Dr.

Mahwish Akhtar
Ph.D. (Pharm. Chem.)
Assistant Professor
DCOP, DUHS

MEDICINAL CHEMISTRY I
617
Lecture 13
4th year, 7th semester
 OBJECTIVES
• At the end of lecture student will be able to
• Water solubility of drugs
• Hydrogen bonding
WATER SOLUBILITY OF
DRUGS
WATER SOLUBILITY OF DRUGS
 WATER SOLUBILITY OF DRUGS
PARTS OF SOLVENT
g/L
DESCRIPTIVE TERM REQUIRED FOR 1
In water
PART OF SOLUTE
Very soluble ≤1 ≥ 1000

Freely soluble 1 to 10 1000 to 100

Soluble 10 to 30 100 to 33

Sparingly soluble 30 to 100 33 to 10

Slightly soluble 100 to 1000 10 to 1

Very slightly soluble 1000 to 10,000 1 to 0.1

Insoluble ≥ 10, 000 ≤0.1

 HYDROGEN BONDING

• Increased water solubility

• Intra-molecular hydrogen bond
decreases water solubility
• Dipole-dipole bonds
• Unequal sharing of electrons
– Adenine-thymine
– Guanine-cytosine
 HYDROGEN BONDING

• HYDROGEN BONDING
 HYDROGEN BONDING

• HYDROGEN BONDING
• Electro-negativities
– Oxygen
– Nitrogen
– Selenium
– Sulfur
 HYDROGEN BONDING

• HYDROGEN BONDING CLASSIFICATION

• Intermolecular hydrogen bonding
 HYDROGEN BONDING

• HYDROGEN BONDING CLASSIFICATION

• Intra-molecular hydrogen bonding
 HYDROGEN BONDING

• HYDROGEN BONDING CLASSIFICATION

• Intermolecular hydrogen bonding
• Intramolecular hydrogen bonding
 HYDROGEN BONDING

• HYDROGEN BONDING CLASSIFICATION

 IONIZATION

• IONIZATION
• Ion-dipole interaction
• Cation (deficiency of e- density)
• Anion

Phenylethyl amine & benzoic acid

 IONIZATION

• IONIZATION
• Salt
• Neutral salt with strong acid & base (NaCl)
• Acidic salt (atropine sulfate)
• Basic salt (sodium Phenobarbital)
• Greater separation b/w charge, more water
soluble
 IONIZATION

• 0.45g/1L
EMPIRICAL APPROACH
 EMPIRICAL APPROACH

• EMPIRICAL APPROACH
– If the solubilizing potential of functional groups
exceeds the total no. of carbon atoms present,
then the molecule is considered to be water
soluble
– Functional groups that can interact either
through intramolecular hydrogen or ion-ion
interactions will decrease solubilizing potential
of each group
– Each charge (anion or cation) contribute 20-30 C
EMPIRIC APPROACH
EMPIRICAL APPROACH

2 1 1 2 2
1 8 1 2 0 1
3 7

9 1 1
0 3
6 1
4
5 9 1
1
8
4
Functional groups
1
1 Ester 3C
5
7 1 Amine 3C x 2 =6C
6
Total 9C
Total no. of carbon atoms
21C
Total no. of C atoms > function groups
= 21 > 9 0.01% SOLUBILITY IN WATER

WATER INSOLUBLE
 EMPIRICAL APPROACH

Chloride salt of Anileridine

2 1 1 2 2
1 8 1 2 0 1
3 7

9 1 1
0 3
6 1
4
Cl 5 9 1 Functional groups
1 4
. 8 Ester 3C
1
1 Amine 3C x 2 = 6C
5
7 1
6
Salt or ion 20-30 C
Total 29-39C
Total no. of carbon atoms
21C
Total no. of C atoms > function groups
= 21 > 29-39 20% SOLUBILITY IN WATER

WATER SOLUBLE
 EMPIRICAL APPROACH

Carboxylic acid (3C)

• Mefenamic acid 1
3

1
1 1 4
2
6 7
2 1
1

5 3 8 1
Amine(3C) 0
Functional groups 4 9

Carboxylic acid 3C
B LE
Amine 3C
O LU
Total 6C
IN S
Total no. of carbon atoms
TE R
WA
14
Total no. of C atoms > function groups
= 14 > 6
 EMPIRICAL APPROACH
1

• Naproxen
2

3 4

2 1 1
0 5 1

1
3 1 6
9
8 7 Carboxylic acid (3C)
Ether (2C)

Functional groups B LE
Carboxylic acid 3C O LU
Ether 2C IN S
Total 5C TE R
Total no. of carbon atoms WA
13
Total no. of C atoms > function groups
= 13 > 5
 EMPIRICAL APPROACH

• Atenolol Alcohol (3-4C)

