1. SEMINAR ON CHIRALITY (PREFORMULATION ASPECTS)
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2. 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
7. CHIRAL RESOLUTION
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3. 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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4. 4/33

5. 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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6. 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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7. Ephedrine (-) Ephedrine (+)
Enantiomer
Isomers which are mirror images to each other and yet are not superimposable are called an EANANTIOMER.
Ephedrine (-) Ephedrine (+)
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8. Diasteriomer Meso compound Racemic mixture Eutomer Distomer
Eudismic index
Racemization
Chiral inversion
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9. 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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10. GEOMETRIC ISOMERS: same side then cis (Z) opposite side then trans (E)
H H H CH3
C=C (CIS) C=C (TRANS)
CH CH CH H
CONFIGURATIONAL ISOMER:
clockwise then R
anticlockwise then S
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11. 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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12. same absorption rate for passive diffusion for enantiomer
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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13. L-DOPA absorbed by an amino acid transport system
is passes 4 to 5 times greater then that of D-
ENANTIOMER.
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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14. 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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15. *S(+) IBUPROFEN R(-) IBUPROFEN
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 R(-) IBUPROFEN
ANTI-INFLAMATORY ACTIVITY NO ANTI-INFLAMATORY ACTIVITY
(*Ref: C.A:147(2) JULY; 2OO7;3868a)
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16. d-PROPOXYPHENE l-PROPOXYPHENE
DRUG ELIMINATION
The renal clearance of S-prenylamine is approximately 2.4 times higher than that of the R isomer.
d-PROPOXYPHENE l-PROPOXYPHENE
ANALGESIC ACTIVITY NO ACTIVITY BUT
INHIBITS RENAL
CLEARANCE OF d-ISOMER
RACEMIC
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17. 4.2 STERIC ASPECTS OF DRUG ACTION
STESIC ASPECTS
Equipotent enantiomers eg.flecainide
eg. S-α-methyl DOPA
Steriospecificity
eg. S-warfarin
Sterioselactivty
Differ in therapeutic and toxicological profile eg.levoDOPA
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18. . 4.3 CHIRAL IMPURITY 18/33 CHIRAL IMPURITY
The opposite enantiomer in single isomer
Excess enantiomer in racemic compound
A diasteriomer in homochiral or racemic mixture .
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19. 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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20. 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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21. Development of enantiomeric assay. Synthesis of individual enantiomer.
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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22. 6. APPLICATION OF CHIRALITY IN F AND D
FORMULATION AND DEVELOPMENT SCIENTIST
ACCEPTANCE/REJECTION OF API-INTRINSIC DISSOLUTION TEST
SELECTION OF ADJUVANT
IN VITRO DISSOLUTION STUDIES AND IN VIVO STUDY
STABILITY STUDY
ANDA/NDA-APPLICATION
ECONOMICAL CONSIDERATION
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23. 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 non-racemic mixtures.
The intrinsic dissolution rate of chiraly pure API may prove to be a useful QUALITY CONTROL PARAMETER.
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24. 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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25. 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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26. 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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27. Thalidomide undergoes chemical racemization in aqueous media.
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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28. 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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29. 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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30. List of official chiral drugs:
Sr. no
Drugs
Official in 1.
Dextroamphetamine
USP
21.
Levomenthol
MartindaleEP, BP 2.
Dextromethorphan
USP, BP
22.
Levomeproprazine 3.
Dextromoramide
MartindaleEP
23.
Levomethadone 4.
Dextropropoxyphene
24.
Livamisol
IP, BP 5.
Esmoprazole
25.
Levonantradol 6.
Levobunolol Hcl
26.
Levonordefin 7.
Levobupivacaine
27.
Levonorgesterol
MartindaleEP, IP, BP 8.
Levocabastine
28.
Levoorphanol 9.
Levocalamine
29.
Levophan
10.
Levocarit
30.
Levophed barbiturate
11.
Levocarnil
31.
Levoprolactine
12.
Levocarnitine
32.
levopropizine
13.
Levodiphenopyrine
33.
Levopropoxyphene
14.
Levodopa
34.
Levopropylhexidine
15.
Levodopum
35.
Levorenin
16.
Levodromaran
36.
Levoresin
17.
Levofloxacine
37.
Levorterenol IP
18.
Levoglutamine
38.
Levoterenol BP
19.
Levomaprolol
39.
Levothoid
20.
Levomenol
40.
Levothyroxin
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31. REFERENCES
Williams Lemke.Foye’s principle of medicinal chemistry. Ed.5. p=49-54
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
Encyclopedia of pharmaceutical technology. Volume-8. p=281.
A.J.Romero and C.T.Rhodes, Chirality, 3, 1 (1991)
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32. Continue…
6. ‘‘Overview on Chirality and Application of Stero-selective Dissolution testing in the Formulation and Development work’’ by Mukesh C.Gohel.
Indian pharmacopoeia 1996
British pharmacopoeia 1993
United state pharmacopoeia 2000
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33. THANK YOU
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