Acidity and basicity of Drugs

Pharmaceutical Medicinal Chemistry-I

Dr. Bilal Al-Jaidi

Assistant Professor in Medicinal Chemistry and Drug Design
Faculty of Pharmacy, Philadelphia University-Jordan
Email: bjaidi@philadelphia.edu.jo
 Learning Outcomes
• At the end of this lesson, students will be able to:
– Define what do we mean by acidic and basic drugs.
– Demonstrate how to calculate the % ionization of
drugs.
– Outline the importance of drug dissociation in
different body compartments.
– Explain the effect of drug chemical structure on
ionization.
– Describe how to study the strength of acidity and
basicity
 Ionisation and dissociation
• ACIDS ARE PROTON DONORS
acid is a substance that can dissociate to give H+
and a negative ion (anion) which is called a
conjugate base:
 Ionisation and dissociation
• BASES ARE PROTON ACCEPTORS
Bases can accept a proton to form the positively
charged cation ( conjugate acid of the base):
 pH in different body compartments

Plasma 7.35 – 7.45

Buccal cavity 6.2 – 7.2
Stomach 1.0 – 3.0
Duodenum 4.8 – 8.2
Jejunum & ileum 7.5 – 8.0
Colon 7.0 – 7.5
 O O
Ka
H3C H3C H
OH O

[CH 3COO  ][ H  ]
Ka 
[CH 3COOH ]
1
Ka for CH3CO2H is approximately 10-5 Ka  5
10
i.e. only 1 molecule in 100,000 is DISSOCIATED (ionised).

-log10Ka = pKa

So pKa for acetic acid is 5

 O O
Ka
HO S OH HO S O H

O O

[ HSO4 ][ H  ]
Ka 
[ H 2 SO4 ]
105
Ka 
Ka for H2SO4 is approximately 105 1

i.e. 100,000 molecules are DISSOCIATED (ionised) for every

one undissociated.

The pKa of H2SO4 is therefore -5

 [ PhCH 2 NH 2 ][ H  ]
Ka  
[ PhCH 2 NH 3 ]
1
Ka 
Ka for PhCH2NH3+ is approximately 10-9 (pKa = 9) 109

i.e. only 1 molecule in 1,000,000,000 is DISSOCIATED (UNIONISED).

A weak conjugate acid does not easily donate its proton

(1 molecule in 1,000,000,000 donates a proton)

Therefore a strong base willingly accepts a proton

(1,000,000,000 molecules accept a proton for every one)
Ionization and dissociation of
drugs-2
 pKa is a different term than pH

pH is simply a measure of the [H+] concentration in a

given solution
pH = 1 ...........the environment is acidic
pKa = 1 DOES NOT mean an acidic molecule

pH = 14 ............the environment is basic

pKa = 1 DOES NOT mean a basic molecule
You can’t tell from the pKa value whether the species in
question is acidic or basic

Weak acid

Strong base
 Factors affecting the strength of acid

• The more stable conjugate base (anion) formed, the

stronger the acid will be.

• So any factor will stabilize the anion will increase the

acidity of the group, such as resonance and induction
stabilization.

• Stable negative charge results from lowering the

electron density on the atom
 Cl Cl
pKa = 0.9
Cl C COOH Cl C COO H

Cl Cl

OH O

H pKa = 10.0

Which one is the stronger acid?

 Considering Ka values relates ratio of products to reactants

pKa = 0.9 [Cl3COO  ][ H  ]

Ka 
Cl Cl

Cl C COOH Cl C COO H Ka = 10-0.9

[Cl3COOH ]
1
Cl Cl K a  0 .9
10

OH O
[ PhO ][ H  ]
pKa = 10.0 Ka 
H [ PhOH ]
Ka = 10-10
1
K a  10
10
Phenols are weaker acids than acetates
Ionization and dissociation of
drugs-3
• If the atom has an available lone pair of
electrons, it can act as a base…

• The availability of these electrons will determine

the strength of the base

• As a result of that, aromatic amino group is much

weaker base than aliphatic one
 tertiary amine: methyl groups compared to phenyl
group are better donating groups by induction
(more available lone pair of electrons)

the lone pair of electrons are not

available....delocalized through the phenyl group
(stable by resonance)
 NH2 pKa = 0.5
NH H

NH3 NH2
pKa = 9.0
H

Which one is the stronger base?

