Acid-Base Properties

of Drugs

Homework

This is part of course 3303202 INTRO PHAR CHEM , Class of 2 /1 2557

Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Science, Chulalongkorn University.

-
o
o Neutral / Acidic / Basic
o
o /

Indomethacin
Alkylcarboxylic acid

pKa (4-5)

arylether

arylamide

Aryl chloride

Indomethacin

Indomethacin pKa = 4.5

Acidic Properties of Imide

Unionized form resonance N

enol form

Keto form

pKa = 9 - 10

enol form

Imide

Imidate ion

Acidic Properties of Imide

o
o

Imidate ion

Imide O Imidate ion

O /
o Resonance Effect Inductive Effect

-dicarbonyl

Sulfonimide Vs Imide
Sulfonimide: Sulfo+ Imide

pKa = 9 - 10
o

o
o
o

pKa = 5- 6

2
o Keto-enol tautomerization O=S=O
o resonance
O=S=O C=O
Sulfonimidate ion resonance form Imidate ion (Sulfonimide
Resonance form Imide)
Sulfonimide Imide

Phenobarbital
Imide

Imide

Imide group

Phenobarbital

Phenobarbital

Enol form

Keto form

Phenobarbital Imide
?
o Electron ( =O 3
)
o H 2
()
2-

( keto form enol form

pKaphenobarbital = 7.5

Saccharin
pKaSaccharin = 1.6

o
o
o

Saccharin Sulfonimide
Benzene

Saccharin resonance form Sulfonimide

Ephedrine
2o Alkylamine pKa (2o Alkylammonium, 10-11)

pKa = 9.6
Hydroxyl group
o

o
o
o

Ephedrine 2o Alkylamine
Hydroxyl Group

Saccharin resonance form Sulfonimide

10

Ciprofloxacin
o pH [ ] = 0.01,0.1 1 M
o Ciprofloxacin form , form

11

HendersonHasselbalch
equation

= + log

HendersonHasselbalch equation

12

Ciprofloxacin
Ox
Flo

Ac

In

In

In

Ci:Cyclo
Pro:Propyl
Flo:Fluoro
Ox:Oxo = Ketone
Ac:Acid= Carboxylic acid
In:Amine

1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid

Ciprofloxacin

Cipro. Acid Base

Ciprofloxacin Zwitterion

Ciprofloxacin
/ Zwitterion

o
o
o

pKaCOOH > pKaNH2+

pH
-COOH --> -COO- + H+ -NH2+ --> -NH + H+
pKa1 pKaCOOH pKa2 pKaNH2+ Zwiterion

1 = 6.0

2 = 8.8

Ciprofloxacin

, 1 = 6.0

, 2 = 8.8

Ciprofloxacin

Mass balance equation-MBE : = + + + + +

Charge balance equation-CBE : + + 3 + = +
1 =

+ 3 +
+

, 2 =

3 +
+

= [3 + ][ ]

+ 3 +

2
+
+ 3 =
+
1
3 +
3 +
+

3 + 2
+ 1 = 2 + +
1

2 + +
+
1

= 7.4
Amphoterics

+1

2 +
+
1

1 2 = 3.98107 108

3 + =

1 2

Amphoterics ()
pH

Ciprofloxacin
3 + =

2 + +
+
+1
1

108.8 + + 1014
+
+1
106

3 +

Ciprofloxacin

+
+
= + log +
2 = + log

HendersonHasselbalch equation

1
+
=
1 + 2 log
2

+ = Isoelectric point

1
; = 1 + 2
2

Ciprofloxacin

= =

1 + 2 6.0 + 8.8
=
= 7.4
2
2

pH 7.4 ??

3 + =

2 + +
+
1

+1

1 2

1 + 2
=
2

Zwitterion ()
pH = pI
Amphoterics Zwitterion pI HCO3-

Ciprofloxacin

1
+
=
1 + 2 log
2

1
= 1 + 2
2
1

=
log
2
+

pH > pI
pH < PI
?

Ciprofloxacin
1

+
= + log +

+
1 = log +

Isoelectronic point;
= = 7.4

+ =

+
6.0 7.4 = 1.4 = log +

+ > + =

>
+/-

=
+

Ciprofloxacin
1

=
log
2
+

+
2 = log

+
1 = log +

pH Isoelectronic point pKa1;

1

0>
log
2
+

+ > +

+ >

>
+

+
0 < log

+
0 < log +

+ >

>
+/-

Ciprofloxacin
1

=
log
2
+

+
2 = log

+
1 = log +

pH pKa1 Isoelectronic point

1

0>
log
2
+

+ > +

+ >

>
+/-

+
0 < log

+
0 > log +

+ >

>
+

Ciprofloxacin
1

=
log
2
+

+
2 = log

+
1 = log +

pH Isoelectronic point pKa2

1

0<
log
2
+

+ > +

+ <

>
+/-

+
0 < log

+
0 > log +

+ >

>
-

Ciprofloxacin
1

=
log
2
+

+
2 = log

+
1 = log +

pH pKa2;
1

0<
log
2
+

+ < +

+ <

<
+

+
0 > log

+
0 > log +

+ <

<
+/-

Ciprofloxacin

+/

Ciprofloxacin
2 = 8.8

1 = 6.0

( 5.6 7)
( 1.0 3.5)

6.0

7.4

8.8

Ciprofloxacin

Un-ionized form

Carboxylate ion -

Ammonium ion +

Zwitterion

??




Ion-Dipole Dipole-Dipole H Bond
Dipole-Dipole Interaction
Ion-Dipole Interaction

Interaction

30

 Zwitterion
Zwitterion [ ] + -
Ionic compound
Zwitterion [ ]
Zwitterion - + + -
H bond

Zwitterionic form of tyrosine showing intramolecular ion-ion interaction

- + H bond

+-
31
dimer

 Ciprofloxacin

Ciprofloxacin Zwitterion Tetramer

Zwitterion Ciprofloxacin
+

Intermolecular
force H Bond , Ion-Dipole
force
Zwitterion
Ciprofloxacin
Tetramer Intermolecular
force
32

!!

33

34

Electron