This document summarizes a presentation on chiral separation from a pharmaceutical industry perspective. It begins by discussing the tragic lessons from Thalidomide, where one enantiomer was teratogenic while the other had desired effects. It emphasizes the importance of separating single enantiomers due to differences in biological activity and toxicity. It then covers topics like chiral stationary phases used for separation, potential advantages of racemic switches and developing single isomers, and considerations for preclinical and clinical development like enantioselective assays and pharmacokinetics. In concluding, it stresses that isomeric purity must be thoroughly studied and chiral switches should improve safety/efficacy.

1. CHIRAL
SEPARATION:
A PHARMA
INDUSTRY
PERSPECTIVE
Presented at the Chiral India 2013 Conference,
Mumbai, November 14-15, 2013
1
Dr. Bhaswat S. Chakraborty
Sr. VP & Chair, R&D Core Committee
Cadila Pharmaceuticals Ltd., Ahmedabad

2. CONTENTS

Chirality – the Tragic lessons from Thalidomide

Importance of separation of single enantiomers

Chiral stationary phases

Racemic switch & life-cycle management

Development of single enantiomer

Science vs efficacy

Stereoselective assay in Bioequivalence

Regulatory issues

Concluding Remarks
2

3. THALIDOMIDE




Thalidomide (late 1950s) was marketed as a
sedative, in the treatment of nausea in pregnant
women in Europe, Australia, and Japan
From the user mothers, ~10,000 children were
born with phocomelia
Thalidomide was banned in most countries in
1961
This tragedy was averted in the USA, because of
its non-approval by Dr. Frances Kelsey of the US
FDA
 She was recognized by President JFK as a
recipient of the Gold Medal Award for
Distinguished Civilian Service.
3
Kim J. et al. Toxicological Sciences 122(1), 1-6 (2011)

4. THALIDOMIDE


The (S)-isomer has the desired
antinausea effects
the (R)-form is teratogenic and causes
phocomelia
Thalidomide transformed the drug regulation
scenario or ever. Now all developed regulatory
jurisdictions demand an examination of isomeric purity
and its clinical and toxic implications thoroughly studied
4

5. 5

6. IMPORTANCE OF CHIRAL
SEPARATION
Chiral drug
Biological activity of enantiomers
Albuterol
D-isomer may provoke airway constriction;
L-isomer avoids side effects
Ethambutol
(S,S)-form of ethambutol is a tuberculostatic
(R,R)-form causes optical neuritis that can lead to
blindness
L-Dopa has anti-Parkinson’s disease effect
D-Dopa causes serious side effects, e.g.,
granulocytopenia
(S)-enantiomer has antiarthritic activity
(R)-form is extremely toxic
Levodopa
Penicillamine
Propoxyphene
α-L-isomer is antitussive (cough)
α-D-isomer is analgesic (pain)
Propranolol
The drug is racemic.
However, only the (S)-(–)-isomer has the desired βadrenergic blocking activity
6

7. CHIRAL STATIONARY PHASES
(CSP)
Enantiomers are separated based on their interaction
with a CSP
 Different CSPs are developed for GC, HPLC, CE and
other techniques
 CSPs include

 Derivatized
cyclodextrins
 Macrocyclic antibiotics
 Proteins/polypeptides
 Polysaccharides
 Chiral surfactants
 Chiral crown ethers

Special chiral techniques, e.g., SFC and SMB
Li B. et al. Encyclopedia of Chemical Processing
7

8. 8
Gubitz G. et al. Biopharm Drug Dispos 22: 291-336 (2001)
Williams K et al. Journal of Chromatography A, 785 (1997) 149-158

9. USEFULNESS OF A SINGLE
ACTIVE ISOMER




Fewer or diminished side effects, which may result from
the unwanted isomeric form
Automatically halved dosage for a patient
Decreased waste due to decrease in manufacturing of
unwanted isomer
New commercial opportunities for ‘‘racemic switching’’


A racemate can be redeveloped as an enantiomerically pure
form, possibly useful for extending patent protection of a
key product
Typically when a specific enantiomeric ratio is
expected to improve the therapeutic profile,
single isomers are developed
9

10. WHEN DEVELOPMENT OF A
RACEMATE
MAY BE JUSTIFIED
The enantiomers are configurationally unstable
in vitro or undergo racemization in vivo
 The enantiomers have similar pharmacokinetic,
pharmacodynamic and toxicological properties
 It is not technically feasible to separate the
enantiomers in sufficient quantity and/or with
sufficient quality


Decision to develop a racemate or a single
isomer is purely that of the sponsor or
manufacturer
10

11. RACEMIC (CHIRAL)
SWITCH

Potential
advantages of a
chiral switch
Less complex, more
selective PD profile
 An improved
therapeutic index
 Less complex PK
profile
 Reduced drug
interactions
 Less complex
relationship between
plasma
concentration and
effect

11

12. ENANTIOMERS AFTER
CHIRAL SWITCH
12

13. LIFE CYCLE
MANAGEMENT
13

14. SCIENCE VS EFFICACY
14
Mansfield P. et al. Clin Pharmacokinet 2004;43(5):287-90

15. PRECLINICAL AND
CLINICAL
CONSIDERATIONS
The in vivo stability of the enantiomer must be
established.
 If the antipode is formed in vivo, it should be
considered to be a metabolite.
 The metabolism and disposition of the enantiomer
should be followed using enatioselective methods

 In
each species in preclinical
 In phase I in clinical (humans)
 If racemization or inversion does not occur,
enantioselective methods may not be necessary in all
studies
15

16. STEREOSELECTIVE ASSAY
IN BIOEQUIVALENCE

A steroselective assay may be necessary
 When
changes in oral input cause changes in vivo
ratio of enantiomers due to a phenomenal such as
high fist pass metabolism of the active enantiomer.
 When
there is a relatively low first pass metabolism
of the active enantiomer but a specific isomer ratio is
important for optimal therapeutic effect.

BE comparisons should be made between
pharmaceutically equivalent products that meet
standards for enantiomeric purity.
16
Canadian TPP Guidelines on Stereochemical Issues in Chiral Drug Development

17. ENANTIOSELECTIVE PK
17

18. 18
Chiral Drugs: Chemistry and Biological Action, Edited by Guo-Qiang Lin et al

19. REGULATORY ISSUES

What to develop?
 Racemic,

pure single isomer or a fixed ratio of isomers?
What should be motivation for chiral switch?
 Life
cycle management, patent extension or actual gain in
efficacy or safety?

Clear understanding of situations where an
enantioselective assay is a must

Chemistry and manufacturing (QC) requirements
especially for an artificial fixed ratio of isomers

Species differences in preclinical studies (PK only?)

Study design issues in clinical trials
19

20. CONCLUDING REMARKS

Thalidomide has taught us that isomeric purity of enantiomers
and its clinical and toxic implications must be thoroughly
studied

Chiral switch should be motivated by both science (patent
extension) and safety/efficacy improvement

In vivo stability, metabolism and disposition of each enantiomer
must be established for preclinical and clinical (phase I)
purposes
For bioequivalence, a steroselective assay may be necessary for
differential in vivo metabolism of enantiomers (e.g. high fist
pass metabolism of eutomer)


All regulatory issues including chiral switches must be
addressed in consultation with the regulators
20

21. Acknowledgement: Ms. Raji Nair
THANK YOU VERY
MUCH
21