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.

1. Lecture by- PriyankaBindlish
GGSCOP-Ymaunanagar

2. 2

3. • The abilityof a chemicalcompoundto elicit a
pharmacological/ therapeutic effect is related to the
influence of various physical and chemical (physicochemical)
properties of the chemical substance on the bio moleculethat 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.

4. •Ionization
•Solubility
• Partition Coefficient
•Hydrogen Bonding
•Chelation
•Protein binding
•Bioisosterism
•Optical andgeometrical isomerism

5. 5
 Most of the drugs are either weak acids or base and can exist in
either ionised or unionised state.
 Ionization = Protonation or deprotonation resulting in
charged molecules.
 The ionization 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.

6.  Ionization form imparts good water solubility to the drug which is
required of binding of drug and receptor interaction
 Unionized form helps the drug to cross the cell membrane.
 Unionized form- nonpolar-----can cross capillary wall + cell
membrane
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9. pKa --------- transport,distribution,absorption
pKa< 2 strong acids
pKa= 4-6 weak acids
pKa = 8-10 very weak acids
pKa > 12 no acidic proerty
Acidic drug basic drug
pKa = 4-5 pKa = 9-10
Non ionic in stomach non ionic in intestine
Partly Absorb in stomach absorb in intestine
Partly in intestine

10. ♣lipophilic................... Lipid loving
♣hydrophobic............... water hating
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11. Importance of solubility:
(1)Formulation of the drug in an appropriate dosage form and
(2) Bio- disposition: Disposition of drugs in the living system after
administration (absorption, distrib ution, metabolism, and
excretion).

12. • The solubility of a substance at a given temperature is defined as
the concentration of the dissolved solute, which is in equillibrium
with the solid solute.
• Solubility depends on the nature of solute and solvent as well as
temperature , pH & pressure.
• The solubility of drug may be expressed in terms of its
affinity/philicity or repulsion/phobicity for either an aqueous or
organic solvent.
• The atoms and molecules of all organic substances are held
together by various types of bonds (e.g. hydrogen bond, dipole –
dipole, ionic bond etc.)
• These forces are involved in solubility because it is the solvent-
solvent, solute-solute, solvent-solute interactions that governs
solubility.

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14. Solubility of organic medicinal agents
In order for a chemical compound to dissolve in a particular
solvent/ medium the compound must establish attractive forces
between itself and molecules of the solvent.
Polar drug non polar drug
Hydrophilic lipophilic
The most important intermolecular attractive forces (bonds)
that are involved in the solubilization process are:
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15. 13
•The relative solubility of a drug is a function of the presence of
both lipophilic and hydrophilic features within its structure,
which serve to determine the extent of interaction with lipid
and/or aqueous phases.
•The relative solubility of a drug can be determined in the
laboratory, i.e. the partition coefficient [P; the ratio of the
solubility of the compound in an organic solvent to the solubility
of the same compound in an aqueous environment (i.e.,
P=[Drug]lipid/ [Drug]aqueous). P is often expressed as a log
value.

16. For example, the relative solubility of a drug is the sum of the
contributions of each group and substituent to overall solubility.
Example:
Examination of the structure of chloramphenicol (indicates the
presence of both lipophilic (nonpolar) and hydrophilic (polar)
groups and substituents.

17. 15
L ip o p h ilic
H y d r o p h i l i c
H y d r o p h i l i c L ip o p h ilic
O 2 N C H C l 2
O H O
C H C H N H C
C H 2 O H
C h l o r a m p h e n i c o l
H y d r o p h i l i c
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.

18. • Partition co-efficient is one of the Physicochemical 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 unionized molecule in two phases.

19. For ionized (acids, bases and salts)
• Partition coefficient responsible to cross the cell
membrane
• The contribution of each functional group & structural
arrangement help to determine the lipophilic or hydrophilic
character of drug molecules.
• It is widely used in QSAR.
P = conc of drug in non aqueous/ conc of drug in
aqueous phase

20. pH
Co solvents
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.

