Basic concepts on

biological/mechanism of action
or Physico-chemical properties
of drugs of action of drugs

Department of Pharmaceutical Sciences, NSU

1. Cell Structure
Plasma membrane

Phospholipid bilayer

Cytoplasm Nucleus
 Cell Structure
, animal and plant cells are eukaryotic cells

ucleus contains the genetic blueprint for life (DNA)

luid contents of the cell are known as the cytoplasm

tures within the cell are known as organelles

hondria are the source of energy production

omes are the cell’s protein ‘factories’

endoplasmic reticulum is the location for protein synthesis

2. Cell Membrane
Proteins
Exterior
High [Na+]

Phospholipid
Bilayer

Interior
High [K+]
2. Cell Membrane

C H 2C H 2N M e 3
O
Polar Polar
Head O P O
Head
Group Group O

CH2 CH CH2
O O
O O

Hydrophobic Tails

Hydrophobic Tails
Cell Membrane
• The cell membrane is made up of a phospholipid bilayer

• The hydrophobic tails interact with each other by van der

Waals interactions and are hidden from the aqueous media

• The polar head groups interact with water at the inner and
outer surfaces of the membrane

• The cell membrane provides a hydrophobic barrier around the

cell, preventing the passage of water and polar molecules

• Proteins are embedded in the cell membrane (ion channels,

receptors, enzymes and transport proteins)
3. Drug targets
Lipids
Cell membrane lipids

Proteins
Receptors
Enzymes
Transport
proteins
Structural
proteins (tubulin)

Nucleic acids
DNA
RNA

Carbohydrates
Cell surface carbohydrates
Antigens and
recognition molecules
3. Drug targets
• Drug targets are large molecules - macromolecules
• Drugs are generally much smaller than their targets
• Drugs interact with their targets by binding to binding sites
• Binding sites are typically hydrophobic hollows or clefts on
the surface of macromolecules
• Binding interactions typically involve intermolecular bonds
• Most drugs are in equilibrium between being bound and unbound
to their target
• Functional groups on the drug are involved in binding
interactions and are called binding groups
•
 Drug Design: Pharmacological
Activity
Structure - Mechanism of action
(Interaction with target)

ture - Physiochemical properties (Bioavailability etc)

• Acid / base properties
• Water solubility
• Partition coefficient ADME
• (Crystal structure)
• Stereochemistry

Absorbtion. Distribution, Metabolism, Excretion

What must a drug do other than bind?

An “ideal” oral drug must be

able to:

Physico-chemical  dissolve
 survive a range of pHs (1.5 to
properties of the drug 8.0)
 survive intestinal bacteria
substances  cross membranes
 survive liver metabolism
 avoid active transport to bile
 avoid excretion by kidneys
 partition into target organ
What are physicochemical properties?
 Physical and chemical reactions involved in the
formation of or changes in the structure of atoms
and molecules and their interaction affecting the
drug kinetics.
 Physical Properties/Processes
( Influence on drug and formulation)
 Chemical Properties/Processes
( Influence on drug and formulation)
Physico-Chemical Properties of
Drugs
Physical Chemical

Solubility Partition Coefficient

Permeability Isomerism

Physical State Intermolecular Forces

Particle Size Ionization

Melting Point pH

Polarity Functional Group

Physical Properties

 Solubility
First requirement for drug absorption

• less or no solubility yields minimal or

no response/effect from the drug
 SOLUBILITY OF ORGANIC MEDICINAL
AGENTS (OMAs)
Importance of solubility:

(1) Formulation of the drug in an appropriate dosage form and

(2) Bio-disposition: Disposition of OMAs in the living system after
administration (absorption, distribution, metabolism, and
excretion).
The solubility expression: in terms of its affinity/philicity or
repulsion/phobicity for either an aqueous (hydro) or lipid (lipo) solvent.
Majority of OMAs possess balanced solubility (have some degree of solubility
in both aqueous and lipid media).

Because there is a need for OMAs to move through both aqueous (plasma,
extracellular fluid, cytoplasm, etc.) and lipid media (biologic membranes) in
 Solubility Prediction
Lipophilic
Hydrophilic
Hydrophilic Lipophilic

OH O
O2N CH CH NH C CHCl2
CH2OH

Chloramphenicol

Hydrophilic

The presence of oxygen and nitrogen containing

functional groups usually enhances water solubility.
While lipid solubility is enhanced by nonionizable
hydrocarbon chains and ring systems.
Methods to improve solubility of drugs

1) Structural modification
2) Use of co solvents
3) Employing surfactants
4) Complexation
Permeability
 way how substances “travel through” cellular
membranes

