PHYSICOCHEMICAL PROPERTIES

1
PHYSICOCHEMICAL PROPERTIES
?
Interatomic distances
?
Intermolecular forces
?
Stereochemistry
Partition coefficient
?
?
Solubility
All affect pharmacokinetics
Ionization
2
IONIZATION (pKa)
Pharmaceutical Applications of pKa
Drug absorption
Distribution elimination
Solubility and compatibility
Chemical stability
Pharmacodynamics
Drug Analysis
3
IONIZATION of DRUGS
Drug Absorption Transport Depends on
Drug solubility
Partition coefficient
Ionization
Drug Transport is a Compromise Between
Increased H2O solubility of ionized
Superior passage of unionized (undissociated)
4
IONIZATION of DRUGS
IN GENERAL drugs pass through membranes in
undissociated form but act as ions, if possible
pKa range of 6 8 seems most favorable (for
passive transport)
5
CALCULATION OF IONIZATION
Ionizable drugs (weak acids bases) do so,
depending upon
Dissociation constant (pKa)
pH of the environment
OBJECTIVE develop equations that permit
calculation of ionization of a drug (weak
acid/base) in a given environment
6
WEAKLY ACIDIC DRUGS
Ka
acid 1
conjugate acid 2
conjugate base 1
base 2
Henderson-Hasselbalch
7
WEAKLY ACIDIC DRUGS
8
WEAKLY BASIC DRUGS
Autoprotolysis Constant of Water (Kw)
Kw
use this equation to define the OH term on next
slide
use this equation to define the Kb term on next
slide
9
WEAKLY BASIC DRUGS
Kb
conjugate acid 1
conjugate base 2
base 1
acid 2
10
WEAKLY ACIDIC DRUGS
11
WEAKLY BASIC DRUGS
12
IONIZATION SUMMARY
Remember
For an acid drug, the smaller the pKa, the
stronger the acid
For a basic drug, the larger the pKa (i.e. the
smaller the pKb), the stronger the base
13
IONIZATION SUMMARY
A useful relationship
Acid strength may be expressed as Ka or Kb of its
conjugate base.
Ka of an acid may be calculated if Kb is known.
Stronger the acid, the weaker its conjugate base.
14
IONIZATION Examples
propranolol
What does this pKa refer to?
i.e. is there an acidic functional group?
pKa 9.45
Is drug acidic, basic, amphoteric?
Kb
conjugate acid 1
conjugate base 2
base 1
acid 2
What is the pKb?
4.55
15
IONIZATION Examples
sulfasalazine
What do the pKas refer to?
i.e. are there acidic and/or basic functional
groups?
pKa 2.4, 9.7, 11.8
Ka
conjugate acid 2
base 2
conjugate base 1
acid 1
16
IONIZATION of POLYPROTIC DRUGS
Polyprotic bases accept gt1 proton
Polyprotic acids donate gt1 proton
Each dissociation stage has an equilibrium express
ion and therefore pKa.
H3PO4
Ka1 7.5 x 10-3
pKa1 3
Ka2 6.2 x 10-8
pKa2 8
Ka3 2.1 x 10-13
pKa3 13
17
IONIZATION of POLYPROTIC DRUGS
Polyprotic acids donate gt1 proton
Each dissociation stage has an equilibrium express
ion and therefore pKa.
It becomes progressively more difficult to
donate protons
pKa1 7.4
pKa2 12 - 13
phenobarbital
18
IONIZATION of AMPHOTERIC DRUGS
Drugs function as acids or bases
One group is generally dominant.
pKb6.13
pKa 7.87
morphine
dominant
pKa 9.85
19
FACTORS THAT AFFECT pKa
1. Method of Determination
Potentiometric titration
Spectrophotometry
Capillary electrophoresis
Raman spectroscopy
Magnetic resonance
Conductimetry
20
FACTORS THAT AFFECT pKa
2. Temperature
Temperature changes generally have modest effect
pKa
21
FACTORS THAT AFFECT pKa
3. Solvent
pKa affected by dielectric constant of solvent
pKa with DC of solvent
Water is a relevant but poor solvent
80 aqueous 2-methoxyethanol is useful
22
FACTORS THAT AFFECT pKa
4. Electronic and related factors
Intramolecular H-bonding
Steric factors
Stereochemical factors
?