 [ Ph2 NH ][ H  ]
pKa = 0.5 Ka 
[ Ph2 NH 2 ]
Ka = 10-0.5
1
K a  0 .5
NH2
NH H

10

NH3 NH2 [ PhCH 2 NH 2 ][ H  ]

pKa = 9.0 Ka 
H [ PhCH 2 NH 3 ]
Ka = 10-9
1
Ka 
109
Aromatic amines are weaker bases than aliphatic amines
• We can quantify how pH changes the ratio of
dissociated to undissociated species as follows:

pH  pK a  log 10
Dissociate d 
Undissocia ted 

10p Hp K a 
Dissociate d  anti log  pH  pK a  
Dissociate d 
Undissocia ted  Undissocia ted 
 Dissociate d 
Undissocia ted 
• For acidic drugs, this ratio describes the %
ionization.

• For basic drugs, this ratio describes the %

unionized form to the ionized form.

*
Effect of ionization on pharmacokinetic
and pharmacodynamic profile
What is the importance of studying the pKa values for
Acidic and basic drugs?

• only the unionised form of a drug can partition across

biological membranes (providing the unionized form is
lipophilic)

• the ionised form tends to be more water soluble

[required for drug administration and distribution in
plasma]
 PARTITIONING OF ACIDS AND BASE

For acidic drugs, with a pKa of 4.0, the ionization state will be as follows

IN stomach

IN intestine
 PARTITIONING OF ACIDS AND BASE

• If the pH shifts the balance towards the unionized

form, the drug would be absorbed.

• If the pH shifts the balance towards the ionized form,

the drug would not be absorbed.

• Assume the pH of the stomach is 2.0 and the pH of

the small intestine is 8.0. Where would you expect
absorption to take place from?
 PARTITIONING OF ACIDS AND BASE

For basic drugs, the ionization will be as follows

IN intestine

IN stomach
 Gentamicin

So we should expect that this compound will not be readily

absorbed though the lipophilic membranes although it is in the
unionized form
 Practice question
• Loratadine is an orally available drug, it has a
pKa of 5, answer the followings according to
its structure:

– Is it basic, acidic or neutral compound?

– Calculate the % ionization:
• In stomach (pH = 2):
• In intestine (pH = 8):
– Based on your calculation, from where do you
think loratadine will be absorbed?
 pH  pK a  log 10
Dissociate d 
Undissociated 
Dissociate d  Unionized 
Undissocia ted  = Ionized  (for basic compounds)
Unionized 
Ionized  = 10-3

% ionization = 99.9% (under stomach pH)

Under intestinal pH:

Unionized 
Ionized  = 103

% ionization = 0.1%
So loratadine will be mainly in unionized form

It will be better absorbed from intestinal

membrane not from stomach
*
Effect of ionization on drug
lipophilicity
 Ionization and lipophilicity

• When the drug become ionized, this will

increase its water solubility because there will
be a better solvation by ionic-dipole
interaction between ionized drug and water
molecule.

• So, once the drug get ionized it will have lower

logP than the unionized from (more polar).
 Ionization and lipophilicity
• Because most drugs are ionizable at different
body pH ranges, the % ionization must be
taken into consideration when we are about
to synthesize or develop certain drug.