To reach the site of action the drug has to cross one or more
membrane barriers

poor permeability can lead to poor absorption across the GI

mucosa or poor distribution throughout the body

Sufficient solubility and membrane permeability is an

important factor for oral absorption.
Drugs penetrate different tissues at
different speeds, depending on the
drug's ability to cross membranes. For
example, the anesthetic thiopental, a
highly fat-soluble drug, rapidly enters
the brain, but the antibiotic penicillin, a
water-soluble drug, does not. In general,
fat-soluble drugs can cross cell
membranes more quickly than water-
soluble drugs can.
 Solutions
Physical Properties
Emulsions
 Physical State
Suspensions
 solid drugs needs to dissociate to
exert its effect, thus it will take time
Capsules

to elicit a response compared to a

Coated Tablets
drug in liquid form.
 Particle Size
Enteric Tablets

smaller
Modified particle
Release Tabletssize

higher dissolution rate

faster absorption
 Physical Properties
 Polarity
“LIKE DISSOLVES LIKE”
 To get across most membranes, the drug must be relatively NON-
POLAR (lipophilic)
 To be soluble in water, a drug must be POLAR (hydrophilic)

Acidic and/or basic properties of OMAs are important in both:

1- Pharmaceutical phase (dosage formulation, etc.) and

2- Pharmacological phases (disposition, structure at target site, etc.).

 2- Recognition of acidic or basic organic functional
groups
1- Common acidic organic functional groups
◙Carboxylic acid (-COOH)
◙Phenol (Ar-OH)
◙Sulfonamide (R-SO2NH2)
◙Imide (R-CO-NH-CO-R)
◙-Carbonyl group (-CO-CHR-CO-)
O +
O
+ H3O+ R SO2 NH2 + H2O R SO2 NH- + H3O
+ H2O R C
R C -
O
O H Sulfonamide
Carboxylic acid
O O
-
O O R
H R
R N- + H3O+
R + H2O + H3O +
N H + H2O
R R
O O
Phenol
Imide
NH3 + NH2
+
R + H2O R + H3O

Anilinium cation
2-Recognition of acidic or basic organic functional
groups(cont.)

2- Common basic organic functional groups

◙Aliphatic 1º (R-NH2), 2º (R2NH) and 3º (R3N)-

amines
◙Heterocyclic amines
◙Aromatic amines (Ar-NH2)
R NH2 NH3 +
R +
R N + H3O R N H+ H2O
+
+ H3O+ + H2O
R R
Aliphatic amines Aromatic amines

+ H3O+ + H2O
N NH
N N+
N N
Heteroaromatic amines R Pyridine H Imidazole
Piperidine
 Estimation of the Relative Acid/Base
Strength

The negative log of the ionization constant (pka) also indicates the
relative strength of the acid or base.

An acid with a pka of 5 (ka=1x10-5) is weaker (less ionized) than one with
pka of 3

Whereas a base with a pka of 9 is stronger (more ionized) than one with a
pka of 7

E.g. Ionization of weak acid (e.g. acetic acid, pka =4.76) is as follows:
- +
CH3COOH CH3COO + H

NH4+ + H2O NH3 + H3O+

Acidic and Basic Functional Group - Salt
Formation
Salt: is the combination of an acid and a base
All salts are strong electrolytes (with few exceptions: mercuric and
cadmium halides and lead acetate)

The salt form of the drug is more soluble than its parent
molecule

Drug salts can be divided into two classes:

1)Inorganic salts: are made by combining drug molecules with
inorganic acids and bases, such HCl, H2SO4, KOH and NaOH. Inorganic
salts are generally used to increase the aqueous solubility of a
compound
2)Organic salts: are made by combining two drug molecules, one
acidic and one basic. The saltsalt
Sodium formed byfrom
formation thiscarboxylic
combination
acid: has
increased lipid solubility and generally is used to make depot
RCOO Na + H2O
- +
injections (e.g. procaine
RCOOH + NaOH
penicillin).

R3N + HCl
+
R 3NH Cl
-

Hydrochloric salt formation from an aliphatic amine

The Top Most Common Drug Salts

Hydrochloride (15.5%)
Sodium (9%)
Sulfate (4%)
Acetate (2.5%)
Phosphate/diphosphate
(1.9%)
Chloride (1.8%)
Potassium (1.6%)
Calcium (1.3%)
Citrate (1.2%)
Nitrate (0.9%)
Tartrate (0.8%)
Aluminum (0.7%)
Chemical
Properties
 Partition Co-efficient
 Partition co-efficient is one of the Physico chemical parameter which influencing the drug
transport & drug distribution., the way in which the drug reaches the site of action from the
site of application.
 Partition co-efficient is defined as equilibrium constant of drug concentration for a molecule
in two phases.
 Estimation of partition coefficient
Laboratory Estimation of Relative Solubility

The relative solubility of an organic compound is measured by determining the extent

of its distribution into an aqueous solvent (usually pH 7.4 buffer) and a lipid solvent
(usually n-octanol). These experiments generate a value, P, the partition coefficient for
that particular compound.
P[Unionized molecule] = [drug]lipid
[drug]water
P[Ionized molecule] = [drug]lipid
[1-a ][drug]water
a=degree of ionization in aqueous
solution
Conc. of compunds in C8H16OH
Partition coefficient =
Conc. of compunds in H2O
Chemical Properties
 Ionization
 only the unionized form of a drug can partition through membranes
 the ionized form is more water-soluble (required for drug administration and drug distribution in plasma)
 Only the unionized form of a drug can partition across biological membranes (providing the unionized
form is lipophilic).

