Download PHYSICo chemicaL PROPERTIES

DEFINITION:
 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.
Various Physico-Chemical Properties are,
Solubility
Partition Coefficient
Ionization
Hydrogen Bonding
Chelation
Surface activity
Isosterism
ROUTES OF ADMINISTRATION
 The choice of appropriate route in a given situation
depends upon both drug as well as patient related
factors.
 Drugs administered locally or systematically.
 The drugs administered through systemic routes is
intended to be absorbed into blood & distributed all
over.
Different Routes Of Drug Administrations
Oral/
Swallowed
Oral/
Sublingual
Rectal
Epithelial
Inhalation Parentral
Topical: local effect, substance is applied directly where its action is
desired.
 Epicutaneous (application onto the skin), e.g. allergy testing, typical
local anesthesia
 Inhalational, e.g. asthma medications
 Enema, e.g. contrast media for imaging of the bowel
 Eye drops (onto the conjunctiva), e.g. antibiotics for conjunctivitis
 Ear drops - such as antibiotics and corticosteroids for otitis externa
ABSORPTION:
 The process by which the drug is released in the body
from its dosage form is known as absorption.
 Drug absorption is the movement of a drug into the
bloodstream.
 The factors which effect the rate of absorption are
◦ Concentration of the drug
◦ Route of administration
◦ Solubility of the drug
◦ Dissolution rate for solid dosage form
◦ Blood circulation to the site of application and the area of the
absorbing surface in local applications.
◦ Physico-chemical parameters of the drug.
 To reach he site of action the drug has to cross one or more
membrane barriers .
 The main process by which a drug molecule cross the neutral
barrier is,
◦ Simple diffusion
◦ Facilitated diffusion
◦ Pore transport
◦ Diffusion of the ion across the membrane
◦ Active transport
◦ phagocytosis
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DISTRIBUTION:
 Once the drug has been absorbed into the blood ,it
distributed around the body. It get distributed throughout
the blood supply , with in a minute. As the blood
recirculates, the drug moves from the bloodstream into
the body's tissues.
 Drug is evenly distributed through out the blood supply,
this does not mean the drug is evenly distributed around
the body . Since he blood supply is rich in some areas of
the body than the other.
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 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, fatsoluble drugs can cross cell membranes more quickly
than water-soluble drugs can.
 Distribution of a given drug may also vary from person to
person. For instance, obese people may store large
amounts of fat-soluble drugs, whereas very thin people
may store relatively little. Older people, even when thin,
may store large amounts of fat-soluble drugs because
the proportion of body fat increases with aging.
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METABOLISM:
 Drug metabolism is the chemical alteration of a drug by
the body.
 metabolism is what the body does to the drug,
Some drugs are chemically altered by the body
(metabolized). The substances that result from
metabolism (metabolites) may be inactive, or they may
be similar to or different from the original drug in
therapeutic activity or toxicity. Some drugs, called
prodrugs, are administered in an inactive form, which is
metabolized into an active form.
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 The
resulting metabolites produce the desired
therapeutic effects. Metabolites may be metabolized
further instead of being excreted from the body. The
subsequent metabolites are then excreted . The
termination of the drug effect
is caused by bio
transformation and excretion .all the substance in the
circulatory system , including drugs ,metabolites ,and
nutrients will pass through the liver.
 A significant portion of the drug metabolised by hepatic
enzyme to inactive chemical.
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Storage sites
 Plasma proteins, certain tissues, neutral fat, bone and
transcelluar fluids(gastro intestinal tract)are found to act
as a drug reservoirs or storage sites for drugs.
 Plasma proteins: approximately 6.5% of the blood
constitute the proteins, of which 50% I albumin.
 The drug can also be stored in the tissue depots. Neutral
fat constitutes some 20%o 50% of body weight and
constitutes a depot of considerable importance.
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 The more lipophilic the drug, the more likely it will concentrate in
these pharmacologically inert depots. The ultra short acting,
lipophilic barbiturate thiopental’s concentration rapidly decreases
below its effective concentration following administration. It
disappears into tissue protein, redistributes into body fat, and then
slowly diffuses back out of the tissue depots but in concentrations
too low for a pharmacological response.
 In general, structural changes in the barbiturate series that favours
partitioning into the lipid tissue stores decrease duration of action
but increase central nervous system depression. Conversely, the
barbiturates with the slowest onset of action and longest duration of
action contain the more polar side chains.
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PROTEIN BINDING:
 The reversible binding of protein with non-specific and
non- functional site on the body protein with out showing
any biological effect is called as protein binding.

Protein + drug ⇌ Protein-drug complex
 Depending on the whether the drug is a weak or strong
acid ,base or is neutral. It can bind to single blood
proteins to multiple proteins. The most significant protein
involved in the binding of drug is albumin, which
comprises more than half of blood volume.
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 protein binding values are normally given as the percentage
of total plasma concentration of drug that is bound to all
plasma protein.
Free drug(Df) + Free protein(Pf)
Drug /protein complex (Dp)
Total plasma concentration (Dt) = (Df)
+
(Dp
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 NEUTRAL FAT:
 Since fat constituents around 10%(starvation) to
50% of the total body weight.it serves as a main
storage site for drugs having a high partition
coefficient(lipid/water system) or a high lipid
solubility(thiobarbiturates).
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Drug Receptor Interactions
RECEPTOR
 A macromolecular component of the organism that binds
the drug and initiates its effect.
