Resolution of racemic mixture

1. Presented By
Mrs. H.S.Bhawar
M. Pharm
(Pharmaceutical Chemistry)
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2.  Introduction
 Enantiomers
 Racemic Mixture
 Resolution
 Need for Resolution of Racemic Mixture
 Methods of Resolution Of Racemic Mixture
 Mechanical Separation or Spontaneous Resolution
 Preferential Crystallization By Inclution.
 Biochemical separation.
 Chromatographic Separation
 Kinetic Method
 Precipitation
 By Disateromers
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3.  A racemic mixture is a 50:50 mixture of two enantiomers.
 Because they are mirror images, each enantiomer rotates
plane-polarized light in an equal but opposite direction and is
optically inactive.
 Separation of racemates into their component enantiomers is a
process called resolution.
 Moving from a racemic drug to a chiral specific drug may done
for a better safety profile or an improved therapeutic index. This
process is called chiral switching and the resulting enantiopure
drug is called a Chiral Switch.
 To cite few examples, Esomeprazole is a chiral switch of (±)-
omeprazole; Levocetrizine is a chiral switch of (±)-cetirizine.
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4. 4
 In chemistry, racemization is a conversion, by heat or by
chemical reaction, of an optically active compound into
a racemic (optically inactive) form.
 Half of the optically active substance becomes its mirror
image (enantiomer) referred as racemic mixtures (i.e.
contain equal amount of (+) and (−) forms).
 If the racemization results in a mixture where the D and L
enantiomers are present in equal quantities, the resulting
sample is described as a Racemic mixture or a racemate.
 Racemization can proceed through a number of different
mechanisms ,and it has particular significance in
pharmacology as different enantiomers may have different
pharmaceutical effects.

5.  Isomers which are non-superimposable mirror images
of each other are called enantiomers.
 Enantiomers are the chiral molecules that are mirror
images of one another and are not superimposable.
 Eg.
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ENANTIOMERS:-
(S)-(+)-Lactic Acid (left) and (R)-(–)-lactic acid (right)
are non-superposable mirror images of each other.

6. 6
These are distinguished by:-
1)+/-
2)D/L

7.  A equimolar (50/50) mixture of the two enantiomers
is called a racemic mixture or a racemate.
Examples include thalidomide, ibuprofen, cetirizine
and salbutamol.
Resolution:-
 The process of seperation of pure enantiomer
from their racemic modification is called resolution.
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8. 8

9. 9
 Levo-Cetrizine is found to be less sedative then
Cetrizine
 CETRIZINE:-

10.  Levodopa (i.e. L-DOPA) is used in the treatment of
Parkinson's disease and dopamine-responsive dystonia.
L-DOPA is converted to dopamine in the brain by
aromatic L-amino acid decarboxylase, also known as
DOPA decarboxylase (DDC).
 Levodopa (L-dopa) is used in treatment of Parkinson’s
disease, its D-form causes serious side effects, such as
granulocytopenia 10
Levodopa

11. Mechanical Separation or Spontaneous
Resolution.
Preferential Crystallization By Inoculation.
Biochemical separation.
Chromatographic Separation
Kinetic Method
Precipitation
By Disateromers
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12.  This involved mechanical separation of the crystal of one
enantiomers from the other in racemic mixture based on
difference in their shapes.
 Crystal of the two forms have different shapes
separated by magnifying lens and forceps.
 This method first used by pasteur for he resolutiuon of
sodium ammonium tartarate which crystallise out in
the form of racemic mixture below 27 degree.
 This methods is time consuming and every compound can
not be crystallized at room temperature.
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13. 2.Preferential Crystallization By
Inoculation:-
 This method involve seeding of a saturated solution of
the racemic mixture with a pure crystal of one the two
enantiomers.
 The solution now become supersaturated with respect to
the added enantiomers.
 It begins to crystallise out.
 Eg. Harda obtained free from amino acid by adding
corresponding D/Lisomers of amino acid.
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14.  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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15.  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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16.  This methodmis based on the fact that one of the
enantiomer of racemic mixture reacts faster with
optically active compound.
 Methanol reacts faster with (+) mandelic acid with (-)
mandelic acid.
 Thus with difference in kinetic of reaction , Racemic
mixture can be seperated.
 Which form of compound get firstly reacted it should get
seperated first. In this way the Racemates get easily
seperated.
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17.  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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18.  When racemic mixture is allowed to interact with
optically active material, it give a diastereomeric
derivatives.
 Distereomers have different physical properties and
hence can be easily seperated into two component by
fractional crystallization.
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19.  The most unremarkably used procedure for separating
enantiomers is to convert them to a mix of
diastereomers which will have totally different physical
properties, freezing point, boiling purpose, solubility,
and so on.
 For example: If you have got a racemic or D,L
mixture of enantiomers of associate acid and convert
this to a salt with a chiral base having the D
configuration, the salt is a mixture of two
diastereomers, D acid. D base and L acid. D base.
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20. These diastereomeric salts are not identical and that they are not
mirror pictures. Hence, they will take issue to a point in their
physical properties, and a separation by physical strategies, like
crystallization, could also be attainable.
If the diastereomeric salts is fully separated, the acid regenerated
from every salt is either completely the D or the L enantiomer.
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21.  To reduce the adverse drug reaction by making
optically inactive form of racemates.
 To improve the Threpeutic effect of drug.
 To improve the chemical stability of a compound; so it
can not change its chemical properties when come in
contact with the atmosphere or humidity.
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22.  Advantages of racemic modification:-
 The use of a single isomer must be seriously taken after
long clinical assessments between racemate and single
enantiomer actions because in some cases, racemates
have more therapeutic advantages than single isomers.
 Disadvantages of racemic modification:-
Side effects of “other” enantiomer could be dangerous.
Larger or double doses of the drug will have to be taken
if drug contains a mixture of enantiomers.
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23.  Amlodipine
 Metoprolol
 Atenolol
 Omeprazole (OME)
 Cetirizine
 Pentoprazole
 Ketamine
 Salbutamol
 Ketoprofen
 Propranolol
 Ibuprofen
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24.  1. O.P Agrawal, “Organic Chemistry Reaction AndReagent”.
Goel Publication Fourty Eight Edition 2012 Page No.137-143.
 2.Ernest L Eliel, “Stereochemistry Of Carbon Compound” Tata Mc
Graw-hill Page No.47-75
 3.Jerry March, “Advance Organic Chemistry” Fourth Edition Page
No.120-124
 4 Morrison Boyd, “Organic chemistry”, edition-6,page-133
 Tillement JP, Testa B, Brée F. Compared pharmacological characteristics in
humans of racemic cetirizine and levocetirizine, two histamine H1-
receptor antagonists. Biochem Pharmacol 2003;66:1123-6.
 Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P.
Binding characteristics of cetirizine and levocetirizine to human H(1)
histamine receptors: Contribution of lys(191) and thr(194). Mol Pharmacol
2002;61:391-9.
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