CHIRAL RESOLUTIONS AN INDUSTRIAL PROSPECTIVE

Presented by

Ch.Vamsi Anil Krishna(10AB1R0026)

Adderss:

Dept of Pharmaceutical Chemistry

Vignan Pharmacy College,Vadlamudi,

Guntur, Andhra Pradesh, India.

Contents: Introduction Resolution Methods Resolving agents Stereoselectivity of action Chiral drug sales Chiral BIOCKBUSTER DRUGS Conclusion

INTRODUCTION:

A chiral molecule and its mirror image are called a pair of

enantiomers. Enantiomers have identical chemical and physical

properties(IR, NMR, mp, mass spectra,…etc), except for their ability to

rotate plane-polarized light(+/-) by equal amounts but in opposite

directions.

RESOLUTION METHODS

Various techniques used:

Chromatography

Widely used in development laboratories

Applicable to >99% of small molecules at analytical scale

Used in manufacturing scale

Methods for Preparing Chiral Compounds

Chromatography

A small scaleseparation of thechiral compounds in labs.

Handling of chromatography

Kinetic Resolution

Evalution of an historical process(> 100 years)

Based upon different reaction rates of the isomers

Theoretically 100% yield

Technology applied on limited scale to date

Diastereomer Crystallisation

Most widely used technique in industry

Widely used in development

Cheap additives

Only one isomer recovered per stage

Resolving Agents

Stereoselectivity of action

SS

Dextro(+)

RR

Levo(-)

ENANTIOMERS

Out 100 drugs sold

in 1994:

Pure enantiomer

20%

Racemate

21%

No chiral

33%

Out 100 drugs sold

in 1997:

Pure enantiomer 30%

Racemate 9%

No chiral 57%

Racemic Mixture Single-enantiomer

Amphetamine(Benzedrine) Dextroamphetamine(Dexedrine)

Bupivacaine(Marcain) