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RESOLUTION OF RACEMIC MIXTURE AND ROLE OF STEREOCHEMISTRY IN

PHARMACOKINETICS AND PHARMACODYNAMICS

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The optical isomers are called enantiomers

These are distinguished by

1)+/-

2)D/L

3)R/S

3

A 50/50 mixture of the two enantiomers is called a

racemic mixture or a racemate.

Enantiomers have identical chemical and physical

properties, except:Their effect on plane polarised

light.

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A B

C DE

F

A Light source produces light vibrating in all directionsB Polarising filter only allows light vibrating in one directionC Plane polarised light passes through sampleD If substance is optically active it rotates the plane polarised lightE Analysing filter is used so light reaches a maximumF Direction of rotation is measured coming towards the observer

If the light appears to have turned to the right turned to the left DEXTROROTATORY LAEVOROTATORY

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Optical isomers rotate the plane of plane polarised light.

(-)-enantiomer(anticlockwise rotation)

(±)-racemate(no overall effect)

(+)-enantiomer(clockwise rotation)

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RESOLUTION OF RACEMIC MIXTURES:

•RACEMISATION: racemisation is the formation of

racemic modification(mixture).

•RACEMIC MODIFICATION:equimolar mixture of

pair of enantiomers is called as racemic

modification.

•RESOLUTION:the process of seperation of pure

enantiomer from their racemic modification is

called resolution.

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NEED FOR RESOLUTION OF RACEMIC MIXTURE:CETRIZINE

 levocetirizine has been found to be less sedating than cetirizine.

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FIG:Levodopa

levodopa (L-dopa) is used in treatment of Parkinson’s disease, its D-form causes serious side effects,such as granulocytopenia.

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THALIDOMIDE

(S)-Thalidomide (R)-Thalidomide

Thalidomide, as a racemic mixture, was the active ingredient in a treatment to relieve the symptoms of morning sickness in pregnant women.

(R) enantiomer is effective against morning sickness, but the (S) isomer causes birth defects.

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METHODS FOR RESOLUTION OF RACEMIC MIXTURES:

1) BY DIASTEREOMERS

2) PREFRENTIAL CRYSTALLIZATION BY INNOCULATION

3) BIOCHEMICAL SEPERATION

4) CHROMATOGRAPHIC SEPERATION

5) KINETIC METHOD

6) PRECIPITATION

7) BY MECHANICAL SEPERATION

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1) BY DIASTEREOMERS:

• When racemic mixture is allowed to interact with

optically active material, it give a diastereomeric

derivatives.

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Fig: Seperation of enantiomers of 2-hydroxylpropionic acid. The two enantiomers interact with (R)-2-phenyl-ethylamine to form two distinct salt species that are diastereomers of each other. The diastereomers can then be crystallized separately.

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2) PREFERENTIAL CRYSTALLIZATION BY INOCULLATION:

It was discovered by GRENEZ in 1866.

This method involves seeding of saturated solution

of the racemic mixture with pure crystals of one of

the two enantiomers.

Example: crystals of aspargine crystallises out (+)

sodium ammonium tartarate from solution of

racemic mixture.

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3) BIOCHEMICAL METHOD:

It was introduced by PASTEUR in 1858.

This method is based on fact that when certain

micro organisms like bacteria,fungi,yeast,moulds,etc

are grown in dilute solution of racemic mixture,they

eat up one enantiomer rapidly than other.

Example: the mould penicillium glaucum

preferentially destroys the (+) isomer of racemic

ammonium tartarate leaving (-) ammonium tartarate

in solution.

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4) CHROMATOGRAPHIC SEPERATION:

The racemic mixture can be separated by

chromatography on an optically active support.

The diastereomeric adsorbates which are formed

have different stabilities.

Thus one enantiomer will be held more tightly

than the other and would be eluted first.

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5) KINETIC METHOD :

This method is based on the fact that one of the

enantiomer of racemic mixture reacts faster than

other with optically active compound.

menthol reacts faster with (+) mandelic acid than

with (-) mandelic acid.

Thus with difference in kinetics of

reaction,racemic mixture can be seperated.

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6) PRECIPITATION:

This method is based on formation of precipitate

by reaction between any reagent and racemic

mixture.

Example: (+) & (-) narcotine when dissolved in

hcl,precipitates (+) narcotine.

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7) MECHANICAL SEPERATION:

This method was introduced by LOUIS PASTEUR

(1848). It is also known as spontaneous resolution

by crystallisation.

(+) and (-) forms of compounds have opposite

crystalline shapes.

