Dr.

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

MEDICINAL CHEMISTRY I
617
Lecture 9-12
4th year, 7th semester
 OBJECTIVES
• At the end of lecture student will be able
to
• Define physicochemical properties
• Define Ferguson principle and acid/base
properties of drugs
PHYSICOCHEMICAL
ACTIVITIES
 INTRODUCTION
• Pharmacokinetics • Pharmacodynamics
• Branch of • Branch of
pharmacology pharmacology
concerned with the concerned with the
movement of drugs effects of drugs and the
within the body mechanism of their
– Absorption action
– Distribution – Action
– Metabolism – Mechanism of action
– Excretion
– Toxicity
 INTRODUCTION
• Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
– Toxicity
 PHYSICOCHEMICAL ACTIVITIES
• Ferguson principle
• Acid base properties
• Relative strength (pKa value)
• Degree of Ionization
• Water solubility of drugs
– Hydrogen bonding
– Ionization
• Predicting water solubility: Empiric Approach
• Predicting water solubility: Analytical Approach
FERGUSON PRINCIPLE
 FERGUSON PRINCIPLE

• Ferguson’s principle states that substances

that are present at the same proportion
saturation in a given medium have the same
degree of biological action
• Structurally nonspecific drugs
• Structurally specific drugs
 FERGUSON PRINCIPLE

STRUCTURALLY NONSPECIFIC
S. No STRUCTURALLY SPECIFIC DRUGS
DRUGS
Biological action is directly related to Biological action does not directly
1
thermodynamic activity related to thermodynamic activity
Thermodynamic activity value varied Thermodynamic activity value is below
2
from 0.01 to 1 0.01
High doses are needed for biological
3 Effective in low concentration
activities
Chemical structure are different, but
Some structural characteristics in
4 they produce similar biological
common to produce biological responses
responses
Slight modifications in their chemical Slight modifications in their chemical
5 structure do not result in pronounced structure may result in substantial
changes in biological action changes in biological action
ACID BASE PROPERTIES
 ACID BASE PROPERTIES

• Most of drugs are small organic

molecules that behave in solution as
either weak acids or weak bases.
 ACID BASE PROPERTIES

• Absorption
• Excretion
• Bio-distribution
• Partitioning characteristics
• Compatibility with other drugs
• Ionized form is more water soluble b/c
of charge
 ACID BASE PROPERTIES
• The human body contains 70 to 75% water, which amounts
to approximately 51 to 55 L of water for a 160-lb (73-kg)
individual. For an average drug molecule with a molecular
weight of 200 g/mol and a dose of 20 mg, this leads to a
solution concentration of approximately 2 × 10−6 M (2
mM). When considering the solution behavior of a drug
within the body, we are dealing with a dilute solution, for
which the Brönsted-Lowry acid–base theory is most
appropriate to explain and predict acid–base behavior.
 ACID BASE PROPERTIES
Amphoteric character of water
• Bronsted Lowry theory
– Acids ---- H+ donor Hydronium ion
– Base -----H+ acceptor
 ACID BASE PROPERTIES

• Conjugate acid
• Conjugate base
 ACID BASE PROPERTIES

• Conjugate acid
• Conjugate base
IONIZATION AND pKa VALUE
ACID BASE PROPERTIES
ACID BASE PROPERTIES
ACID BASE PROPERTIES
ACID BASE PROPERTIES
RELATIVE ACID STRENGTH
(pKa value)
 IONIZATION AND pKa VALUE

• pKa
• pKa is defined as the pH were a drug exists as
50% ionized and 50% unionized
• If pKa - pH = 0, then 50% of drug is ionized
and 50% is unionized
 RELATIVE STRENGTH (pKa value)

• Degree of dissociation (pKa)

