PHYSICOCHEMICAL

PRINCIPLES OF
DRUG ACTION
 INTRODUCTION
Drug molecules interact with biological structures

drug effect

lipoproteins/enzymes
membranes
nucleic acids
 DRUG EFFECT

Drug effect is preceded by drug transport

from site of application to site of action

and is dependent on

physicochemical properties
 PHYSICOCHEMICAL
PROPERTIES
Interatomic distances
Intermolecular forces
Stereochemistry
Partition coefficient
Solubility
Ionization All affect
pharmacokinetics
 PHARMACOKINETICS
ABSORPTION Receptors
Tissue Depots
TO UNDERSTAND unbound
unbound drug ALL drug
Plasma
THIS WE MUST
bound drug unbound drug
UNDERSTAND bound drug

PHYSICOCHEMICAL
bound drug

EXCRETION
PROPERTIES
metabolites
METABOLISM
 PHYSICOCHEMICAL
PROPERTIES
Interatomic distances
Intermolecular forces
Stereochemistry
Partition coefficient
Solubility
Ionization
 PARTITION
COEFFICIENT
Hydrophobic bonding interactions are critical
Can be approximated by partition coefficient
PC
Drug (W) Drug (O)

[drug]O Thus, PC
PC = describes
[drug]W the entire
drug.
 PARTITION
COEFFICIENT
Useful to know the hydrophobic bonding
properties of substituent groups.

Hydrophobic bonding constant  for a

substituent is obtained as a difference
In log P.

 = log PX - log PH
Thus, describes
PX = PC for substituted compound
the substituent.
PH = PC for parent compound
 REPRESENTATIVE
 VALUES
Substituent Aromatic Aliphatic
C6H11 2.51 2.51
n-C4H9 2.00 2.00
Cl 0.76 0.39
H 0.00 0.00
NO2 -0.28 -0.82
COOH -0.28 -1.26
OH -0.67 -1.16
 SOLUBILITY
Drugs must be in solution to interact with
receptors.

Drugs have some degree of solubility in both

aqueous and lipid compartments (PC).
Solubility is a function of:
ionization
molecular structure
molecular weight
stereochemistry
electronic structure
SOLUBILITY of WEAK
ELECTROLYTES
Solubility will be affected by pH.

Acidic drugs barbiturates, NSAIDs

Basic drugs phenothiazines,  -blockers

Amphoterics tetracyclines, ACEIs

 SOLUBILITY of WEAK
ELECTROLYTES
indomethacin

tetracycline

Aqueous
solubility

chlorpromazine

2 6 12
pH
 PREDICTING WATER
SOLUBILITY
Empiric method Analytic method

Solubility in water
ionic compounds, i.e. salts of WA, WB

polar compounds, i.e. those that H-bond

 EMPIRIC METHOD
Solubility Properties of Na Salts of Common
Organic Acids
O O
+ +
R C OH MOH R C O M H2O

O
H H

O
R C O H H
O

H Na
O
H
 EMPIRIC METHOD
Solubility Properties of Na Salts of Common
Organic Acids
RCOO-Na+ Solubility
(g/100g H2O)
C6 H5 55.5
CH3 125.0
CH3CH2 100.0
H2O solubility
can be increased CH3(CH2)16 10.0
by salt formation
 EMPIRIC METHOD
Solubility Properties of Common Organic
Acids
RCOOH Solubility
(g/100g H2O)
CH3(CH2)2 
CH3(CH2)4 1.0

COOH brings into

CH (CH )
3 2 8 0.015
solution 5 – 6 C’s CH (CH ) insoluble
3 2 16
to extent of 1%
 EMPIRIC METHOD
Solubility Properties of Common Alcohols

ROH Solubility
(g/100g H2O)
2-propanol 
1-butanol 7.9

ROH brings into

2-butanol 12.5
solution 5 – 6 C’s 1-pentanol 2.3
to extent of 1%
 EMPIRIC METHOD
Solubility Properties of Common Amines
NR1R2R3 Solubility
R1 R2 R3 (g/100g H2O)
Me H H very soluble
Me Me Me 91
Et H H very soluble
N brings into Et Et Et 14
solution 6 – 7 C’s Ph H H 3.7
to extent of 1%
Ph Me Me 1.4
 EMPIRIC METHOD
Solubility Properties of Common Phenols

ArOH Solubility
(g/100g H2O)
cyclohexanol 3.6
phenol 9.3
p-cresol 2.3
ArOH brings into m-chlorophenol 2.6
solution 6 – 7 C’s
to extent of 1% catechol 45.0
 BASIS OF EMPIRIC
METHOD
For monofunctional compounds a single
functional group (capable of H-bonding)
will bring into solution 5 – 7 carbons to the
extent of 1%.
but

Drugs are usually not simply monofunctional.

