Download 1 - Physical Pharmacy Laboratory

SOLUBILITY AND
PARTITION PHENOMENA
CONTENTS
Solubility
• Definitions
• Factors influencing solubility
• The effect of pH on solubility
• The effect of pressure
• Influence of solvents on solubility
CONTENTS
Partition Phenomena
• Partition concepts
• For weak electrolytes as solutes
• Drug absorption
• pH partition hypothesis
• Site of drug partitioning
DEFINITIONS

Solubility is the concentration of a solute
when the solvent has dissolved all the solute that
it can at a given temperature
• Martin’s Physical Pharmacy & Pharmaceutical Sciences 6th edition
Patrick J. Sinko
FACTORS INFLUENCING SOLUBILITY

Dissolution of a crystal
1. A solute (drug) molecule is
removed from its crystal
2. A cavity for the molecule is
created in the solvent
3. The solute molecule is
inserted into this cavity
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
FACTORS INFLUENCING SOLUBILITY

Temperature

Solubility is an equilibrium
value that is dependent on a
given temperature and
pressure

Solubility does not depend on
how fast a substance dissolves
in the solvent
FACTORS INFLUENCING SOLUBILITY

Temperature

Heat of solution (ΔHsoln)

The enthalpy change associated
with the dissolution of a
substance in a solvent
* Applied Physical Pharmacy
Mansoor M.Amiji, Beverly J.Sandmann
* Table. Heat of solution
Solute
ΔHsoln (25℃) kcal/mole
HCl
- 17.96
NaOH
- 10.6
CH3COOH
- 0.36
NaCl
+ 1.0
KMnO4
+ 10.4
Mannitol
+ 5.26
KI
+ 4.3
FACTORS INFLUENCING SOLUBILITY

Temperature
S ∝exp (-ΔHsoln/RT)

If ΔHsoln is negative, increasing the temperature of
the solvent will decrease the solubility of the solute
FACTORS INFLUENCING SOLUBILITY

Chemical structure

Dipole moment

A measure of polarity
Molecules that have a
high dipole moment are
more soluble in polar
solvents such as water
FACTORS INFLUENCING SOLUBILITY

Chemical structure

Dielectric properties
Related to the ability to
store charge
 How a substance interacts
with solvents

* Applied Physical Pharmacy
Mansoor M.Amiji, Beverly J.Sandmann
* Table 6-5 Dielectric Constants of
Some Solvents at 25℃
Solvent
Dieletric
constant
Water
78.5
Glycerin
40.1
Propylene glycol
32.01
Methanol
31.5
Acetone
19.1
PEG 400
12.5
Cottonseed oil
6.4
Ether
4.3
FACTORS INFLUENCING SOLUBILITY

Chemical structure

Hydrogen bonding
The attractive interaction
of a hydrogen atom with
an electronegative atom,
such as nitrogen, oxygen
or fluorine
 Major factor on solubility
in water

• Amines with small alkyl groups
are very soluble in water. This is
because hydrogen bonding occurs
between the amine and water
molecules
FACTORS INFLUENCING SOLUBILITY

Chemical structure
*

Hydrogen bonding
The attractive interaction
of a hydrogen atom with
an electronegative atom,
such as nitrogen, oxygen
or fluorine
 Major factor on solubility
in water

* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
• The presence of hydroxyl groups
or nitro groups can markedly
increase the solubility.
FACTORS INFLUENCING SOLUBILITY


A high melting point means
low water solubility
*
cis (z) Isomer is more
soluble than trans (e)
isomer
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
# Kirk-Othmer Encyclopedia of Chemical Technology
18 OCT 2001
THE EFFECT OF PH ON SOLUBILITY

Acidic drugs (HA)

Total saturation solubility of drug S, the solubility of
the undissociated species HA S0
S = S0 + (concentration of ionised species)
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
THE EFFECT OF PH ON SOLUBILITY

Acidic drugs (HA)

The dissociation constant Ka

According to previous page, [HA] = S0, [A-] = S – S0
THE EFFECT OF PH ON SOLUBILITY

Acidic drugs (HA)

Taking logarithms,

[A-] = S – S0, S0 = [HA]
<Henderson-Hasselbalch Equation>
THE EFFECT OF PH ON SOLUBILITY

Basic drugs (RNH2)

Total saturation solubility of drug S, the solubility of
the undissociated species RNH2 S0
S = S0 + (concentration of ionised species)
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
THE EFFECT OF PH ON SOLUBILITY

Basic drugs (RNH2)

