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 CONTENTS
1. INTRODUCTION
2. TERMS
3. NOMENCLATURE OF CHIRAL COMPOUNDS
4. IMPORTANT OF CHIRALITY
5. SPECIFIC REQUIREMENTS FOR CHIRAL CRUG
DEVELOPMENT
6. APPLICATION OF CHIRALITY IN FORMULATION AND
DEVELOPMENT
7. CHIRAL RESOLUTION
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1. INTRODUCTIOIN
•
•
•
•
Chiral drug contain chiral atom
More than 50% drugs are chiral
Opposite enantiomer of chiral drug often
differs in pharmacodynamic, pharmacokinetic
and toxicological properties.
“Racemic switch”
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2.TERMS
•
CHIRAL :Molecules that are not super
imposable on their mirror images.
•
CHIRAL CARBON is to which four
different groups are attached.
e.g, LACTIC ACID
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 Stereoisomer
• The particular types of isomer that differ from each
other only in the way the atoms are oriented in space
are called as STEREOISOMERS.
2-METHYL-1-BUTANOL
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•
•
Enantiomer
Isomers which are mirror images to each other and yet are
not superimposable are called an EANANTIOMER.
Ephedrine (-) Ephedrine (+)
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Diasteriomer
 Meso compound
 Racemic mixture
 Eutomer
 Distomer
 Eudismic index
 Racemization
 Chiral inversion

8 /33
3. NOMENCLATURE OF CHIRAL COMPOUNDS
 OPTICAL ISOMERS:
clockwise then dextro (+)
anticlockwise then levo (-)
 CIRCULAR DICHROISM:
Differential absorption of left and right circularly
polaried rotation.
There are differences in absorption of the left and right
handed components of circularly polarised light by a non
racemic sample.
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• GEOMETRIC ISOMERS: same side then cis (Z)
opposite side then trans (E)
H
H
H
CH3
C=C
(CIS)
C=C
(TRANS)
CH3
CH3
CH3
H
•CONFIGURATIONAL ISOMER:
clockwise then R
anticlockwise then S
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4. IMPORTANT OF CHIRALITY
4.1 STERIC ASPECTS OF PHARMACOKINETICS
4.2 STERIC ASPECTS OF PHARMACODYNEMICS
4.3 CHIRAL IMPURITIES
4.4 ADVANTAGES OF SINGLE ENANTIOMER AS A
DRUG
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4.1 STERIC ASPECTS OF PHARMACOKINETICS
4.1.1 DRUG ABSORPTION
• same absorption rate for passive diffusion for
enantiomer
• sterioselective absorption for carrier mediated
absorption
• Stereoisomers with structural similarities to
endogenous entities and nutrients display
difference in permeability rates across the g.i.
membrane and hence in bioavailability.
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•
L-DOPA absorbed by an amino acid transport system
is passes 4 to 5 times greater then that of DENANTIOMER.
•
Bioavailability of D-METHOTREXATE appears markedly
lower then L-ISOMER.
•
The L-METHOTREXATE is absorbed by active processes and
the D-METHOTREXATE is by passive absorption.
•
Crystalline structure of racemates may not same as individual
sterioisomers and there may be difference in dissolution rate of
racemate and single enantiomer.
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4.1.2 DRUG DISTRIBUTION
•
•
•
•
The interaction of enantiomer with a plasma
protein yields a diastereomeric association.
(+)Oxazepam hemisuccinate has 30 to 50
time
higher association constants for albumin than
its
(-) isomer.
The S isomer of warfarin is bound to a greater
extent to albumin than R isomer.
Human albumin binds R-propranolol more
strongly than S-form.
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4.1.3 DRUG BIOTRANSFORMATION
•
The intrinsic hepatic clearance of S-warfarin is reported to
be approximately two fold greater than that of R-warfarin.
CHIRAL INVERSION
*S(+) IBUPROFEN
ANTI-INFLAMATORY ACTIVITY
R(-) IBUPROFEN
NO ANTI-INFLAMATORY ACTIVITY
(*Ref: C.A:147(2) JULY; 2OO7;3868a)
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4.1.4 DRUG ELIMINATION
•
The renal clearance of S-prenylamine is approximately 2.4
times higher than that of the R isomer.
d-PROPOXYPHENE
ANALGESIC ACTIVITY
l-PROPOXYPHENE
NO ACTIVITY BUT
INHIBITS RENAL
CLEARANCE OF d-
ISOMER
RACEMIC
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4.2 STERIC ASPECTS OF DRUG ACTION
Equipotent enantiomers
eg.flecainide
Differ in
therapeutic and
toxicological
profile
eg.levoDOPA
STESIC
ASPECT
S
Steriospecificity
eg. S-α-methyl DOPA
Sterioselactivty
eg. S-warfarin
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4.3 CHIRAL IMPURITY
.
CHIRAL
IMPURITY
The opposite
enantiomer in
single isomer
Excess
enantiomer in
racemic
compound
A diasteriomer
in homochiral or
racemic mixture
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
The presence of small amounts of opposite
enantiomer may significantly reduce the apparent
solubility of the enantiomer, because the racemic
compound will form in the solution and may
precipitate from the solution.

