PHARMACEUTICAL CHEMISTRY -1

Lecture 2
Physicochemical
properties

Asmaa Mohamed Atta, PhD

 Outline
1 Physicochemical properties

2 Routes of drug administration

3 Lipinski rule of five

4 Dissociation constant (pKa)

5 Partition coefficient (log P)

 Physicochemical properties of drugs
 Approximately 30-40 % of potential drugs are latter rejected for their
inappropriate pharmacokinetic properties.
 The physicochemical properties of compounds (partition coefficient and
dissociation constant) have been used to predict or estimate pharmacokinetic
processes (ADME).

Chemical Physical and

Biological
structure of chemical
activity
drug properties
 Physicochemical properties of drugs
Any modification in chemical structure may lead to considerable changes in
biological activity.

Morphine N-methylmorphine Heroin

 Pharmacokinetic

Pharmacokinetics examines the movement of a drug

over time through the body (ADME):
A - Absorption
–Movement of drug from site of application into
bloodstream.
D - Distribution
–Movement of drug from blood to target site of action.
M - Metabolism
–Transformation of the drug, usually with the aid of an
enzyme.
E - Excretion
–Elimination of drug from body.
 Routes of drug administration
Parental route
 The three main parenteral routes are
intravenous (I.V), intramuscular (I.M) and
subcutaneous (S.C).
 The intravenous route of administration by
passes the absorption step (immediately
available to body fluids for distribution to the
site of action. (Physicochemical properties
are less important)
 In case of I.M and S.C, drug passes some
membrane barriers to reach blood
circulation. [Physicochemical properties are
more important].
 Routes of drug administration
Enteral route:
1- oral
 The oral route places the greatest demands
on the chemical and physical properties of
the drug,
 Several factors can influence the
dissolution rate of drug from solid dosage
forms. These factors include solubility of a
drug, particle size and surface area of drug
particles and rate of disintegration.

Dosage Dissolution Absorption

Drug in solution Drug in general circulation
form
 Routes of drug administration
1- Oral route
 The gastrointestinal and other biologic membranes act like lipid barriers.
 The un-ionized form (more lipophilic) of drug is preferentially absorbed.
 Most drugs are absorbed by passive diffusion (movement of drug from high
concentration to low concentration).

Cell membrane Passive transport

 Routes of drug administration
Oral route (first pass metabolism)
 Most drugs absorbed from the GI tract undergo
first-pass metabolism in the liver (portal
circulation), where they may be extensively
metabolized before entering the systemic
circulation.
 Drugs that exhibit high first-pass metabolism
should be given in sufficient quantities to ensure
that enough of the active drug reaches the target
organ.

 Orally taken drugs have to be chemically stable to survive the acidic conditions of
the stomach and metabolically stable to survive digestive and metabolic enzymes.
 Routes of drug administration
2- Sublingual
 Drugs diffuse into the capillary network and therefore enter the systemic
circulation directly.
 Advantages: avoidance of the harsh GIT environment and avoidance of first-pass
metabolism.
 Lipinski’s Rule of Five
 Also known as Pfizer's rule of five or simply the rule of five (RO5).
 The rule was formulated by Christopher A. Lipinski in 1997.
 Lipinski's rule states that, in general, an orally active drug has no more than
one violation of the following criteria:
Note: All numbers
are multiples of 5
1- A molecular mass less than 500 daltons which if the origin of
rule’s name.
2- Partition coefficient (log P) does not exceed 5 (not > 5).

3- No more than 5 hydrogen bond donors (the total number of OHs and NHs).

4- No more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms).

 Lipinski’s Rule of Five
Which of the following compounds obeys Lipiniski’s rule of five and why ?
Cephalexin Ceftriaxone

Molecular weight = 347.1 Molecular weight = 554.57 X

Log P = 0 Log P = -1.7
No. of H-bond donor = 4 No. of H-bond donor = 5
No. of H-bond acceptor = 7 No. of H-bond acceptor = 15 X
 Dissociation constant (pKa)
 The drug passes through hydrophobic lipid membrane in its
unionized form.
 The degree of ionization of drug is therefore an important parameter
that determines what amount of unionized drug (soluble in lipid) is
available for transport across lipid membrane.
 The fraction of the drug existing in its un-ionized form in a solution
is a function of both the dissociation constant of a drug (pKa) and
the pH of the solution at the absorption site.
 Dissociation constant (pKa)
For weak acids
HA H+ + A -
Acid proton conjugate base
unionized ionized

[H+] [A-]
Ka = Where Ka is the dissociation constant
[HA]
Acidity pKa
pKa = - log Ka

The higher the pKa value the weaker the acid.