• Increased ionization--- increased water
solubility
• Leveling effect of water
 IONIZATION AND pKa VALUE
Biological activity
Depend on ionized form;
increased with
increased ionization
• Ionized molecules
– Aceylcholine
– Quartenary salt as ganglionic
blocking agents, muscle
relaxants, antiseptics
Depend on unionized form;
decreased with
increased ionization
• Un-dissociated molecules
– Un-dissociated --- Cross
membrane
– Tetracycline
– Local anesthetics, d-
tubocurarine, phenol
 RELATIVE STRENGTH (pKa value)

• Hydration of ions
• Increases
• size of drug increases
• difficult diffusion through pores.
 RELATIVE STRENGTH (pKa value)

Weakly acidic drugs Weakly basic drugs

• Phenytoin, • Guanithidine
barbiturates • Ionized
• Unionized • poorly absorbed
• transport rapid
• pH in-depended
 PREDICITING THE DEGREE
OF IONIZATION OF MOLECULE
pH of Human Intestine
 IONIZATION AND pKa VALUE

• Ionized • Non-ionized
• Water soluble • Lipid soluble
• Poor absorption • Absorbed well (cell
through membranes are
– Stomach composed of lipids)
– BBB
– Placenta
 IONIZATION AND pKa VALUE

ACIDIC DRUG BASIC DRUG

ACIDIC
NON IONIZED IONIZED
ENVIRONMENT

BASIC
IONIZED NON IONIZED
ENVIRONMENT
IONIZATION AND pKa VALUE
IONIZATION AND pKa VALUE
 IONIZATION AND pKa VALUE
• pKa <2: strong acid; conjugate base has no
meaningful basic properties in water
• pKa 4 to 6: weak acid; weak conjugate base
• pKa 8 to 10: very weak acid; conjugate base
getting stronger
• pKa >12: essentially no acidic properties in
water; strong conjugate base
 IONIZATION AND pKa VALUE

• When the pH is lower than the pKa,

– The un-ionized form of a weak acid predominates,
– The ionized form of a weak base predominates
 IONIZATION AND pKa VALUE

• Henderson-Hasselbalch equation
• FOR ACIDIC DRUGS

pH = pKa + log Ionized drug concentration [A-]

Unionized drug concentration [HA]

% ionization = 10 pH- pKa x 100

1+ 10 pH- pKa

Strong acid has low pKa value

weak acid has high pKa value
 IONIZATION AND pKa VALUE

• FOR BASIC DRUGS

pH = pKa + log Unionized drug concentration [B]
Ionized drug concentration [BH+]

% ionization = 10 pKa - pH x 100

1+ 10 pKa - pH

Strong base has high pKa value

weak base has low pKa value
IONIZATION AND pKa VALUE
 IONIZATION AND pKa VALUE

• Percent Ionization of Aspirin [Stomach]

pKa of Aspirin [weak acid] = 3.4 (50% HA and A- at pH 3.4)
pH stomach = 1.4 pH
pH = pKa + log (A-)/(HA)
pH - pKa = log (A-)/(HA)
1.4 – 3.4 = log (A-)/(HA)
- 2 = log of 0.01= -2 (stomach)
A- / HA= 0.01/ 1 so HA is 100 fold greater than A-
HA moves from the stomach into the blood (good absorption)
 IONIZATION AND pKa VALUE

• Blood (pH=7.4)
pH - pKa = log (A-)/(HA)
7.4 – 3.4 = 4 log of 10,000 = 4 (blood)
A- / HA= 10,000/ 1 so A- is 10,000 fold greater than HA
Stomach blood
A- + HA ↔ HA + A-
[.01] + [1] [1] + [10,000] 10,000/1
 IONIZATION AND pKa VALUE

• Calculate % ionization
– A basic drug with a pKa of 7.8 is a known
teratogen. If given IV to woman whose blood pH
is 7.4.
 CALCULATE % IONIZATION

Acidic drugs Basic drugs

• Salicylic acid • Atropine

• Levodopa • Diazepam

• Methotrexate • Morphine

• Phenytoin • Imipramine

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