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PHAYG062 – Preformulation

Dr Gareth Williams; x 5868; Room 323.

Learning outcomes

By the end of this lecture, you should be able to:

• Understand the concepts of equilibrium solubility and ideal solubility;

• Explain the factors that control dissolution rate;

• Describe how intrinsic dissolution rate is measured;

• Discuss the rationale for dissolution testing.

Why is solubility so important?

• No drug can be absorbed until it’s in solution – BUT most drugs are
formulated as solids!

• Must transition from solid state into solution - dissolution

• Solubility is an intrinsic property; it’s a function of molecular structure

and polymorphic form;

• Dissolution rate is an extrinsic property. It is affected by changes in

bulk properties, like particle size, shape, stirring etc.


Equilibrium solubility

• The concentration attained when solid drug is in equilibrium with its


Drug ( s)  Drug(aq )

Solution is saturated

If a drug can ionise, then the solubility of

the un-ionised form is called the intrinsic

The process of dissolution

1. A drug molecule is ‘removed’

from the crystal +

2. A cavity for the drug molecule

is created in the solvent

3. The drug molecule is inserted

into the cavity +

The process of dissolution

• When a solid is heated it becomes a liquid at the melting


• The intramolecular bonds holding the crystal lattice together are

broken in the s  l transition;

• Intermolecular bonds must also be broken for dissolution to occur.


Melting and dissolution

• The process of dissolution can be rewritten

Drug(s) « Drug (l ) « Drug (aq)

Melting Mixing with solvent

 fus H  mix H

 sol H   fus H   mix H

Heat of fusion (and so melting point) of drug will affect solubility

Melting and dissolution

Weak intermolecular interactions Strong intermolecular interactions

Easy to prise molecules apart Hard to prise molecules apart

Low MP/BP High MP/BP

High solubility Low solubility

Ideal solubility

• In the special case where heat of mixing is zero, the solubility is said
to be ideal;

• Ideal solubility is the theoretical maximum:

  fus H  fus H
ln x2  
Mole fraction RT RTm Melting point of pure
of solute compound

• Allows prediction of solubility as a function of temperature if melting

point and heat of fusion are known (DSC).


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

• How does this compare with measured solubilities in different


Measured solubilities of aspirin

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

Where do you think solubility in water would rank?

Measured solubilities of aspirin

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

Note that these solvents are commonly used in preformulation assays


What causes non-ideal mixing?

Three principal factors:

• Dipole moment Aspirin

Often the solute has localised positive charge on

one end of the molecule and localised negative δ-
charge on the other O
If so, the solute is termed polar – water is a polar δ+ δ+
molecule and the general rule is ‘like dissolves

Dielectric constant

• Related to capacity of a molecule to store a charge;

• Polar solvents may induce a dipole in a solute, increasing solubility.

Solvent Dielectric constant

Water 78.5
Water is an
Methanol 31.5 extreme
Ethanol 24.3
Acetone 19.1
Benzyl alcohol 13.1
Ether 4.3
Ethyl acetate 3.0

Capacity to form hydrogen bonds

• Occurs when electronegative atoms (O,

N, F) come into close contact with
hydrogen atoms (water!);

• Electrons are pulled towards

electronegative atoms, creating strong
force of interaction;

• Any drug with a functional group capable

of forming an H-bond with water (-OH, -
NH, -SH) should have increased solubility.


Solubility as a function of temperature

• Since  fus H must be positive, solubility should increase with


 sol H   fus H   mix H

Assumed equal as heat of mixing is zero for ideal solubility

• But, the heat of mixing is frequently not zero;

• If the heat of solution is negative (exothermic), solubility will decrease

with temperature.

solH negative (exothermic)

ln x2

solH positive (endothermic)

1/Temperature (K )

Solubility and physical form

• Remember:
  fus H  fus H
ln x2  

• 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


Solubility of ionisable compounds

• Intrinsic solubility is that of the un-ionised compound;

• If a compound ionises, then solubility will change with pH;

• Ionisable compounds are either acidic or basic;

• In 2000, 63% of drugs were ionisable. Of these, roughly 75% were

weak bases, so…

• We need to understand acid and base behaviour!


• Dissociation will occur in water;

HA + H2O  A   H3O 

• It is possible to derive the following relationships:

[H3O  ][A  ] [A  ]
Ka = pH = pK a  log
[HA] [HA]

Acid dissociation constant Henderson-Hasselbalch equation

Acids and bases

• And for bases

B + H3O   BH  H2O

• Correspondingly

[H3O  ][B] [B]

Ka = pH = pK a  log
[BH ] [BH ]

Note that dissociation constant for bases written as if an acid


Degree of ionisation with pH

Weak base Weak acid
(Ionised) (Ionised)
% Ionised




(Un-ionised) (Un-ionised)
pKa- 2 pKa pKa+ 2
4 5 6 7 8 9 10

Solubility as a function of pH

• Solubility will change with pH as degree of ionisation of drug changes;

• Increasing degree of ionisation increases solubility;

• Can calculate the change in solubility from the Henderson-

Hasselbalch equation.