21. • The hydrogen bond is a special dipole-dipole interaction
between the hydrogen atom in a polar bond such as N-H, O-H
or F-H & electronegative atom O, N, F atom.
• Dipoles result from unequal sharing of electrons between
atoms within a covalent bond.
•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 into 2 types:
• Intermolecular
• Intramolecular

22. • It occurs betweentwo or more than two molecules ofthe same
or different compound.
• Due to this increasethe boilingpoint ofthe compound&
increasethe molecular weightofcompoundhencemore energy
isrequired to dissociatethe molecular for vaporization.

23. • H- bonding occurs within two atoms of the same molecules.
• This type of bonding is known as chelation and frequently
occurs in organic compounds.
• Sometimes h-bond develop six or five member rings
• Due to decrease the boiling point
salicylicacid o-nitrophenol
O H
C
O
OH
O H
N
O
O

24. N
N
CH3
H3C
O
Eg.1) Antipyrin i.e. 1- phenyl 2,3- dimethyl 5- pyrazolone has
analgesic activity.
C6H5
HN
H3 C
O
1-phenyl-3-methyl-5-pyrazolone is
inactive.
C6 H5
HN
H
N
H3 C
O
Active form
Can’t form H- bonding
Freely soluble in non-polar
Solvents so easily cross BBB
So have analgesic activity
Inactive form
Intermolecular
H-bond
Less soluble in
non polar
solvents

25. O
H
O
C
OH
OH C
OH
O
HO C
O
OH
Para and meta Hydroxy Benzoic acids are inactive.
Ortho
Active form
Intramolecular H bonding
Less soluble
300 times more partition
coefficient
para
Inactive form
Intermolecular H
bonding
More soluble
less partition
coefficient

26. All physical properties affected by H-bonding,
1. Boiling and Melting point
2. Water solubility
3. Strength of acids
4. Spectroscopic properties
5. On surface tension and viscosity
6. Drug-receptor interaction

27. • Complex of drug molecules can’t cross the natural
membrane barriers, they render the drug biological
ineffectivity.
• The rate of absorption is proportional to the concentration of
the free drug molecules i.e. the diffusion of drug.
• Due to reversibility of the Complexation, equillibrium
between free drug and drug complex
•Drug + complexing agent Drug complex
• Complexation reduce the rate of absorption of drug but not
affect the availability of drug
• Natural complexing agents= Hb and cyanocobalamin

28. 1.Dimercaprol(BAL) is a chelating agent make complex with
mercury , gold , arsenic
a)Antidote for metal poisoning
2.Penicillamine- make complex with copper

29. • Phenobarbital forms a non-absorbable complex
with polyethylene glycol-4000.
• Calcium with EDTA form complex which is increase
the permeability of membrane.
• Tetracyclin- make complex with Ca, Mg, Al ions
Sequestration process-
•Water soluble chelating agents

30. • Thereversible bindingofprotein with non-specific and
non- functionalsite on the bodyprotein without showing
any biological effect is called asprotein binding.
Protein + drug ⇌ Protein-drugcomplex
• Depending on the whether the drug isaweakor strong acid,
baseor isneutral, it canbindto singlebloodproteins to
multiple proteins (sereum albumin, acid-gycoprotienor
lipoproteins).The most significantprotein involvedin the
bindingofdrug isalbumin, whichcomprises more than halfof
blood proteins.

31. protein binding values are normally given as the percentage of
total plasma concentration of drug that is bound to all plasma
protein.
Freedrug(Df) + Freeprotein(Pf) Drug/protein complex (Dp)
Total plasma concentration
Protein drug complex- act as a reservoir
Protein binding affects- solubility, half life, biotransformation,
interaction with other drugs.
Placenta- significance of placenta in protein binding
Advantage & disadvantage of protein binding

32. • Stereochemistry involve the study of three dimensional
nature of molecules. It is study of the chiral molecules.
• Stereochemistry plays a major role in the pharmacological
properties because;
1. Any change in stereo specificity of the drug will affect
its pharmacological activity
2. The isomeric pairs have different physical properties ( pKa
etc.) and thus differ in pharmacological activity.
• The isomer which have same bond connectivity but different
arrangement of groups or atoms in the space are termed
stereoisomer.