For example, the solubility of (+) dexclamol
hydrochloride is five times that of (_) dexclamol
hydrochloride.

In ephedrine and pseudoephedrine studies
demonstrated that traces of the enantiomeric impurity
might cause significant changes in the
physicochemical properties of the pure enantiomer.
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4.4 ADVANTAGES OF USE OF SINGLE ENANTIOMER AS A
DRUG
 Separating
unwanted pharmacodynamic
side effects
 Reduce metabolic/renal/hepatic drug load.
 Reduce drug interactions.
 Avoid bioinversion
 Easier assessment of physiology, disease,
and drug co-administration effects.
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5. SPECIFIC REQUIREMENTS FOR CHIRAL DRUG DEVELOPMENT
•
•
•
•
•
•
Development of enantiomeric assay.
Synthesis of individual enantiomer.
Safety evaluation of the individual enantiomer.
Pharmacokinetic of individual enantiomers.
Resolution of the individual enantiomer.
Chiral conversion
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6. APPLICATION OF CHIRALITY IN F AND D
ACCEPTANCE/REJECTION
OF API-INTRINSIC
DISSOLUTION TEST
ECONOMICAL
CONSIDERATION
FORMULATION
AND
DEVELOPMENT
SCIENTIST
ANDA/NDAAPPLICATION
STABILITY
STUDY
SELECTION OF
ADJUVANT
IN VITRO
DISSOLUTION
STUDIES AND IN
VIVO STUDY
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6.1 ACCEPTANCE AND REJECTION OF API
The Chiraly pure drugs should be quantitatively
analyzed for the presence or absence of chiral
impurities besides the routine determination of
related impurities.
 The quantitative chiral analysis could be done by
TANDEM MS.
 Accept or reject a sample of API is based on the
ratio of the active/inactive enantiomers in the nonracemic mixtures.
 The intrinsic dissolution rate of chiraly pure API
may prove to be a useful QUALITY CONTROL
PARAMETER.

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6.2 SELECTION OF ADJUVANTS

The adjuvant may be
 chiral or

non-chiral
•
The type and amount of the adjuvant may determine the
functionality of the dosage form, especially the drug release
rate.

