Dr. B.

Madhu Harika
Vikas Institute of Pharmaceutical sciences
 The ability of a chemical compound to elicit a
pharmacological/ therapeutic effect is related to the
influence of various physical and chemical
(physicochemical) properties of the chemical substance
on the bio molecule that it interacts with.
1)Physical Properties
Physical property of drug is responsible for its
action
2)Chemical Properties
The drug react extracellularly according to
simple chemical reactions like neutralization,
chelation, oxidation etc.
 PartitionCoefficient
 Covalent Bonding
 Hydrogen Bonding
 Chelation
 Surface activity
 Redox potential
 Enantiomerism
 Geometrical isomerism
 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.
 P[Unionized molecule] = [drug]lipid
[drug]water
P[Ionized molecule] = [drug]lipid
[1-a ][drug]water
a=degree of ionization in aqueous
solution.
 Factors affecting Partition Co-efficient

 pH
 Cosolvents
 Surfactant
 Complexation

 Partition Co-efficient are difficult to measure in

living system.
 They are usually determined in vitro 1-octanol as a
lipid phase and phosphate buffer of pH 7.4 as the
aqueous phase.
 • The Partition co-efficient, P is dimensionless and
its logarithm, log P is widely used as the measure
of lipophilicity.

• The log P is measured by the following methods.

1) Shake flask method
2) Chromatographic method
3) Spectroscopy method

• Phenobarbitone has a high lipid/water partition

coefficient of 5.9. Thiopentone sodium has a
chloroform/water partition coefficient of about
100, so it is highly soluble in lipid.
 surfactant is defined as a material that can reduce the surface
tention of water at low concentration.

 Surface active agents affect the drug absorption

which depends on:

1.The chemical nature of surfactant

2.Its concentration
3.Its affect on biological membrane and the miscelle
formation.
 At lower concentration the surfactant enhances the
absorption rate, the same in higher concentration
reduce the absorption rate.

Applications:

1.The antihelmentic activity of hexylresorcinol

2.Bactericidal activity of cationic quaternary
ammonium compounds.
3.Bactericidal activity of aliphatic alcohols.
4.Disinfectant action of phenol and cresol.
 Covalent bonding forms a strongest
interaction between drug and receptor or
protein.
 It produces irreversible binding.
 Prolonged drug action
 Eg: anticancer drugs and DNA
 Insecticides and enzymes
 Penicillin and bacterial cell wall
 The hydrogen bond is a special dipole-dipole
interaction between non bonding electron pairs of
hetero atoms like N, S, O and electron deficient
hydrogen atom in polar bonds such as OH, NH, F etc.
These are weak bonds and denoted as dotted lines.
O-H…….O, HN-H…….O,

• The compounds that are capable, of forming

hydrogen bonding is only soluble in water.
 Hydrogen bonding is classified in 2 types.
1) Intermolecular hydrogen bonding
H

R-O-H O R H O H H O H

H O H
H H-O-R
O H
O H

O
O
C
N

OH
O
 C6H5

CH3 N
N
O

H3C

1-phenyl-3-methyl-5-pyrazolone is inactive.
C6H5

HN H
N
O HN
O

H3C
H3C
Salicylic acid(O-Hydroxy Benzoic acid has antebacterial activity

O
H

O
C

OH

para and meta Hydroxy Benzoic acids are inactive.

O O

OH C HO C

OH OH
CHELATION
 DEFINITON: The compounds that are
obtained by donating electrons to a metal
Ion with the formation of a ring structure
are called chelates.

 LIGANDS: The compounds capable of

forming a ring structure with a metal are
termed as ligands.
a)Antidote for metal poisoning

1.Dimercaprol is a chelating agent.

CH2SH CH2S

As++ As
CHSH + CHS

CH2OH CH2OH

2.Penicillamine
CH3 CH3 CH3
++
H CU H H
CH3 C C COOH CH3 C C COOH CH3 C C COOH

SH NH2 S NH2 S NH2

CU
UC
1:1 chelate
NH2 S

1:2 chelate HOOC

CH3
CH3
 b)8-Hydroxyquinoline and its analogs acts as antibacterial and
anti fungal agent by complexing with iron or copper.

