Download Lec. # 2

King Saud University
College of Pharmacy
Pharm. Chem. Dept.
PHC 271
1428/1429 H
Lec. # 2
Some Physicochemical Properties of Drugs
Acid-Base Properties:
ý The acid-base properties of drug molecules directly effect:
ü Absorption.
ü Excretion.
ü Compatibility with other drugs in solution.
ý Theory, an acid is any substance capable of yielding a proton (H+), and a base
is any substance capable of accepting a proton.
Acid:
e.g.: acetic acid
Base:
e.g.: methylamine
ý Strong acids and bases completely dissociate or accept a proton in aqueous
solution to produce their respective conjugate bases and acids.
ý They undergo 100% dissociation in water with equilibrium shifted completely
to the right side.
ý Many different organic functional groups behave as acids or bases, and these
are listed in table 1 and 2 respectively.
ý Organic functional groups that cannot give up or accept a proton are
considered to be "neutral" or non-electrolyte with respect to their acid-base
properties, table 3.
ý Passive diffusion is the only route responsible about the transport of the unionized form of the drug. Drugs usually weak acids or weak bases and their
degree of dissociation depend on the pH of the environment which is either
acidic (stomach) or basic (intestine).
ý Dissociation constant for both weak acids and weak bases are expressed as
pKa values.
Dissociation constant (pKa):
ý Henderson-hassalbach equation can be used to calculate the percentage
ionization of a compound at a given pH.
[acid form]
pKa = pH + log
[base form]
ý Because pKa is a constant for any given molecule, the ratio of acid to base
will determine the pH of the solution. Conversely, a given pH determines
the ratio of acid to base.
ý This equation expresses the dissociation of weak acids (e.g. aspirin) and
weak bases (e.g. amphetamine) as follows:
a) Weak acids
- Example
COO-
COOH
pKa 3.4
+
H+
OCOCH3
OCOCH3
(ionized)
Aspirin (un-ioized)
Q.: At pH of stomach (1), what is the percent ionization of aspirin?
Answer:
3.4 = 1 + log acid / base
2.4 = log acid/base
Acid
10
2.4
=
251
=
Base
1
251 . 100
% acid form =
= 99.6% nu-ionized aspirin
252
ý Calculation indicates that 99.6% of the molecules are in the acid (unionized) form, leaving 0.6% I the conjugate base (ionized) form.
Accordingly stomach is the site of absorption of aspirin.
b)
Weak bases:
- Example
pKa 9.5
NH2
+
Amphetamine (un-ionized)
H+
NH3
(Ionized)
Question: At pH of 6 (pH of intestine), calculate the %ionization of amphetamine?