Functional groups
Amide 2-3C
Ether(2C)
Amine 3C
Amine(3C)
Ether 2C
Alcohol 3-4C Amide(2-3C)
Total 10-12C B LE
Total no. of carbon atoms
O LU
13
I N S
Total no. of C atoms > function groups
T E R r B L E
= 13 > 12 WA O LU
S O
I A L
R T
PA
 EMPIRICAL APPROACH
Amide (3C)
• Clorazepate

Functional groups
Amine 3C
Carboxylic acid 3C
Ketone 2-3C
Total 8-9 C Amine(3C) Carboxylic
Total no. of carbon atoms acid (3C)
14
Total no. of C atoms > function groups
B L E
= 14 > 8-9 OLU
I N S
T ER
WA
 EMPIRICAL APPROACH

• Diclofenac acid
Amine(3C)
Carboxylic
acid (3C)
Functional groups
Amine 3C
Carboxylic acid 3C
Total 6C
Total no. of carbon atoms
13
Total no. of C atoms > function groups
B L E
= 13 > 6
OLU
R INS
TE
WA
 EMPIRICAL APPROACH

• Diclofenac Na
Amine(3C)
Functional groups
Carboxylic
Amine 3C
acid (3C)
Carboxylic acid 3C
Ion or salt 20 -30
Total 26- 36C
Total no. of carbon atoms
13
Total no. of C atoms < function groups
= 13 > 26 -36
BL E
S O LU
T ER
WA
 EMPIRICAL APPROACH

Dopamine hydrochloride
Amine(3C)

Functional groups
Phenol (3-4C)
Phenol 3-4C x 2 = 6-8C
Amine 3C
Total 9-11C
Total no. of carbon atoms
8
Total no. of C atoms < function groups
= 8 < 9-11
B LE
O LU
R S
T E
WA
EMPIRIC APPROACH
 WATER SOLUBILITY OF DRUGS

• PARTITION COEFFICIENT (P)

• Ability of drug substance to
partition itself b/w 2 immiscible
solvent (organic/inorganic)

• P = conc in organic medium

conc in aqu. medium
Octanol
Water (7.4)
Shake flask method
 WATER SOLUBILITY OF DRUGS

• Solubility contributions (groups and

substituents) are expressed as hydrophilic
(negative value) or lipophilic (positive value)
fragment constants.
Log Pcalc = Σπ
• Where; Log Pcalc = log of partition coefficient
and Σπ= sum of hydrophilic-lipophilic
constants.
ANALYTICAL APPROACH
ANALYTICAL APPROACH
 WATER SOLUBILITY OF DRUGS

• The molecule is dissected into its various

groups, functionalities and substituents
• Appropriate hydrophilic/lipophilic fragment
constants are assigned and summed
• Compounds with log Pcalc values greater log P
+0.5
than +0.5 are considered water insoluble
(lipophilic) and those with log Pcalc values
less than +0.5 are considered water
soluble (hydrophilic).
 WATER SOLUBILITY OF DRUGS

B L E
O LU
R INS
ATE
W
 WATER SOLUBILITY OF DRUGS
6

4
5
-0.32

2
3 1
+2.15

B L E
OLU
IN S
TE R
WA
 WATER SOLUBILITY OF DRUGS
-0.97

1
-0.32
2
7

0 6
4
3

B L E
OLU
IN S
TE R
WA
 WATER SOLUBILITY OF DRUGS

4 -0.67
3
5

+0.65
6
7

-1.12
-0.02

+2.15
8

9 11

-1.12 10

+0.65 -1.12

WATER INSOLUBLE
 WATER SOLUBILITY OF DRUGS
-1.19

0.00

1
-0.97 Fragments π
2 3 4

+0.82 1 4 aliphatic C +2
+0.71
2 2 aromatic C +1.64
1 phenyl +2.15
+2.15 -0.97 1 Chloride +0.71
-0.32 1 primary amine -1.19
1 sulfur 0.0
2 amides -1.94
B L E 1 carboxyl -0.32
O LU Log P +3.05
R INS
AT E
W
-1.12 WATER SOLUBILITY OF DRUGS
1 -0.27
2

B LE
3 4
-0.27
O LU
N S
5-6
16
TE RI
7
15
17
WA
10
9 11 12 18
8

1 3 13
Fragments π
2
4
14 18 aliphatic C +9
+0.82 * 4 4 aromatic C +3.28
1 alcohol -1.12
2 carboxyl -0.54
Log P +10.62
 WATER SOLUBILITY OF DRUGS

p-Hydroxybenzoic acid Salicylic acid

π Value Fragment π Value Fragment
+2.0 Phenyl +2.0 Phenyl
-1.0 OH -1.0 OH
-0.7 COOH -0.7 COOH
- - +0.65 IMHB
+0.3 +0.95 Sum

Water soluble Prediction Water insoluble Predictio

n
 REFERENCES
• Foye’s the Principles of Medicinal Chemistry, 6th ed,
Lippincott William & Wilkins
• Textbook of medicinal chemistry, Vol 1, by V.
Alagarsamy, Elsevier.