Acid/base recognition
23
ACID/BASE RECOGNITION
Acidic Hydrogens on O, N, S, C
Oxygen
The higher the electronegativity of X, the
stronger the acid
8-11
0-2
2-5
14
16
aroyl
sulfonyl
gt
gt
acyl
gt
aryl
gt
H
gt
alkyl
24
ACID/BASE RECOGNITION
Acidic Hydrogens on O, N, S, C
Nitrogen
acids
neutral amides
bases
gt
gt
gt
gt
gt
6-8
25
ACID/BASE RECOGNITION
exceptions to neutral amides
6-8
bases
acids
neutral amides
gt
gt
gt
gt
gt
acylureas
RCONHCONHR
imides
RCONHCOR
8-10
7-9
ureides
barbiturates
13
RNHCONHR
hydantoins
carbamates
13
RNHCOOR
26
ACID/BASE RECOGNITION
Acidic Hydrogens on O, N, S, C
Sulfur
9-11
5-7
Carbon
Ketones
gt20
4-12
?-Diketones
?10
?-Triketones
?5
27
ACID/BASE RECOGNITION
Bases
acids
neutral amides
bases
gt
gt
gt
gt
gt
weak
strong
6-8
e-donating groups increase basicity
e-withdrawing groups decrease basicity
28
BASICITY
Stronger Bases
Weaker Bases
aliphatic amines
aromatic amines
3.5
10.8
Neutral
diaryl amines
9.3
29
BASICITY
Heterocyclics Containing Nitrogen
Are they basic?
?
?
?
?
?
?
?
?
?
X
X
?
?
?
X
?
?
?
X
X
30
PREDICTION of pKa VALUES
Electron-withdrawing substituent
Electron-donating substituent
acid weakening
acid strengthening
base strengthening
base weakening
Heteroaromatic N and aromatic NO2
8.4
8.7
31
PREDICTION of pKa VALUES - ACIDS
1. Aliphatic acids RCH2COOH
R1R2CHCOOH
pKa 4.8 ? 0.1
2. Aliphatic acids RC(CH3)2COOH
pKa 5.0 ? 0.1
32
PREDICTION of pKa VALUES - ACIDS
3. Acid strength increases with increases
in I effect
X H
4.75
X-CH2COOH
I
3.12
Cl, Br
2.86
F
2.66
33
PREDICTION of pKa VALUES - ACIDS
4. Increase in of I groups
increases the acidity
Cl-CH2COOH
2.86
1.30
Cl2-CHCOOH
0.65
Cl3-CCOOH
34
PREDICTION of pKa VALUES - ACIDS
5. I effect decreases with increasing
distance
Cl-CH2COOH
2.86
4.08
Cl-CH2CH2COOH
4.52
Cl-CH2CH2CH2COOH
35
PREDICTION of pKa VALUES - ACIDS
6. Alkyl groups decrease acidity
H-COOH
3.77
4.75
CH3-COOH
4.88
CH3CH2-COOH
(CH3)3C-COOH
5.05
36
PREDICTION of pKa VALUES - ACIDS
7. Phenols more acidic than alcohols
9.9
8.4
6.0
7.1
0.38
8.7
0.9
37
PREDICTION of pKa VALUES - BASES
Nitrogen is the most important basic element in
uncharged bases
pKa values of typical alkylamines 9-11
Remember this pKa refers to the conjugate acid
formed by the base
10.6
38
PREDICTION of pKa VALUES - BASES
1. Aliphatic primary amines RCH2NH2
pKa 10.8 ? 0.2
2. Aliphatic secondary amines RCH2NHCH2R
pKa 11.15 ? 0.2
39
PREDICTION of pKa VALUES - BASES
3. Aliphatic tertiary amines N(CH2R)3
pKa value is 10.5 less (0.2 x n) where n is the
number of Me groups attached to the nitrogen
N(CH3)3
10.5 (0.2 x 3) 9.9
steric hindrance
actual value 9.8
40
PREDICTION of pKa VALUES - BASES
4. Saturated rings fused to aromatics are
equivalent to methyls
by extension
4.42
4.77
10.65
10.68
4.92
4.87
41
PREDICTION of pKa VALUES - BASES
5. Conjugation of amine will decrease
