1. Solubility and Partition Phenomena
Chapter. 9
Solubility and Partition Phenomena

2. Factors influencing solubility The effect of pH on solubility
Contents
Solubility
Definitions
Factors influencing solubility
The effect of pH on solubility
The effect of pressure
Influence of solvents on solubility

3. For weak electrolytes as solutes Drug absorption
Contents
Partition Phenomena
Partition concepts
For weak electrolytes as solutes
Drug absorption
pH partition hypothesis
Site of drug partitioning

4. 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

5. 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

6. 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

7. Factors influencing solubility
Temperature
Heat of solution (ΔHsoln)
The enthalpy change associated with the dissolution of a substance in a solvent *
Table. Heat of solution
Solute
ΔHsoln (25℃) kcal/mole
HCl
NaOH
- 10.6
CH3COOH
- 0.36
NaCl
+ 1.0
KMnO4
+ 10.4
Mannitol
+ 5.26 KI
+ 4.3
* Applied Physical Pharmacy
Mansoor M.Amiji, Beverly J.Sandmann

8. Factors influencing solubility
Temperature
If ΔHsoln is negative, increasing the temperature of the solvent will decrease the solubility of the solute
S ∝exp (-ΔHsoln/RT)

9. 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

10. Factors influencing solubility*
Table 6-5 Dielectric Constants of Some Solvents at 25℃
Chemical structure
Dielectric properties
Related to the ability to store charge
How a substance interacts with solvents
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
* Applied Physical Pharmacy
Mansoor M.Amiji, Beverly J.Sandmann

11. 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

12. 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 *
The presence of hydroxyl groups or nitro groups can markedly increase the solubility.
* Physicochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood

13. 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

14. 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

15. The effect of pH on solubility
Acidic drugs (HA)
The dissociation constant Ka
According to previous page, [HA] = S0, [A-] = S – S0

16. The effect of pH on solubility
Acidic drugs (HA)
Taking logarithms,
[A-] = S – S0, S0 = [HA]
<Henderson-Hasselbalch Equation>

17. 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

18. The effect of pH on solubility
Basic drugs (RNH2)
The dissociation constant Kb
According to previous page, [RNH2] = S0, [RNH3+] = S – S0

19. The effect of pH on solubility
Basic drugs (RNH2)
Taking logarithms,
[RNH3+] = S – S0, S0 = [RNH2]
<Henderson-Hasselbalch Equation>

20. 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

21. 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

22. Influence of Solvents on Solubility
Cosolvents
Solubility enhancements caused by cosolvent addition occur because of changes in the bulk properties of the isotropic solution

23. 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

24. 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

25. For weak Electrolytes as solutes
Using the Ka expression, an equation can be developed that gives the hydrogen ion dependency
Substitution in Kd1 gives

26. For weak Electrolytes as solutes
Substitution of Kd for (HA)0/(HA)w gives
This equation can be made linear

27. 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

28. For weak Electrolytes as solutes
Using the Ka expression, an equation can be developed that gives the hydrogen ion dependency
Substitution in Kd1 gives

29. For weak Electrolytes as solutes
Substitution of Kd for [B:]0/[B:] gives
This equation can be made linear

30. 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

31. Drug absorption Factors influencing drug absorption
Lipid/water partition coefficient (P)
Water solubility
Molecular weight
Chemical structure

32. 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)

33. 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

34. pH Partition Hypothesis
Using Henderson-Hasselbalch equation
I = ionized drug (dissociated weak acid)
U = unionized drug (associated weak acid)

35. pH Partition Hypothesis
Calculating the % ionization of papaverine at pH = 3.9
Papaverine is a weak base, pKa = 5.9

36. pH Partition Hypothesis
If pH = pKa ± 2, a small change in pH will result in a large change in ionization

37. 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

38. Site of Drug Partitioning
Absorption from the intestines (pH 4 to 6)
The weaker the base (pKa < 6), the grater th percent ionization in the intestine
Urinary excretion (pH 5 to 7)
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)