The release of salbutamol and ketoprofen enantiomers from
hydroxypopylmethylcellulose (HPMC) matrixes shows that
stereoselectivity is dependent on the amount of chiral
excipient in the formulation
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•
The release of eutomer R-salbutamol was higher
than that of the distomer S-salbutamol from the
gamma cyclodextrin tablets.
• So by selecting proper chiral excipient, distomer
can be retained in the dosage form.
• Applications of interaction between API and
chiral excipient may be explored in the areas of
sustained release buccal dosage form and colon
drug delivery system.
• Drug delivery system containing D-pantothanic
acid entrapped in pillared hydrotalcite*
( * CA Sep.10,2007.no.11 vol.147)
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6.3 IN VITRO DISSOLUTION STUDIES AND VIVO STUDY
•
Crystals of both enantiomer & racemic compound are
having different molecular arrangement.
•
Due to the difference between the crystal lattice of both
forms, the solubility of pure enantiomers may be different
from the racemic compound.
•
The initial dissolution rate of racemic PROPRANOLOL
HCL was three times greater than that of enantiomers in
distilled water.
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6.4 STABILITY STUDY
•
Racemization, or an optically inactive mixture of
corresponding dextro (d-) and levo forms is a major
factor in PHARMACEUTICAL STABILITY.
•
Thalidomide undergoes chemical racemization in
aqueous media.
• Besides chemical stability, dissolution stability is
also important for tablets and capsules.
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6.5 NDA/ANDA APPLICATION
We should also keep in mind that increasing the
desired activity should not accompanied by a rise
in the untoward effect.
 FDA requires toxicology testing on the
racemate.
 The data of stereoselective dissolution testing
should be submitted for the enantiomers that
exhibit different action.

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7. CHIRAL RESOLUTION
Separation of racemic mixture in to the
individual enantiomer.
 Methods use are :
 crystallization method
 chemical method
 biochemical method
 electrophoresis
 chromatography

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List of official chiral drugs:
Sr.
no
1.
Drugs
Official in
Drugs
Official in
USP
Sr.
no
21.
Dextroamphetamine
Levomenthol
MartindaleEP, BP
2.
Dextromethorphan
USP, BP
22.
Levomeproprazine
MartindaleEP, BP
3.
4.
Dextromoramide
Dextropropoxyphene
MartindaleEP
MartindaleEP, BP
23.
24.
Levomethadone
Livamisol
MartindaleEP
IP, BP
5.
6.
7.
Esmoprazole
Levobunolol Hcl
Levobupivacaine
MartindaleEP
25.
26.
27.
Levonantradol
Levonordefin
Levonorgesterol
MartindaleEP
MartindaleEP
MartindaleEP, IP, BP
8.
Levocabastine
MartindaleEP
28.
Levoorphanol
MartindaleEP, BP
9.
10.
Levocalamine
Levocarit
MartindaleEP
MartindaleEP
29.
30.
Levophan
Levophed barbiturate
MartindaleEP
MartindaleEP
11.
12.
13.
14.
Levocarnil
Levocarnitine
Levodiphenopyrine
Levodopa
MartindaleEP
MartindaleEP
MartindaleEP
MartindaleEP, IP, BP
31.
32.
33.
34.
Levoprolactine
levopropizine
Levopropoxyphene
Levopropylhexidine
MartindaleEP
MartindaleEP
MartindaleEP
MartindaleEP
15.
16.
17.
18.
19.
20.
Levodopum
Levodromaran
Levofloxacine
Levoglutamine
Levomaprolol
Levomenol
MartindaleEP
MartindaleEP
MartindaleEP
MartindaleEP
MartindaleEP
MartindaleEP
35.
36.
37.
38.
39.
40.
Levorenin
Levoresin
Levorterenol
Levoterenol
Levothoid
Levothyroxin
MartindaleEP
MartindaleEP
IP
BP
MartindaleEP
MartindaleEP, IP, BP
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REFERENCES
1.
Williams
Lemke.Foye’s
principle
of
medicinal
chemistry. Ed.5. p=49-54
2.
3.
Morrison Boyd. Organic chemistry. Ed.6. p=133
‘‘Relationship between physical properties
and
crystal structures of chiral drug’’Z.jane Li and David
J.W.Grant. October 1997, Volume-86,Number 10
4.
Encyclopedia
of
pharmaceutical
technology.
Volume-8. p=281.
5.
A.J.Romero and C.T.Rhodes, Chirality, 3, 1 (1991)
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Continue…
6.
‘‘Overview on Chirality and Application of Steroselective Dissolution testing in the Formulation and
Development
work’’
by
Mukesh
C.Gohel.
www.dissolutiontech.com
7.
www.harrisononline.com
8.
Indian pharmacopoeia 1996
9.
British pharmacopoeia 1993
10.
United state pharmacopoeia 2000
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