basicity
4.25
2.5
5.3
1.O
2.78
5.06
0.9
42
PREDICTION of pKa VALUES - BASES
6. Amides and nitriles much less basic than
amines
0.18
0.61
7. Imines, heterocyclic amines, guanidines
5.15
11-14
43
IONIZATION and DRUG ACTION
knowing pKa and pH allows determination of
ionization
100 ionized when pH is ? 2 units above pKa
Acidic groups
Basic groups
100 ionized when pH is ? 2 units below pKa
44
IONIZATION and DRUG ACTION
Acidic drugs that are highly ionized at pH 7.4
All gt 99 ionized
45
IONIZATION and DRUG ACTION
Basic drugs that are highly ionized at pH 7.4
All gt 85 ionized
46
IONIZATION and DRUG ACTION
Groups on receptors may also be highly ionized at
pH 7.4
All gt 99 ionized
47
IONIZATION and DRUG ACTION
Groups on receptors may also be highly ionized at
pH 7.4
All gt 98 ionized
48
PREDICTING pKa VALUES
benzylpenicillin
3
expected pKa (from table)
predicted pKa (your estimate)
3
actual pKa (experimental)
2.76
49
PREDICTING pKa VALUES
sulfadiazine
aniline
sulfonam
pyrimid
expected pKa (from table)
3-5
6-8
1-2
predicted pKa (your estimate)
3
6
1-2
actual pKa (experimental)
2
6.5
?
dominant
50
PREDICTING pKa VALUES
acetazolamide
diazole
sulfonam
expected pKa (from table)
3
6-8
predicted pKa (your estimate)
3
7
actual pKa (experimental)
?
7
dominant
51
PREDICTING pKa VALUES
procaine
Arom N
Aliph N
expected pKa (from table)
3-5
9-11
predicted pKa (your estimate)
3
9
actual pKa (experimental)
3
8.8
52
PREDICTING pKa VALUES
chlorcyclizine
Piperaz 1
Piperaz 2
expected pKa (from table)
7-8
3-4
predicted pKa (your estimate)
7-8
3
actual pKa (experimental)
8.2
2.1
53
PREDICTING pKa VALUES
moxalactam
COOH 1
COOH 2
phenol
expected pKa (from table)
5-7
2-3
8-10
predicted pKa (your estimate)
7
2-3
9
actual pKa (experimental)
7.7
2.5
10.2
54
PREDICTING pKa VALUES
adrenaline
phenol
phenol
amine
expected pKa (from table)
10
10
9-11
predicted pKa (your estimate)
10
12
9-10
actual pKa (experimental)
9.9
11.5
8.5
dominant
55
PREDICTING pKa VALUES
lisinopril
COOH
NH
NH2
proline
expected pKa (from table)
2-3
8-11
8-11
2-3
predicted pKa (your estimate)
2-3
8-9
10
2
actual pKa (experimental)
3.3
7
11
1.7
dominant
56
PREDICTING pKa VALUES
pamaquine
pyridine
aniline
amine
expected pKa (from table)
4-6
3-5
8-11
predicted pKa (your estimate)
5-6
3
10
actual pKa (experimental)
3.5
1.3
10
57
PREDICTING pKa VALUES
aztreonam
NH2
COOH
SO3H
expected pKa (from table)
3-5
2-5
0-2
predicted pKa (your estimate)
3-4
2-3
1
actual pKa (experimental)
3.9
2.9
0.7
dominant
58
PREDICTING pKa VALUES
dicoumarol
enol 1
enol 2
expected pKa (from table)
10-11
10-11
predicted pKa (your estimate)
lt10
lt10
actual pKa (experimental)
5
8
59
PREDICTING pKa VALUES
guanethidine
amine
guanidine
expected pKa (from table)
8-11
11-14
predicted pKa (your estimate)
8-9
12
actual pKa (experimental)
8.3
11.9
60
PREDICTING YOUR FEELINGS