The dissociation constant Kb

According to previous page, [RNH2] = S0, [RNH3+] = S –
S0
THE EFFECT OF PH ON SOLUBILITY

Basic drugs (RNH2)

Taking logarithms,

[RNH3+] = S – S0, S0 = [RNH2]
<Henderson-Hasselbalch Equation>
THE EFFECT OF PRESSURE

Henry’s Law
C2= σp
C2= concentration of the dissolve gas (g/l)
p = partial pressure (mm of the undissolvegas)
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
INFLUENCE OF SOLVENTS ON SOLUBILITY

Strong electrolytes
Strong acids and bases and all salts are soluble in
water
 The polar nature of water attracts the ions


Weak electrolytes
Weak acids and bases with high molecular weight
are not soluble in water
 Cosolvents such as alcohol, propylene glycol and
polyethylene glycol are required for solubility

INFLUENCE OF SOLVENTS ON SOLUBILITY

Cosolvents

Solubility enhancements
caused by cosolvent
addition occur because
of changes in the bulk
properties of the
isotropic solution
PARTITIONING CONCEPTS

A solute distributes itself between two
immiscible solvents so that the ratio of its
concentration in each solvent is equal to the
ratio of its solubility in each one
C0 = molar concentration in organic layer
 Cw = molar concentration in aqueous layer
 P = partition coefficient or distribution constant

FOR WEAK ELECTROLYTES AS SOLUTES

The partition law for weak electrolytes depends
on pH

Kd1 = the apparent partition coefficient and its value
depends on pH
FOR WEAK ELECTROLYTES AS SOLUTES

Using the Ka expression, an equation can be
developed that gives the hydrogen ion
dependency

Substitution in Kd1 gives
FOR WEAK ELECTROLYTES AS SOLUTES

Substitution of Kd for (HA)0/(HA)w gives

This equation can be made linear
FOR WEAK ELECTROLYTES AS SOLUTES

The partition law for weak electrolytes depends
on pH

Kd1 = the apparent partition coefficient and its value
depends on pH
FOR WEAK ELECTROLYTES AS SOLUTES

Using the Ka expression, an equation can be
developed that gives the hydrogen ion
dependency

Substitution in Kd1 gives
FOR WEAK ELECTROLYTES AS SOLUTES

Substitution of Kd for [B:]0/[B:] gives

This equation can be made linear
DRUG ABSORPTION

Drug absorption occurs by
partitioning through the
mucosal membrane of an
epithelial cell of the
gastrointestinal tract and
then moving through the cell
and partitioning through the
serosal membrane
DRUG ABSORPTION

Factors influencing drug absorption

Lipid/water partition coefficient (P)

Water solubility

Molecular weight

Chemical structure
DRUG ABSORPTION

SMEDDS (Self-microemulsifying drug delivery system)
*

Lipid/water partition
coefficient and water
solubility are increased
by using SMEDDS

Drug absorption is
increased and bioavailability
is increased too.
* European Journal of Pharmaceutics and Biopharmaceutics
76 (2010) 475 - 485
PH


PARTITION HYPOTHESIS
Drug absorption is a function of pH for weak
electrolytes because pH changes ionization
Only the uncharged molecular form of the
organic weak electrolytes is absorbed
→ The unionized drug is provided for aqueous
extracellular medium and out of the cell
PH

PARTITION HYPOTHESIS
Using Henderson-Hasselbalch equation
I = ionized drug (dissociated weak acid)
 U = unionized drug (associated weak acid)

PH

PARTITION HYPOTHESIS
Calculating the % ionization of papaverine at pH =
3.9

Papaverine is a weak base, pKa = 5.9
PH

PARTITION HYPOTHESIS
If pH = pKa ± 2, a small
change in pH will result in
a large change in
ionization
SITE OF DRUG PARTITIONING


In the human body, the ratios calculated would
be for only an instant as the drug enters into
tissue and is metabolized and eliminated
Absorption from the stomach (pH 1 to 3)

The weaker the acid (pKa > 7), the greater the
percent unionized in the stomach
SITE OF DRUG PARTITIONING

Absorption from the intestines (pH 4 to 6)


Urinary excretion (pH 5 to 7)




The weaker the base (pKa < 6), the grater th percent
ionization in the intestine
Barbiturate poisoning may be treated by increasing the
pH of plasma and urine, which clears barbiturate ion from
the body
Excretion of drugs in sweat (pH 5-7)
Excretion of drugs in human milk (pH 6.6)
Rectal administration (pH 7.8)