The lower the pKa value the stronger the acid.
 Dissociation constant (pKa)
Henderson Hasselbach equation
The Henderson-Hasselbalch equation can be used to calculate the percent ionization of
a compound at a given pH.
For weak acid
Benzoic acid
pH – pKa = log [Ionized] [RCOO-]
[Un-ionized] pH - pKa = log
[RCOOH]

If pKa of acid = pH of medium [unionized] = [ionized].

If pKa of acid > pH of medium the unionized form predominates.
If pKa of acid < pH of medium the ionized form predominates.
Common acidic organic functional groups and their conjugate base
Acid (pka) Structure Conjugate base
Sulfonic acid (0-1)

Arylcarboxylic acid (4-5)

Alkylcarboxylic acid (5-6)

N-Arylsulfonamide (6-7 )

Imide (9-10)

Phenol (9-11)
 Dissociation constant (pKa)
Henderson Hasselbach equation
For weak base

B + H+ BH+
Base Conjugate acid
unionized Ionized phenylpropanolamine
[R-NH3+]
[Ionized] pKa - pH = log
pKa – pH = log [R-NH2]
[Un-ionized]

If pKa of base = pH of medium [unionized] = [ionized].

If pKa of base > pH of medium the ionized form predominates.
If pKa of base < pH of medium the unionized form predominates.
Common basic organic functional groups and their conjugate acid

Base (pka) Structure Conjugate acid

Guanidine (12-13)

Amidine (10-11)

Alkylamines (2° 10-11)

Alkylamines (1° 9-10)

Arylamine (9-11)

Imine (3-4)
 Dissociation constant (pKa)
 Most drugs are either weak acids or weak bases.
 There's always equilibrium between unionized
& ionized forms of the drug. When part of
unionized part is absorbed, some ionized forms
are converted into unionized forms to restore
equilibrium.
 Most weak acidic drugs are predominantly in
the un-ionized form at lower pH of the gastric
fluid and therefore, are absorbed from the
stomach.
 Most weak bases are poorly absorbed in the
stomach, because they are present largely in the
ionized form at pH 1 to 2.
 Partition coefficient
 Some drugs are poorly absorbed after oral administration
even though they are available predominantly in the un-
ionized form in the gastrointestinal tract. This is attributed
to the low lipid solubility of the un-ionized molecule.
 Therefore, the hydrophobic character of a drug is crucial
to how easily it crosses cell membranes and may also be
important in receptor interactions.
 The most commonly used measure of lipophilicity is P,
this is the partition coefficient of a molecule between an
aqueous and lipophilic phases, usually water and octanol.
Partition coefficient is more
Conc. of compound in organic layer (octanol)
 P= commonly expressed as log
Conc. of compound in aqueous layer (water) P values.
 Partition coefficient
 The octanol/water partitioning system seems to mimic the lipid
membranes/water systems found in the body

 Hydrophobic molecules will prefer to dissolve in the octanol layer of this two
phase system, whereas hydrophilic molecules will prefer the aqueous layer.

Hydrophobic compounds high log P value

Hydrophilic compounds low log p value

 Compounds having a log P value close to 2 should be capable of entering the

CNS efficiently.
For example, the most potent barbiturates for sedative and hypnotic activity are
found to have log P values close to 2.
 Partition coefficient
 Examples of polar or hydrophilic molecules that are poorly absorbed following
oral administration and therefore must be administered parentally include
gentamicin, ceftriaxone.
 Partition coefficient
 Log P is a measure of the lipid/water solubility characteristics of the entire
molecule.
 Each functional group contained within the molecule contributes to the overall
hydrophilic/hydrophobic character of the molecule.
 This contribution is known as the substituent hydrophobicity constant (π) and
is a measure of how hydrophobic a substituent is relative to hydrogen.
πX = log PX - log PH

PH is the partition coefficient for the standard compound (parent).

PX is the partition coefficient for the standard compound with the substituent
(derivative).
 A positive value of π indicates that the substituent is more hydrophobic than
hydrogen.
 A negative value of π indicates that the substituent is less hydrophobic.
 Partition coefficient
Calculate the hydrophobic substituent constant (π) for CONH2
group?

Benzene Benzamide
(log P = 2.13) (log P = 0.64)

πCONH2 = log Pbenzamide - log Pbenzene

= 0.64 - 2.13
= - 1.49 ( less hydrophobic)
 Partition coefficient
Calculate the hydrophobic substituent constant (π) for chloro
substituent?

Benzene Chlorobenzene
(log P = 2.13) (log P = 2.84)

πCl = log Pchlorobenzene - log Pbenzene

= 2.84 - 2.13
= 0.71 (more hydrophobic than hydrogen)
 Partition coefficient
Calculate log P of m-chlorobenzamide?

πCONH2 = -1.49 πCl = 0.71 log P benzene = 2.13

Benzene m-chlorobenzamide
(log P = 2.13) Log P = ?

Log P m-chlorobenzamide = log P benzene + πCl + πCONH2

= 2.13 + 0.71+ (-1.49)
= 1.35