 Traditional model was a rigid “Lock and Key”
– Lock  Receptor surface
– Key  Drug or Ligand
TYPES OF RECEPTORS
Four Primary Receptor Families
(i)Ligand-gated ion channels
(ii) G-protein (Guanine nucleotide-regulatory protein) coupled
receptors.
iii) Tyrosine Kinase-linked Receptors
(iv) Intracellular receptors regulating gene transcription
Covalent interactions
Ionic interactions
Drug
Receptor Interactions
Hydrogen bonding
interactions
Vander Waals interactions
Hydrophobic interactions
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
 In ascending homologous series, the Physico chemical
properties like boiling point, viscosity, surface activity and
partition coefficient increases then the aqueous solubility
decreases.
 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)
 Methods to improve solubility of drugs
1) Structural modification
2) Use of co solvents
3) Employing surfactants
4) Complexation
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.
 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.
Shake flask method
2) Chromatographic method
3) Spectroscopy method
1)
•
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.
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.
 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.
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.
 Hydrogen bonding is classified in 2 types.
1) Intermolecular hydrogen bonding
H
R-O-H
O
R
H
O
H
H
H
H-O-R
H
O
O
H
H
2) Intramolecular Hydrogen bonding
O
H
O
H
O
C
OH
salicylic acid
O
N
O
o-nitrophenol
Hydrogen Bonding and biological action
Eg. 1) Antipyrin i.e. 1- phenyl 2,3- dimethyl 5- pyrazolone has
analgesic activity.
C6H5
CH3
N
N
O
H3C
1-phenyl-3-methyl-5-pyrazolone is inactive.
C6H5
H
N
HN
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
OH
C
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.
Importance of chelates in medicine:
a)Antidote for metal poisoning
1.Dimercaprol is a chelating agent.
CH2S
CH2SH
As++
+
CHSH
As
CHS
CH2OH
CH2OH
2.Penicillamine
CH3
CH3
CH3
CH3
C
H
C
SH
NH2
++
CU
COOH
CH3
C
H
C
S
NH2
COOH
CH3
CU
C
H
C
S
NH2
UC
1:1 chelate
NH2
1:2 chelate
COOH
HOOC
S
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.
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:
 1) Riboflavin analogues
 The biological activity of riboflavin is due to E =-0.185
volt.
Examples,
1) Riboflavin analogues
The biological activity of riboflavin is due to E =-0.185 volt.
OH
OH
OH
OH
OH
OH
OH
OH
N
N
Cl
N
Cl
N
N
O
O
NH
NH
O
N
Dichloro riboflavin
O
riboflavin
Riboflavin E0 = -0.185 V
Riboflavin analogue E0 = -0.095V
2).The optimum bacteriostatic activity in quinones is associated
with the redox potential at +0.03 volt, when tested against
Staphylococcus aureus.
Ionisation and Pka
 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
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.
in
Acids are two types-Unionized acid - HA
Ionized acid - BH +
H2O
HA
Unionized
Acid
BH+
H2O
ionised
H3O+
Conjugate
acid
H3O+
Conugate
acid
AConugate
base
B
Conugate
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.
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
OH
HO
OH
HO
trans-diethylstibesterol
Estrogenic activity
cis-diethylstibesterol
Only 7% activity
of the trans isomer
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.
+
H N
N+
H
H
H
H
H
H
H
N
N
OCOCH3
OCOCH3
H3COCO
H
H
H
H
H
H
H
H
OCOCH3
Eclipsed
Fully Eclipsed
GAUCHE
Staggered
I
-
N+
O
O
2-Acetoxycyclo propyl trimethyl ammonium iodide
 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.
(-)-Adrenaline
(+)-Adrenaline
E.g. Ephedrine & Psuedoephedrine
CH3
CH3
H
NHCH3
H
OH
H
HO
NHCH3
H
MP = 37-39
MP = 118-120
1 gram/20 mL
1 gram/200 mL
Ephedrine
(Erythro)
Pseudoephedrine
(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
(s)-(-)warfarin
O
O
(R)-(+)warfarin
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
cis-diethylstibesterol
Only 7% activity
of the trans isomer
 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.
 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=
 Application of Classical Bioisosteres in in drug design
i) Replacement of –NH 2 group by –CH3 group.
R
SO2 NH CONH(CH2)3CH3
Carbutamide R= NH2
Tolbutamide R= CH3
ii)Replacement of –OH & -SH
X
HN
NH
H2N
N
N
Guanine= -OH
6-Thioguanine = -SH
 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
O
O
O
S
 Hydroxyl group –OH, -NHSO2R, CH2OH
 Catechol
HO
N
HO
N
H
Catechol
 A classical e.g. of ring Vs. noncycclic structure is
Diethylstilbosterol & 17-ß oestradiol.
OH
OH
H
H
H
HO
HO
trans-diethylstibesterol
17-ß oestradiol.
REFERENCES:
1.Thomas L . LEMKE , David A . WILLIAMS , Victoria
F.ROCHE,S . William ZITO, Foye’s Principles of
Medicinal Chemistry ,Wolters kluwer Pvt .Ltd, New
Delhi , 6th Edition ,Pg . no. 210 – 298.
2.William A.Remers,Jaimes N .Delgado, Wilson&
Grissvold’s Text book of organic, Medicinal and
pharmaceutical Chemistry ,10thEdition ,Pg .no.3-10
59
3. DonaldJ. Abraham ,BURGER’S Medicinal chemistry
Drug Discovery , Wiley inter science publication ,
6th Edition ,Volume -2, Pg. no. 649 – 653.
4. Rama rao Nadendla ,Principles of organic Medicinal
Chemistry , New age International Pvt . Limited
Publishers , Pg . no. 14 - 28.
5. www.wikipedia.com
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