 C) Undesirable side effects caused by drugs, which chelates

with metals .
 A side effect of Hydralazine a antihypertensive agent is
formation of anemia and this is due to chelation of the drug
with iron.
  The oxidation-reduction potential may be defined as
a quantitative expression of the tendency that a
compound has to give or receive electrons.
 The redox potential of a system may be calculated
from the following equation.
 E=E0+0.0592/n log[conc. of reductant /conc.of oxidant]

 Examples of interfering with natural redox system in

biological conditions:

 1) Riboflavin analogues
 The biological activity of riboflavin is due to E =-0.185 volt.
 OH

OH
OH
OH

OH OH
OH OH

Cl N N O
N N O

NH
Cl N
NH
O
N
Dichloro riboflavin
O
riboflavin
Riboflavin analogue E0 = -0.095V
Riboflavin E0 = -0.185 V

2).The optimum bacteriostatic activity in quinones is associated

with the redox potential at +0.03 volt, when tested against
Staphylococcus aureus.
 Most of the drugs are either weak acids or base and can
exist in either ionised or unionised state.
 The ionisation of the drug depends on its pKa & pH.

 The rate of drug absorption is directly proportional to the

concentration of the drug at absorbable form but not the
concentration of the drug at the absorption site.

 Eg: Aspirin in stomach will get readily absorbed because it is in

the un-ionosed form(99%).

 Eg; Barbituric acid is inactive because it is strong acid.

5,5 disubstituted Barbituric acid has CNS depressant
action because it is weak acid.
Acids are two types-Unionized acid - HA
Ionized acid - BH +

HA H2O H3O+ A-
Unionized Conugate
Conjugate
Acid base
acid

BH+ H2O H3O+ B

ionised Conugate Conugate
acid base

According to Henderson-Hasselbalch equation

PH = pka+log[Un ionised form]\[ionised
form

% ionisation = 100\( 1+10 (pH-pka) )

 By using drug pKa, the formulation can be
adusted to pH to ensure maximum solubility
in water or maximum solubility in non-polar
solvent.

 The PH of a substance can be adjusted to maintain

water solubility and complete ionisation.
 Eg:Phenytoin injection must be adjusted to Ph 12 with Sodium
Hydroxide to obtain 99.98% of the drug in ionised form.

 Tropicamide eye drops,an anti cholinergic drug has a pka of

5.2 and the drug has to be buffered to Ph 4 to obtain more than
90% ionisation.
The drug most possess a high degree of structural specificity or stereo
selectivity.

Many drugs show stereo selectivity because mostly reeptor binds are
optically active biological macromolecules such as protein, polynuclootide or
glycolipds.

For e.g. Diethyl stilbosterol

OH
HO OH

HO
cis-diethylstibesterol
trans-diethylstibesterol Only 7% activity
Estrogenic activity of the trans isomer
 Optical Isomers (enantiomers)
 Stereochemistry, enantiomers, symmetry and chirality
are impotant concept in therapeutic and toxic effect of
drug.

 A chiral compound containing one asymmetric centre

has two enantiomers. Although each enantiomer has
identical chemical & physical properties, they may have
different physiological activity like interaction with
receptor, metabolism & protein binding.

 A optical isomers in biological action is due to one

isomer being able to achieve a three point attachment
with its receptor molecule while its enantiomer would
only be able to achieve a two point attachment with the
same molecule.
 CH3 CH3

H NHCH3 H NHCH3

H OH HO H

MP = 37-39 MP = 118-120

1 gram/20 mL 1 gram/200 mL

Ephedrine Pseudoephedrine
(Erythro) (Threo)
 The category of drugs where the two isomers
have qualitatively similar pharmacological
activity but have different quantitative
potencies.
O
O

OH
OH

O O O O

(s)-(-)warfarin (R)-(+)warfarin
 OH
HO OH

HO
cis-diethylstibesterol
trans-diethylstibesterol Only 7% activity
Estrogenic activity of the trans isomer