Solubility as a function of pH

For an acid:
• If [A-] is the saturated concentration of ionised drug, Si ; and,

• [HA] is the intrinsic solubility S0;

• Since total solubility St = S0 + Si, then:

pK a  pH + log or St  So [1  10pH - pK a ]
St  So


Solubility of an acidic drug with pH

Solubility (mg mL )
pKa = 7.4
So = 10 mg mL-1
300 The equation
predicts an infinite
increase in
200 solubility - but
in practice solute-
solvent bonds
prevent this!
6 7 8 9

Solubility as a function of pH

For a base:
• If [BH+] is the saturated concentration of ionised drug, Si and

• [B] is the intrinsic solubility S0;

• Since total solubility St = S0 + Si, then:

St  So
pK a  pH + log or St  So [1  10pKa - pH ]

Solubility of a basic drug with pH

Solubility (mg mL )

300 pKa = 4.5

So = 10 mg mL-1




3 4 5 6 7


What does this mean for drug delivery?

Solubility lowest Solubility increasing Solubility highest
if pKa ca. 5-6

Good for modified release products

Stomach Duodenum Small intestine

pH 1-3 pH 5-6 pH 7-8

Good for immediate release products, but may precipitate

Solubility highest Solubility decreasing Solubility lowest


Solubility and pKa data for top 10 drugs 2010*

Product Drug substance pKa Aq. solubility

Lipitor Atorvastatin calcium 4.46 20.4 μg mL-1 (pH 2.1)

1.23 mg mL-1 (pH 6.0)
Plavix Clopidogrel bisulphate n/a 0.05 mg mL -1

Seretide Fluticasone / salmeterol 12.5 / 0.51 μg mL-1

9.9 / sparingly soluble
Nexium Esomeprazole Mg 4.0 0.3 mg mL -1
Seroquel Quetiapine fumarate 6.8 35 mg mL -1 (pH 1)
1.3 mg mL-1 (pH 7.4)
Crestor Rosuvastatin calcium 4.6 7.8 mg mL -1

Zyprexa Olanzapine 7.4 Practically insoluble

*MAB drugs not shown

Dissolution rate

• Solubility and pKa are two very important parameters that define the
in vivo behaviour of a drug substance;

• Solubility is the concentration at equilibrium – but it says nothing

about rate at which equilibrium is achieved!

• Early work by Noyes and Whitney led to:

 k(St  C )
Rate of change of dt
A constant of proportionality

Noyes and Whitney, J. Am. Chem. Soc. 19 (1897) 930


Dissolution model

• Further work led to elucidation of factors that affected k

Diffusion coefficient
Rate of change in mass Surface area

dm DA
 (St  C )
dt h
Thickness of boundary layer

Brunner et al, Z. Phys. Chem. 35 (1900) 283; 43 (1904) 56

Nernst, Z. Phys. Chem. 47 (1904) 52

Theory of dissolution
Solid Boundary layer Bulk solvent


Note that this region is

saturated – we will return to the
Concentration (mg mL )

effects of this in a later lecture

Distance (mm)

Dissolution plot
Concentration (mol L )

The rate of dissolution

is constantly changing!

Time (min)


How is dissolution rate measured?

• With a dissolution test;

• Specified in pharmacopoeia

Dissolution medium important

- Typically 900 mL
- 37 oC
- 0.1M HCl
- pH 7.4 buffer
- Simulated fluid

A typical dissolution bath

Powders/granules held in a basket Dissolution medium placed in
plastic or glass beaker

Sink conditions

• Pharmacopoeia requires dissolution testing to be performed under

‘sink conditions’


Sink conditions

C = St/10
Concentration (mol L )

Concentration (mol L )

Time (min)
C = St /10

Time (min)

Rationale for dissolution testing

• Is dissolution testing designed to predict in-vivo dissolution


• No!

• Originally introduced ONLY as an analytical method to ensure batches

of product met release specification;

• Why is a dissolution test not representative of in-vivo conditions?

In vivo-in vitro correlation (IVIVC)

• Volume of solvent:

Location in GI-tract Condition Volume (mL)

Stomach Fed 686 ± 93
Stomach Fasted 45 ± 18
Small intestine Fed 54 ± 41
Small intestine Fasted 105 ± 72
Large intestine Fed 11 ± 26
Large intestine Fasted 13 ± 12

• Moreover, even this fluid exists in discrete pockets, not as a

continuous phase
Schiller et al, Ailment Pharmacol. Ther. 22 (2005) 971


Other factors

• Biological media are complex:

– Proteins;
– Bile salts;
– High ionic strength.

• Rate of agitation lower than stirring;

• Drug can be absorbed across GI-Tract, so concentration in solution

lower than expected (will increase rate of dissolution);

• pH variable patient-to-patient.


• Solubility is the concentration achieved when solid is in equilibrium

with solution;
• Ideal solubility assumes no heat of mixing (and is maximum
• Solubility in water and solvents generally non-ideal;
• Physical form will affect solubility;
• Knowledge of solubility does not inform dissolution rate;
• Dissolution rate described by Noyes-Whitney equation and measured
with dissolution tester;
• Dissolution testing is in no way representative of in-vivo behaviour
and should be used for release specification testing!