There is a trend in pharmaceutical industry towards the development of chiral drugs. Several factors have
influenced this trend in the pharmaceutical industry towards the development of the chiral drugs to provide more
potent selective and specific drugs. Over 1/3 rd of the marketed drugs worldwide are chiral and the regulators now
only will approve new chiral drugs in the single enantiomer form and even then insists on full profiling of the role
of the individual enantiomers invivo. The importance of chirality lies not only in the product development but in
the area of analytical and bioanalytical method development. Development of chiral analytical method/bioanalytical methods as per regulatory requirements requires a series of selection process to get the adequate resolution and quantification. Selection of compatible mobile phases and stationary phase that suits the particular need is very important. This presentation gives a brief description of chiral products, excipients followed by
functions and effects of its chiral forms. This presentation also describes the case studies of the chiral quantification in bioanalytical and analytical methods and their applications.
2. INTRODUCTION
WHAT IS CHIRALITY
IMPORTANCE FOR DRUG DESIGN
IMPACT ON TODAY PORTFOLIO
POTENTIAL ADVANTAGES
DIFFERENCES
REGULATORY REQUIREMENTS
Pharmacokinetics
Toxicity
Stability
Labeling
3. WHAT IS CHIRALITY
Chirality is a property of asymmetry related to three-
dimensional structure. Human hands represent a
special illustration of chirality because they are related
to each other by a reflection: they are non-super
imposable mirror images of each other. Hands are
chiral because there is no way to rotate the left hand
so that it looks like the right hand .In chemistry, stereo
isomers are molecules that have the same molecular
formula or atomic composition, but which are arranged
differently in space.
4. IMPORTANCE FOR DRUG DESIGN
Enantiomers of compounds can react differently in the
body, with greatly helpful or harmful outcomes
“Many molecules are chiral, and their unique handedness
has both intricate and dramatic influences on how they
interact with biological systems.”
5. IMPORTANCE FOR DRUG DESIGN
Molecular chirality is a fundamental phenomenon that plays an
important role in biological processes.
A wide range of biological and physical functions are generated
through precise molecular recognition because enzymes,
receptors and other natural binding sites within biological
systems interact with different enantiomers in decisively in
different ways
As a result of such chiral recognition, drug enantiomers may
differ in their pharmacokinetic handling and their
pharmacological and/or toxicological profiles
6. Importance For Drug Design
German drug maker Chemie Grünenthal introduced
thalidomide, under the name Contergan, to the German
market on Oct. 1, 1957
It was a sedative to treat insomnia as well as to reduce
nausea associated with pregnancy.
By 1960, the drug was in more than 20 countries in Europe
and Africa.
On Nov. 18, 1961, the German paper Welt am Sonntag
reported on a study finding that pregnant women who had
been taking thalidomide were giving birth to babies with
gross deformities.
"By November 27, Grünenthal had pulled the drug off the
market, blaming the sensationalism of the press"
7. IMPACT ON TODAY’S GENERIC PORTOFOLIO
Today it is often easier to submit single enantiomeric
chiral drugs rather than racemic chiral drugs
Old racemates are often reassessed as single
enantiomers
Synthesis, separation and analysis of chiral compounds
has advanced greatly, and is highly sought
8. Potential advantages of single enantiomer
products
Less complex, more selective Pharmacodynamic profile
Potential for an improved therapeutic index
Less complex pharmacokinetic profile
Reduced potential for complex drug interactions
Less complex relationship between plasma concentration
and effect
9. SOME DIFFERENCES
• “the mean daily dose … was reduced by approximately
one third compared to the racemate”
• “the cardio toxicity of the drug appears to be
predominantly associated with the (R)-enantiomer”
• “significantly reduced negative isotropic effect
(approximately half) was observed with the single
enantiomer compared to the mixture”
• “between 130 and 160 fold more potent than the (R)-
enantiomer”
• “faster onset of action, reduction of side effects and
improved tolerability profile”
• “the S-enantiomer being effectively inactive”
10. REGULATORY REQUIREMENTS
Applications for drug products that contain an enantiomer or
racemic drug substance should include a stereo chemically
specific identity test and/or a stereo chemically selective
assay method. The choice of the controls should be based
upon the product's composition, method of manufacture and
stability characteristics.
11. REGULATORY REQUIREMENTS
STABILITY
The stability protocol for enantiomeric drug substances and
drug products should include a method or methods capable of
assessing the stereo chemical integrity of the drug substance
and drug product. However, once it has been demonstrated
that stereo chemical conversion does not occur, stereo
selective tests might not be needed
12. REGULATORY REQUIREMENTS
Pharmacology
The pharmacologic activity of the individual enantiomers
should be characterized for the principal pharmacologic
effect and any other important pharmacological effect,
with respect to potency, specificity, maximum effect, etc.
13. REGULATORY REQUIREMENTS
Pharmacology
The pharmacologic activity of the individual enantiomers
should be characterized for the principal pharmacologic effect
and any other important pharmacological effect, with respect
to potency, specificity, maximum effect, etc.
14. REGULATORY REQUIREMENTS
Pharmacokinetic profile
To monitor in vivo inter conversion and disposition, the
pharmacokinetic profile of each isomer should be
characterized in animals and later compared to the
clinical pharmacokinetic profile obtained in phase 1
15. REGULATORY REQUIREMENTS
Toxicology
It is ordinarily sufficient to carry out toxicity studies on the
racemate.
If toxicity other than that predicted from the pharmacologic
properties of the drug occurs at relatively low multiples of
the exposure planned for clinical trials.
The toxicity study where the unexpected toxicity occurred
should be repeated with the individual isomers to ascertain
whether only one enantiomer was responsible for the
toxicity.
16. REGULATORY REQUIREMENTS
Toxicology
If toxicity of significant concern can be eliminated by
development of single isomer with the desired
pharmacologic effect, it would in general be desirable to do
so. The agency would be pleased to discuss any cases
where questions exist regarding the definition of "significant
toxicity."
17. REGULATORY REQUIREMENTS
• LABELING
The labeling should include a unique established name and a
chemical name with the appropriate stereo chemical
descriptors.
18. REGULATORY REQUIREMENTS
IMPURITY LIMITS
It is essential to determine the concentration of each isomer
and define limits for all isomeric components, impurities,
and contaminants on the compound tested preclinical that
is intended for use in clinical trials. The maximum allowable
level of impurity in a stereoisomeric product employed in
clinical trials should not exceed that present in the material
evaluated in nonclinical toxicity studies.
19. CURRENT CHIRAL METHODS:
COST AND TIME
• SEPARATION
• Preparative chiral
chromatography
• Cheaper despite waste
• Applicable to most
small chiral molecules
• Crystallization of
diastereomeric salts
• SELECTIVITY
• Chiral pool
• A lot of catalysis
• Enantioselective
processes
• Conversion of
enantiomers
“Speed is essential, and you don’t always have the luxury of trying to come
up with the best synthesis”
20. CURRENT CHIRAL METHODS:APPROACH
Enantiomeric supply and absolute configuration
Detector response and racemization potential
Instrumentation and flexibility of the application
Chiral derivatization reaction, diastereomer confirmation and
stability
Stereo selective kinetics of diastereomers formation (kinetic
resolution)
Chromatography, separability and elution order
21. CONCLUSION
Chiral drugs are very important, in terms of efficacy
and applications in the human body, but they are not
a universal solution, and there are still many risks in
their development.
“Nature has a way of knowing how to make things
work. Reactions often run in a catalytic mode, and
material use, energy, and waste are minimized.
Many molecules are chiral, and their unique
handedness has both intricate and dramatic
influences on how they interact with biological
systems.”