Simple summation of “water-solubilizing” potential

may not give accurate predictions.
 EMPIRIC METHOD
Water Solubilizing Potential of Functional Groups
Group Mono Poly
ROH 5-6 C 3-4 C
ArOH 6-7 3-4
ROR 4-5 2
solubility RCHO 4-5 2
defined as R2CO 5-6 2
 1% N(R)3 6-7 3
RCOOH 5-6 3
RCOOR 6 3
RRNCOR 6 2-3
Urea, carbamate, etc 2
 EMPIRIC METHOD
CH2CHCOOH
tyrosine
NH2
HO

Prediction: 17 – 20 C
COOH 5–6C should be brought into
OH 6–7C solution.

NH2 6–7C Only 9 C present, so

should be >1% soluble.

Experimental Results: 0.045% solubility

WHY?
 EMPIRIC METHOD
O
intramolecular ionic
CH2CHC O
bonding reduces solubility

HO NH3 pH adjustment increases

solubility

Polyfunctional data compensates for intra- and inter-

molecular bonding.

Group Mono Poly

ROH 5-6 C 3-4 C
ArOH 6-7 3-4
 EMPIRIC METHOD
OCH3 C21 H23 NO 5
C19 H19 NO 4 CH3COO
HO

O
O
O N NCH3
CH3
CH3COO

Mono 5 + 5 + 5 + 7 + 7 = 29 6 + 6 + 5 + 7 = 24
soluble soluble

Poly 2 + 2 + 2 + 3 + 4 = 13 3 + 3 + 2 + 3 = 11
insoluble insoluble
 ANALYTIC METHOD
[drug]octanol
log P is a measure
log P =
[drug]water of the solubility
of the whole drug

 is the log P of the fragment

solubility logPcalc =  fragments

defined as
>3.3% if calc. logP is > +0.5 then compound is H2O insoluble

if calc. logP is < +0.5 then compound is H2O soluble

 ANALYTIC METHOD
 Values for Organic Fragments
Fragment  Value
C (aliphatic) +0.5
phenyl +2.0
Cl +0.5

solubility O2NO (nitrate) +0.2

defined as IMHB + 0.65
>3.3% S 0.0
OCO, OCN -0.7
O, N -1.0
O2N (aliphatic) -0.85
O2N (aromatic) -0.28
 ANALYTIC METHOD
1. table is only a brief compilation
2.  values are approximations

3.  values depend on whether fragment aromatic

or aliphatic

4.  values are obtained under nonionizing conditions

5. intramolecular H-bonding must be considered

6. values for heterocycles can be estimated
 ANALYTIC METHOD
O Et
H2N C O CH2CH2 N procaine
Et

6 C @ +0.5 +3.0
solubility
defined as phenyl +2.0
>3.3% 2 N @ -1.0 -2.0
O=C-O -0.7
insoluble
+2.3
 ANALYTIC METHOD
S

chlorpromazine
N Cl
CH3
CH2CH2CH2N
CH3

5C @ +0.5 +2.5
solubility
defined as 2 Ph @ +2 +4.0
>3.3% Cl +0.5
2 N @ -1 -2.0 Exp. +5.3
S 0.0
Calc. +5.0
 ANALYTIC METHOD
H
O N O
amobarbital
CH3CH2 N
H
CH3CHCH2CH2
O
CH3

9C @ +0.5 +4.5
solubility
defined as 1 O @ -1 -1.0
>3.3% 2 OCN @ -0.7 -1.4
Exp. +2.1
Calc. +2.1
 ANALYTIC METHOD
O
Me
OCH2 C NH S penicillin V
Me
N
O COOH

7C @ +0.5 +3.5
solubility
defined as 1 O @ -1 -1.0
>3.3% 3 OCN, OCO @ -0.7 -2.1
1 Ph @ +2 +2.0 Exp. +2.1
S 0.0
Calc. +2.4
 ANALYTIC METHOD
CH2OH
CHOH glycerol
CH2OH

3C @ +0.5 +1.5
solubility
defined as 3 O @ -1 -3.0
>3.3%

Calc. -1.5 Exp. –1.7