physicochemical properties of Drug (1).ppt

By- Saumya Shukla
M.S(Pharm)
Medicinal Chemistry

DEFINITION:
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 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.
SAUMYA SHUKLA M.S(Pharm)

Various Physico-Chemical Properties are:
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 Solubility
 Partition Coefficient
 Ionization
 Hydrogen Bonding
 Chelation
 Surface activity
 Isosterism

ROUTES OF ADMINISTRATION
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 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.

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Different Routes Of Drug Administrations
Oral/ Oral/ Rectal Epithelial Inhalation
Parentral
Swallowed Sublingual
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:
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 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

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◦ 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

DISTRIBUTION:
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 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, fat-soluble 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.

METABOLISM:
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 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.

PROTEIN BINDING:
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 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).

Drug Receptor Interactions
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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

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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

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Covalent interactions
Ionic interactions
Drug
Receptor Interactions Hydrogen bonding
interactions
Vander Waals interactions
Hydrophobic interactions

Solubility:
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• 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

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 In ascending homologous series, the Physicochemical 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)

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 Methods to improve solubility of drugs
1) Structural modification
2) Use of co-solvents
3) Employing surfactants
4) Complexation

Partition Co-efficient:
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 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.

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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.

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• 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.

Surface Activity:
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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.

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 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:
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 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.

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 Hydrogen bonding is classified in 2 types.
1) Intermolecular hydrogen bonding:
R-O-H
H
O R
H-O-R
H
H O H
H O H
O H
H

2) Intramolecular Hydrogen bonding:
salicylic acid o-nitrophenol
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O H
C
O
OH
O H
N
O
O

Hydrogen Bonding and biological action:
Eg. 1) Antipyrin i.e. 1- phenyl 2,3- dimethyl 5- pyrazolone has analgesic activity.
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N
N
CH3
H3C
O
C6H5
HN
H3C
O
C6H5
HN
H
N
H3C
O
1-phenyl-3-methyl-5-pyrazolone is inactive.

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C
O
H
O
OH
: Salicylic acid(O-Hydroxy Benzoic acid has antebacterial activity
OH C
OH
O
HO C
O
OH
para and meta Hydroxy Benzoic acids are inactive.

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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:
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CH2SH
CHSH
CH2OH
+ As++
CH2S
CHS
CH2OH
As
A)Antidote for metal poisoning
1.Dimercaprol is a chelating agent.
CH3 C
CH3
SH
H
C
NH2
COOH
CU++
CH3 C
CH3
S
H
C
NH2
COOH
CU
CH3 C
CH3
S
H
C
NH2
COOH
UC
NH2 S
HOOC
CH3
CH3
2.Penicillamine
1:1 chelate
1:2 chelate

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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.

Ionisation and Pka
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 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.

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Acids are two types- 1.Unionized acid - HA
2. Ionized acid - BH +
According to Henderson-Hasselbalch equation
PH
= pka+log[Un ionised form][ionised form
% ionisation = 100( 1+10 (pH-pka) )
HA H2O H3O+
A-
BH+ H2O H3O+
B
Unionized
Acid
Conjugate
acid
Conugate
base
ionised Conugate
acid
Conugate
base

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 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.

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THANK YOU

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