PASTEUR used this process to separate (+) & (-)

tartaric acid from mixture of tartaric acid.

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Fig: MECHANICAL SEPERATION

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ROLE OF STEREOCHEMISTRY IN PHARMACOKINETICS:

The study of absorption, distribution, metabolisum

and excretion (ADME) of drug are called as

pharmacokinetics.

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CHIRAL BIOLOGIOCAL MACROMOLECULES ARE:

1. Chiral biopolymers proteins glycoprotein 2. Chiral building blocks L- amino acids D- carbohydrates 3. Many of natural ligands at target site neurotransmitters autocoids hormones etc..

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STEREOCHEMICALASPECTS

IN ABSORPTION

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ABSORPTION:

“The process of movement of unchanged drug

from the site of administration to systemic

circulation is called as absorption”

MECHANISM:

1) passive diffusion.

2) active transport.

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1) PASSIVE DIFFUSSION:

Also called as non-ionic diffusion.

It is major process of absorption of more than

90% of the drugs.

The driving force for this process is concentration

gradient.

It is defined as the difference in drug

concentration on either side of membrame.

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The aqs solubility of ampicillin with [D-epimer]

configuration is greater than configuration [L-epimer]

N

S CH3

CH3

H

CONHH

NH2

O COOH

HH

N

S CH3

CH3

H

CONHH

NH2

O COOH

HH

*

2R [D-epimer]

*

2S [L-epimer]

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2) ACTIVE TRANSPORT:

The drug is transported from a region of lower to

higher concentration i.e against the concentration

gradient.

The process is faster than passive diffusion.

This process is uphill process and requires

expenditure of energy.

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STEREOCHEMICAL ASPECTS IN DISTRIBUTION

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DISTRIBUTION:

Distribution of a drug is defined as the reversible

transfer of a drug between one compartment and

another.

One of compartment is always the blood or plasma

& other represents extra vascular fluid & other

body tissues.

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PROTEIN BINDING:

The phenomenon of complex formation with

proteins is called as protein binding of drugs.

Protein binding may be divided into:

1) Intracellular binding:where drug is bound to cell

protein.

2) Extracellular binding:where drug is bound to

extracellular protein.

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STEREOCHEMICAL ASPECTS

IN METABOLISM

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Metabolism of drug is defined as the conversion of one

chemical form to another.

The decreasing order of drug metabolising ability of

various organs is: liver > lungs > kidneys > intestine

>skin.

The pathways of drug metabolism is divided into two

categories:

1) Phase 1 reactions.

2) Phase 2 reactions

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STEREOCHEMICALASPECTS

IN EXCREATION

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Excreation is defined as the process where by drugs or

their metabolites are irreversibly transferred from

internal to external environment.

Renal excretion is the net result of :

1) glomerular filtration

2) Active tubular secretion

3) Active tubular reabsorption.

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Eg.The renal clearance of quinidine has been reported

to be four times greater than that of its diastereoisomer

quinine.

In oral administration of racemaic pindolol,its renal

clearance of the S-enantiomer was 1.2-folds greater

than that of R-enantiomer

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ROLEOF

STEREOCHEMISTRYIN

PHARMACODYNAMIC

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PHARMACODYNAMIC: it is study of action of drug on living organism.

RECEPTORS: A macromolecular component of a cell with which a

drug interacts to produce a pharmacologic response.

A molecule which binds to a receptor is called a

ligand, and may be a peptide or other small

molecule, such as a neurotransmitter, a hormone, a

pharmaceutical drug, or a toxin.

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Receptor Drug interaction

Pharmacologic effect

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Morphine is an asymmetric molecule containing several asymmetric centers, and exist naturally as (-) morphine

Epimerization of single asymmetric center can result in a drastic change of shape, making it difficult for the binding of molecule with receptors.

O

OH

OH

N CH3

H H

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ADVANTAGES OF SINGLE ENANTIOMERIC PRODUCTS:

Improved therapeutic index.

Improved duration of effect.

Increased potency.

Less complex and more selective pharmacological

profile.

Less complex pharmacokinetic profile.

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REFERENCES:Wilson & gisvold’s textbook of organic medicinal &

pharmaceutical chemistry. eleventh edition ,lippioncott,williams & wilkins publication.

Biopharmaceutics & pharmacokinetics by D.M. BRAHMANKAR, S.J. JAISWAL.

Stereochemistry of organic compounds ,by D.NASIPURI

Smith & william’s introduction to principle of drug design & action.

Essentials of medical pharmacology by KD Tripathi.

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