• Lipophilicity will determine from where the

drug will be absorbed and what target tissue
will reach.
 Partition coefficient P

P = [Co ]/[Cw]
LogP = Log[Co ]/[Cw].
This equation does not determine the effect of
ionization on the lipophilicity of drugs
Partitioning of acids and base
• Papp can be used to predict the behaviour of a compound at all pH values,
as long as we know P.

• For acids, at pH values below the pKa, Papp = P

• At pH values above the pKa the value of Papp decreases because the
species is ionizing and moving into the aqueous layer.

P
Papp  pH  pKa
1  10
Partitioning of acids and base

• For bases, the equation becomes:

P
Papp  pKa  pH
1  10
 PARTITIONING OF ACIDS AND BASE

Consider drugs that are acids, for example RCOOH, which has a pKa of 4.0, and
a Partition coefficient of 200.
Gut Contents Biological
Membrane

RCOOH RCOOH Drug Absorption

P
No Drug Papp 
1  10 pH  pKa
H + RCOO X
Absorption

• Papp becomes 198 in the stomach suggesting that absorption will take
place

• pH 8.0 in the small intestine, the calculated Papp suggests no absorption.

• This equation allows to predict that an acidic drug whose unionized form
has a very low partition coefficient would not be absorbed.
 Oral administration and absorption

• If a drug is to be absorbed through the mucosal

membranes that line the gut, then it must be in its
lipophilic unionised form to partition out of the aqueous
medium.

• The partition co-efficient of the unionised form will also

determine how much is absorbed.

• The absorption phase of the dose-response curve is

therefore heavily influenced by the pKa and log P of a
drug.
 Oral administration and absorption

Orally administered drugs must have:

• logP < 5.
• No more than 10 hydrogen bond acceptors.
• No more than 5 hydrogen bond donors.
• A molecular weight less than 500 Dalton.

These points are called ‘’ Lipinski’s rule of five’’

• Not more than 7 rotatable bonds.

Applications of drug ionization
 Remember the followings

For acids: 1. a high pka means the species is predominantly

unionised, is a bad proton donor, and a weak acid
2. a low pka means the species is predominantly
ionised, is a good proton donor, and a strong acid

pH < pKa by 2 units, 99% unionised

pH > pKa by 2 units, 99% ionised

For bases: 1. a high pka means the species is predominantly ionised, is a

good proton acceptor, and a strong base
2. a low pka means the species is predominantly
unionised, is a bad proton acceptor, and a weak base

pH < pKa by 2 units, 99% ionised

pH > pKa by 2 units, 99% unionised
 Common acidic functional groups in
pharmaceutical chemistry and their pKa values

R
4-5
OH 10
OH

9.9
<2
O

R NH

8-10
R O
Examples of acidic drugs
 Common basic functional groups in
pharmaceutical chemistry and their pKa values

NH2 10.0 NH2 4.6

R

NH

R 10.6-11.0 HN
N
6.5

R R 9.8-10.8 5.2
N
Examples of basic drugs
Common neutral functional groups in
pharmaceutical chemistry

R
R
O
NH2
R R
O
O
R
O R
NH

O R

O R HN

R R

R
N
OH H
 Molecular properties and routes of administration

• Oral
• rectal
• vaginal
• topical
• parenteral
• Respiratory

• The molecular properties of the drug must be determined before any

route can be considered, but other factors are important
 Factors to consider when choosing
a route of administration

• molecular properties of the drug

• physiological nature of the route
• patient compliance
• onset of action
• the condition being treated
• systemic or local effect (side effects)
• metabolism
1. An introduction to Medicinal Chemistry by Graham L. Patrick. 4th
edition, Oxford, 2009
2. Wilson and Gisvolds text book of organic medicinal and
pharmaceutical chemistry by John H. Black and John M. Beale, jr.
12th edition, Lippincott Williams and Wilkings 2011.
3. Foyes principle of medicinal chemistry by David H. Williams,
Thomas L. Leuke, Williams O. Foye. Lippincott William and
Wilkins. 7th edition, 2013.
The End