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PHAYG062 – Preformulation
Solubility
Dr Gareth Williams
Learning outcomes
• No drug can be absorbed until it’s in solution – BUT most drugs are
formulated as solids!
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Equilibrium solubility
Drug ( s) Drug(aq )
Solution is saturated
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fus H mix H
Ideal solubility
• In the special case where heat of mixing is zero, the solubility is said
to be ideal;
fus H fus H
ln x2
Mole fraction RT RTm Melting point of pure
of solute compound
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An example: Aspirin
• The melting point of aspirin is 137 oC and its heat of fusion is 29.80 kJ
mol-1. What is the ideal solubility at 25 oC?
29,800 29,800
ln x2 3.286 So x2 0.037
8.314 298 8.314 410
Solvent Solubility
Ideal (calculated) 0.037
THF 0.036
Methanol 0.026
Ethanol 0.023
Acetone 0.018
Chloroform 0.015
1-Propanol 0.011
Acetonitrile 0.006
Solvent Solubility
Ideal (calculated) 0.037
THF 0.036
Methanol 0.026
Ethanol 0.023
Acetone 0.018
Chloroform 0.015
1-Propanol 0.011
Acetonitrile 0.006
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Dielectric constant
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-1
1/Temperature (K )
• Remember:
fus H fus H
ln x2
RT RTm
• For two compounds with same heat of fusion, the compound with the
lower m.p. will have greater solubility;
• Similarly, for two compounds with same m.p., the compound with
lower heat of fusion will have greater solubility;
• For polymorphic forms both the heat of fusion and m.p. will vary, so
different crystalline forms of same drug will have different
solubilities.
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Acids
HA + H2O A H3O
[H3O ][A ] [A ]
Ka = pH = pK a log
[HA] [HA]
• Correspondingly
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60
40
20
(Un-ionised) (Un-ionised)
0
pKa- 2 pKa pKa+ 2
4 5 6 7 8 9 10
pH
Solubility as a function of pH
Solubility as a function of pH
For an acid:
• If [A-] is the saturated concentration of ionised drug, Si ; and,
So
pK a pH + log or St So [1 10pH - pK a ]
St So
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Solubility as a function of pH
For a base:
• If [BH+] is the saturated concentration of ionised drug, Si and
St So
pK a pH + log or St So [1 10pKa - pH ]
So
200
150
100
50
Intrinsic
solubility
0
3 4 5 6 7
pH
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Acid
Solubility lowest Solubility increasing Solubility highest
if pKa ca. 5-6
Base
Dissolution rate
• Solubility and pKa are two very important parameters that define the
in vivo behaviour of a drug substance;
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Dissolution model
Diffusion coefficient
Rate of change in mass Surface area
dm DA
(St C )
dt h
Thickness of boundary layer
Theory of dissolution
Solid Boundary layer Bulk solvent
St
Distance (mm)
Dissolution plot
St
Concentration (mol L )
-1
Time (min)
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• Specified in pharmacopoeia
Sink conditions
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Sink conditions
St
C = St/10
Concentration (mol L )
-1
Concentration (mol L )
-1
Time (min)
C = St /10
Time (min)
• No!
• Volume of solvent:
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Other factors
• pH variable patient-to-patient.
Summary
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