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drugs-1
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
[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
O O
[ HSO4 ][ H ]
Ka
[ H 2 SO4 ]
105
Ka
Ka for H2SO4 is approximately 105 1
Weak acid
Strong base
Factors affecting the strength of acid
Cl Cl
OH O
H pKa = 10.0
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…
NH3 NH2
pKa = 9.0
H
10
pH pK a log 10
Dissociate d
Undissocia ted
10p Hp 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.
*
Effect of ionization on pharmacokinetic
and pharmacodynamic profile
What is the importance of studying the pKa values for
Acidic and basic drugs?
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
IN intestine
IN stomach
Gentamicin
Unionized
Ionized = 103
% ionization = 0.1%
So loratadine will be mainly in unionized form
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.
• 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
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
P
No Drug Papp
1 10 pH pKa
H + RCOO X
Absorption
• Papp becomes 198 in the stomach suggesting that absorption will take
place
• 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
• logP < 5.
• No more than 10 hydrogen bond acceptors.
• No more than 5 hydrogen bond donors.
• A molecular weight less than 500 Dalton.
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
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