33. • Different arrangementofatomsthat canbe converted into one
another byrotation about singlebondsare calledconformations.
• Rotation about bondsallowsinter conversionof conformers.

34. H H
OCOCH3
Staggered
H H
N+ H N+
H
H
H
OCOCH3
Eclipsed
H3COCO H
N
H
H
H
GAUCHE
OCOCH3
N
H
H H
H
Fully Eclipsed

35. 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.

36. Different examples of stereospecificity
(-)Adrenalin (+)Adrenalin
More active less active
Warfarin- anticoagulant drug
used as racemate
S (-) warfarin is 2-5 times more active
than R (+)
(-)hyoscyamine (+)hyoscyamine
15-20 times more active
mydriatic drug

37. Examples where two enantiomers have different pharmacogical
Activities-
L-Thyroxine with S configuration- thyroid activity
D- Thyroxine with R configuration- hypocholesterolemic
D-Penicillamine(S) - antiarthritic drug
L- Penicillamine(R) - extremely toxic
D- Asparagine - sweet taste
L- Asparagine - tasteless

38. (-)-Adrenaline

39. MP = 37-39 MP = 118-120
Ephedrine
(Erythro)
CH3
NHCH3
OH
H
H
Pseudoephedrine
(Threo)
CH3
NHCH3
H
H
HO

40. O
O
OH
O
(s)-(-)warfarin
O
O
H
O O
(R)-(+)warfarin

41. • Geometric Isomerism
Geometric isomerism is represented by cis / trans isomerism
resulting from restricted rotation due to carbon-carbon double
bond or in rigid ring system.
OH
HO OH
HO
trans-diethylstibesterol
Estrogenic activity
E - isomer
cis-diethylstibesterol
Only 7% activity
of the trans isomer
Z-isomer

42. •Geometric isomers have different physical and chemical properties .
so receptor binding is in structurally specific manner.

43. Isosteres should be isoelectric i.e. they should possess same
total charge.
ISOSTERISM
Example
Carboxylate and sulphonamido(SO₂NR)
Chloro and trifluoromethyl (-CF₃)
Amine and methylene (-CH₂-)

44. Bioisosterism is defined as compounds or groups that possess near or
equal molecular shapes and volumes, approximately the same
distribution of electron and which exhibit similar physical
properties.
They are classified into two types.
i) Classical biososteres or essential
ii) Non classical bioisosters or non essential
BIOISOSTERISM

45. The classical bioisosteres may be,
Univalent atoms and groups
i)Cl, Br, I ii) CH₂, NH₂, -OH, -SH
Bivalent atoms and groups
i)R-O-R,R-NH-R, R-S-R, RCH2R
ii)–CONHR, -COOR, -COSR

46. Trivalent atoms and groups
i)-CH=, -N= ii) –p=, -AS=
Tetravalent atoms and groups
=c=, =N=, =P=
Ring equivalent
-CH=CH-, -S-, -O-, -NH, -CH2-

47. i) Replacementof–NH₂ group by–CH₃ group.
Carbutamide
Tolbutamide
R= NH2
R= CH3
ii)Replacementof–OH & -SH
Guanine= -OH
6-Thioguanine= -SH
R SO2 NH CONH(CH2)3CH3
N H
N
N
H 2 N
H N
x

48. They do not obey the stearic and electronic definition of
classical isosteres.
Non-classical biosteres are functional groups with dissimilar
valence electron configuration.
Specific characteristics:
Electronic properties
Physicochemical property of molecule
Spatical arrangement
Functional moiety for biological activity

49. Ether -S-,-O-
Carbonyl group
Hydroxylgroup –OH,CH₂OH
Halogens Cl, F, Br, CN
Catechol
HO
HO
Catechol
O
S
O O

50. O
H
H
H H
H
O
17-ßoestradiol.
OH
HO
trans-diethylstibesterol

51. THANKYOU