 •The ionized form tends to be more water soluble[required for drug administration and distribution in
plasma]
 When the drug become ionized, this will increase its water solubility because there will be a better solvation
by ionic-dipole interaction between ionized drug and water molecule.
Classification

Optical
 Chemical Properties

Constitutional Isomers
 (Sedative drug)
Pentobarbital
(short-acting)  Amobarbital (intermediate-
acting)
18 structural isomers of non-cycloalkanes C8H18
Receptors and Drug Action
Binding
regions

Drug Binding
groups
Pharmacological
response
Intermolecular
bonds
Binding site

Binding Drug

site
Drug

Macromolecular target Macromolecular target

Bound drug
 Drug-Receptor Interactions
vdw
interaction

Drug
H-bond

H ionic
O Phe
bond
Active site Ser
CO2

Asp

receptor
 Chemical Properties
Intermolecular Forces
drugs interact and bind to the binding sites
(receptors/proteins/enzymes) through intermolecular forces

― relatively weak forces must be involved in the drug-receptor

complex yet be strong enough that other binding sites will not
competitively deplete the site of action
ntermolecular bonding forces

1 Electrostatic or ionic bonds

• Strongest of the intermolecular bonds
•Takes place between groups of opposite charge
• The strength of the ionic interaction is inversely proportional to the distance between the two
charged groups
• Stronger interactions occur in hydrophobic environments
•Ionic bonds are the most important initial interactions as a drug enters the binding site

O
Drug Drug NH3 O
O H3N Target Target
O
ermolecular bonding forces
2 Hydrogen bonds
• Vary in strength
• Weaker than electrostatic interactions but stronger than van der Waals interactions
• A hydrogen bond takes place between an electron-deficient hydrogen and an electron-rich
heteroatom (N or O)
• The electron-deficient hydrogen is usually attached to a heteroatom (O or N)
• The electron-deficient hydrogen is called a hydrogen bond donor
• The electron-rich heteroatom is called a hydrogen bond acceptor
• Examples of strong hydrogen bond acceptors
- carboxylate ion, phosphate ion, tertiary amine

• Examples of moderate hydrogen bond acceptors

- + - - amide oxygen, ketone, ester, ether, alcohol
- + - Drug Y H X
X H Y Target Target • Examples of poor hydrogen bond acceptors
- sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic
Drug amine
HBD HBA HBA HBD
• Example of good hydrogen bond donors
- aminium ions (HNR3+)
ntermolecular bonding forces
3. Van der Waals interactions
• Very weak interactions
•Transient areas of high and low electron densities cause temporary dipoles
• Interactions drop off rapidly with distance
• Drug must be close to the binding region for interactions to occur
• The overall contribution of van der Waals interactions can be crucial to binding

Hydrophobic regions

d+ d-Transient dipole on drug

DRUG
van der Waals interaction

d+ d-

d- d+ Binding site
Intermolecular bonding forces

4. Ion-dipole interactions
• Occur where the charge on one molecule interacts with the dipole moment of
another
• Stronger than a dipole-dipole interaction
• Strength of interaction falls off less rapidly with distance than for a dipole-dipole
interaction
R O d-
C
d+
R R O d-
C
d+
O H3N
O C R

Binding site Binding site

ntermolecular bonding forces
5. Dipole-dipole interactions
• Polar molecules have a partial negative end and a partial positive end.
•The partially positive end of a polar molecule is attracted to the partially negative end of another.
•Dipole alignment orientates the molecule in the binding site
• Orientation is beneficial if other binding groups are positioned correctly with respect to the
corresponding binding regions
• Orientation is detrimental if the binding groups are not positioned correctly
• The strength of the interaction decreases with distance more quickly than with electrostatic
interactions, but less quickly than with van der Waals interactions
Intermolecular bonding forces
6. Ion-Induced dipole interactions
• Occur where the charge on one molecule induces
a dipole on another
• Occur between a quaternary ammonium ion and an
aromatic ring

d+
+
R NR3 d-

Binding site
 Chemical Properties

 Functional Group

 Phase I and II reactions

 addition of polar functional groups results in more
water soluble and readily excretable metabolites