 Ideal Solutions  Nonideal Solutions

a. Negative deviation
Pi  Pi  X i
0
Raoult’s Law: b. Positive deviation
 Raoult’s Law
 Negative deviation

A A A B
Associated with hydrogen bonding
between polar comp

Increased solubility

Chloroform & acetone

 Raoult’s Law
 Positive deviation

A A A B

Cannot mingle with each other

Partial solubility
Decreased solubility
 Miscibility

 Complete Miscibility  Partial Miscibility

Solvents are said to be When certain amounts of two
completely miscible when they liquids are mixed, two liquid
are mix in all proportions layers are formed, each
containing some of the other
liquid in the dissolved state
Miscibility
Influence of Foreign Substances

Binary addition Ternary

 If the added material is soluble  When the third substance is

in only one of the two soluble in both of the liquids
components / if the solubilities roughly the same extent
in the two liquids are markedly the mutual solubility of the
different liquid pair is increased
mutual solubility of the  Blending : the increase in mutual
liquid pair is decreased solubility of two partially miscible
solvents by another agent
 Micellar Solubilization : solubility
in water of a non-polar liquid is
increased by a micelle-forming
surface-active agent
Ⅴ Solubility of Solids in Liquids
1. Ideal Solutions
2. Nonideal Solutions
3. Solvation and Association in Solutions of Polar
Compounds
4. Solubility and the Heat of Solution
5. Solubility of Strong Electrolytes
6. Solubility of Slightly Soluble Electrolytes
7. Solubility of Weak Acids and Weak Bases in Water as
Influenced by pH
8. The Influence of Solvents on the Solubility of Drugs
Ideal Solutions
Depends on temperature, melting point of the solid, and molar
heat of fusion
H fT0  T
 log X 2 
i
( )
2.303R T0T
T = absolute temp. of the solution
T0 = melting point of the solid solute
X2i = ideal solubility of the solute expressed in mole fraction
∆Hf = Heat of solutions → Heat of fusion

• Heat of solution = Heat of fusion

• Not affected by the nature of the solvent
• No longer applies when T > T0 and at temperatures
considerably below the melting point
Nonideal Solutions

H f T0  T
 log X 2  ( )  log  2
2.303RT T0

T = absolute temp. of the solution

T0 = melting point of the solid solute
∆Hf = Heat of solutions → Heat of fusion
γ2 = the mole fraction scale is known as the rational activity
coefficient
log γ2 : intermolecular forces of attraction in removing a molecule
from the solute phase and depositing it in the solvent
(a) W22

solute Liberation of a molecule from

the solute
(b)
W11

solvent Creation of a hole in the solvent

(c)
-2W12

solute
solvent molecule solution
Total work : (W22 + W11 -2W12)
 Solubility Parameter

H v  RT 1 2
 ( )
Vl
ΔHv = the heat of vaporization
Vl = the molar volume of the liquid at the desired temperature


lnr 2  w 11   w 22 
1/2

1/2 2 v 2Φ12
RT
V2Φ12
logr2  δ 1 δ 2 
2

2.303RT
 Solvation and Association in Solutions of Polar
Compounds

 Solvation  Association
- 2w12 > w11 + w22 - interaction occurs between like
- H v = negative molecules of one of the
- negative deviation from Raoult’s components in a solution
law - H v = positive
- positive deviation from Raoult’s
law

V2 Φ12
lnr 2  (w 22  w 11  2w 12 )
RT
Solubility and the Heat of Solution

 ∆Hsoln : heat of solution

H so ln T ' 'T '
ln( c' ' / c' )  ( )
vR T 'T ' '
Solubility of Strong Electrolytes

 Endothermic process  Exothermic process

(absorbs heat) (heat is evolved)
a rise in temperature increases the the solubility decreases with an
solubility of a solid elevation of the temperature
Solubility of Slightly Soluble Electrolytes

 Solubility product, : K sp
the real solution solubility of poorly soluble strong electrolytes in water is
calculated by using the solubility product constant obtained from
thermodynamics
 Common ion :
adding a common ion is to reduce the solubility of a slightly soluble
electrolyte
 Solubility of Weak Acids and Weak Bases in
Water as Influenced by pH

 Weak Acids  Weak Bases

HA  H   A B  BH   OH 
  [ BH  ]  [OH  ]
Ka 
[ H ][ A ] Kb 
[ HA] [ B]

S0 K a
S  S0 
[ H 3O  ]

S  S0 S0
pHp  pK a  log pHp  pK a  log
S0 S  S0
 The Influence of Solvents on the Solubility of
Drugs

 Strong Electrolytes :
strong acids and bases and all salts are soluble in water

 Weak Electrolytes :
weak acids and bases with high molecular weight are not soluble in water

 Nonelectrolytes :
high-molecular-weight organic drugs that do not dissociate or associate in water
are generally soluble in organic solvents and have little or no solubility in water

 Cosolvency :
a solute is more soluble in a mixture of solvents than in one solvent alone
Cosolvency

The solubility of
phenobarbital in a
mixture of water,
alcohol, and
glycerin at 25℃
Ⅵ. Partition Phenomena

1. General Partitioning Concepts

2. For Strong Electrolytes as Solutes
3. For Nonelectrolyte Solutes
4. For Weak Electrolytes as Solutes
5. Application of Distribution Concepts
6. Drug Action / Absorption
7. Site of Drug Partitioning Considering pH Effects Alone
General Paritioning Concepts

 The partition law :

a solute will distribute itself between two immiscible solvents
so that the ratio of its conc. in each solvent is equal to the
ratio of its solubility in each one
C0
Kd 
Cw

Co = molar conc. in organic layer

Cw = molar conc. in aqueous layer
Kd = partition coefficient or distribution constant
 For Strong / Nonelectrolytes as Solutes

Strong Electrolyte Nonelectrolyte

 Strong electrolytes are completely

dissociated in aqueous solution
→ cations & anions in aqueous
layer
→ water soluble
 Without ion pairing, do not
partition into the organic layer

C0
Kd  O Kd 
Cw
For Weak Electrolytes as Solutes

 The partition law : depends on pH

 pH different from pKa
(pH < pKa for weak acid ; pH > pKa for weak base)

 For a weak organic acid,

C0 [ HA]0
Kd  Kd 
Cw [ HA]w

 For a weak organic base,

C0 [ B ]0
Kd  Kd 
Cw [ B ]w
Application of Distribution Concepts
 Preservation of Emulsions
The total preservative added = C, where C = C0 + Cw

C  [ HA]0  [ HA]w  [ A ]w
[ HA]0
Kd  [ HA]0  K d [ HA]w
[ HA]w
[ H 3O  ][ A ]w K [ HA]w
Ka   [ A  ]w  a
[ HA]w [ H 3O  ]
[ HA]w
C  K d [ HA]w  [ HA]w  K a
[ H 3O  ]
C
Ka [ HA]w 
 [ HA]w ( K d  1  ) Ka

[ H 3O ] Kd 1
[ H 3O  ]
Drug Action / Absorption

 Drug Action  Drug Absorption

; by passive diffusion ; water solubility of the drug, the
; due only to a concentration lipid/water partition coefficient of
gradient across the barrier the drug molecule, MW, chemical
structure
; drugs must be in solution in
aqueous intestinal fluids
 Site of Drug Partitioning Considering pH
Effects Alone

 Absorption from the stomach (pH 1-3)

 Absorption from the intestines (pH 4-6)
 Urinary Excretion (pH 5-7)
 Excretion of drugs in sweat (pH 5-7)
 Excretion of drugs in human milk (pH 6.6)
 Rectal administration (pH 7.8)