2. Physicochemical Properties
• Physical and chemical reactions involved in the formation of and change in the
structure of atoms and molecules and their interactions affecting the drug kinetics.
Some are mentioned below
• Ionization constant
• Partition coefficient
• Solubility
• Polymorphism
• Crystallization
• Hygroscopicity
• Surface activity
• Hydrogen bond
• Chelation
4. IONIZATION
• It is protonation and deprotonation which results in charged molecule
• About 85% of marketed drugs contain functional groups that are ionised to some extent at
physiological pH (pH 1.5 – 8).
• The acidity or basicity of a compound plays a major role in controlling
Absorption and transport
Binding
Elimination
• 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-ionised 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.
5. IONISATION CONSTANTS
• Henderson–Hasselbalch equation provides an estimation of ionized and
unionized drug concentration at particular pH range
• FOR ACIDS
pH=pKa + log [ioinized drug]/[unionized drug]
• For BASES
pH= pKa + log [unionized drug]/[ionized drug]
6. Continue…
Weakly acidic drugs for pKa value greater than 3
• Unionized form is present in acidic contents of stomach
• but drug is ionized predominantly in neutral media of intestine
For basic drugs pKa value is 8-9
• Ionized form is predominant in both the stomach and intestines
In general unionized drug is absorbed from GIT
7. PARTITION COEFFICIENTS
• 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.
8. Continue…
• 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.
9. SOLUBILITY
• 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.
• Sufficient solubility and membrane permeability is an
important factor for oral absorption.
• The measurement of aqueous solubility depends upon
the following facts.,
1) Buffer & Ionic strength
2) Polymorphism & Purity of the sample
3) pH
4) Super saturation
5) Thermodynamic Vs Kinetic solubility
10. Application
• The solubility characteristics of a drug can be
increased or decreased by derivatisation.
• Eg: Methyl predinisolone acetate(water insoluble)
is changed to Methyl predinisolone Sodium
succinate(water soluble).
• Eg: Convertion of chloramphenicol(slightly
soluble) to chloramphenicol Palmitate (insoluble)
11. • Methods to improve solubility of drugs
1) Structural modification
2) Use of co solvents
3) Employing surfactants
4) Complexation
12. Polymorphism
• Polymorphism comes from the Greek words, Polus = many and morph = shape.
Thus it is defined as the ability of a substance to exist as two or more crystalline
phases that have different arrangements or conformations of the molecules in the
crystal lattice
Importance
• Polymorphic forms of a drug substance can have different chemical and physical
properties, including melting point, chemical reactivity, apparent solubility,
apparent solubility, dissolution rate, optical, electrical and mechanical properties,
vapor pressure, stability, and density
• These properties can have a direct effect the ability to process and/or manufacture
the drug substance and the drug product, as well as on drug product stability,
dissolution, and bioavailability
13. Applications
• Purification of drugs
• Better processing characteristics
• Improved physical stability
• Ease of handling
• Better chemical stability
• Improved bioavailability
• Manufacture of Sustained release dosage form
14. Crystallization
• A crystal is a solid in which the constituent atoms, molecules, or ions are
packed in a regularly ordered, repeating pattern extending in all three
spatial dimensions.
• The study of the crystalline form as a part of preformulation studies is
termed as crystallinity studies
• crystallization has been applied for thousands of years in the production of salt
and sugar, many phenomena occuring during crystallization are still poorly
understood
• The change in solubility is accomplished by:
• decreasing the temperature of the solution (cooldown Xon)
• Changing composition of solvent by adding a solvent in which the compound is
insoluble (antisovent crystallization)
16. Hygroscopicity
• is the ability of a material to absorb or adsorb moisture from surrounding
environment
• Hygroscopicity of pharmaceutical solids is often evaluated due to the fact that the
up-taken moisture can impact physical and chemical stability of
the pharmaceutical products
• Deliquescence refers to the property of a substance to absorb water from the air
to dissolve itself and form an aqueous solution. Materials with this property are
termed deliquescent. ... In order to be deliquescent, a substance must both
absorb a large amount of water and be sufficiently soluble to dissolve in it.
• Efflorescense is the property of a substance to loose water to form low hydrate or
become anhydrous
17. • Some drugs have tendency to absorb moisture
• The change in moisture level greatly influence chemical
• Stabilty
• Flowability
• Compactibility
• EXAMPLES
• Hygroscopic and deliquicent Ephedrine,Hyoscyamine,Phenobarbital etc
• Efflore
18. SURFACE ACTIVITY
• 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.
19. 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
20. HYDROGEN BOND
• 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.
21. 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.
22. APPLICATIONS
a)Antidote for metal poisoning
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.
23. Redox potential
• 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:
24. APPLICATIONS
• Riboflavin analogues
The biological activity of riboflavin is due to E =-0.185 volt.
•The optimum bacteriostatic activity in quinones is associated with the redox potential
at +0.03 volt, when tested against Staphylococcus aureus.
25. STERIC FEATURES OF DRUGS
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
26. Conformational Isomers
• Different arrangement of atoms that can be converted into one another by
rotation about single bonds are called conformations.
• Rotation about bonds allows inter conversion of conformers.
• A classical example is of acetylcholine which can exist in different conformations.
27. Optical Isomers
• 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.
• E.g. Ephedrine & Psuedoephedrine
28. • The category of drugs where the two isomers
have qualitatively similar pharmacological
activity but have different quantitative
potencies.
29. 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
• Trans-diethystibestrol shows estrogenic activity while cis-diethystibestrol
shows only 7% of activity as compared to that of trans
30. • Longmuir introduced the term isosterism in 1919, which postulated that two
molecules or molecular fragments containing an identical number and
arrangament of electron should have similar properties and termed as isosteres.
• Isosteres should be isoelectric i.e. they should possess same total charge.
• 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
ii)Non classical bioisosters.
31. Classical Bioisosteres
• They have similarities of shape and electronic configuration of atoms, groups and
molecules which they replace.
• The classical bioisosteres may be,
Univalent atoms and groups
i)cl, Br, I ii) CH3NH2, -OH, -SH
Bivalent atoms and groups
i) R-OR,RNH-R, RSR,RSeR
ii) –CONHR, -COOR, -COSR
• Trivalent atoms and groups
i)-CH=, -N= ii) –p=, -AS=
• Tetravalent atoms and groups
=c=, =N=, =P=
32. Non classical Bioisosteres
They do not obey the stearic and electronic definition of classical
isosteres.
• These isosteres retain activity by the retention of their properties
such as pKa, electrostatic potentials, which can alter selective
enzyme processes. Examples
• Halogens cl, F, Br,CN
• Ether -S-, -O-
• Carbonyl group
• Hydroxyl group –
