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26/09/2017

UCL SCHOOL OF PHARMACY

PHAYG062 – Preformulation

Solubility
Dr Gareth Williams

g.williams@ucl.ac.uk; 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.

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Equilibrium solubility

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


solution

Drug ( s)  Drug(aq )

Solution is saturated

If a drug can ionise, then the solubility of


the un-ionised form is called the intrinsic
solubility

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


temperature;

• 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.

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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).

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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

• How does this compare with measured solubilities in different


solvents?

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

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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
H H
If so, the solute is termed polar – water is a polar δ+ δ+
molecule and the general rule is ‘like dissolves
like’

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.

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Solubility as a function of temperature

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


temperature:

 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
1/Temperature (K )

Solubility and physical form

• 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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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!

Acids

• 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

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Degree of ionisation with pH


Weak base Weak acid
100
(Ionised) (Ionised)
80
% Ionised

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 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:

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

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Solubility of an acidic drug with pH


-1
Solubility (mg mL )
400
pKa = 7.4
So = 10 mg mL-1
300 The equation
predicts an infinite
increase in
200 solubility - but
in practice solute-
solvent bonds
100
prevent this!
Intrinsic
solubility
0
6 7 8 9
pH

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 ]
So

Solubility of a basic drug with pH


-1
Solubility (mg mL )
350

300 pKa = 4.5


So = 10 mg mL-1
250

200

150

100

50
Intrinsic
solubility
0
3 4 5 6 7
pH

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What does this mean for drug delivery?

Acid
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

Base

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
trihydrate
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:


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

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

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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

St

Note that this region is


saturated – we will return to the
Concentration (mg mL )
-1

effects of this in a later lecture

Distance (mm)

Dissolution plot
St
Concentration (mol L )
-1

The rate of dissolution


is constantly changing!

Time (min)

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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
- FeSSIF
- FaSSIF

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’

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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)

Rationale for dissolution testing

• Is dissolution testing designed to predict in-vivo dissolution


behaviour?

• 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

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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.

Summary

• Solubility is the concentration achieved when solid is in equilibrium


with solution;
• Ideal solubility assumes no heat of mixing (and is maximum
solubility);
• 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!

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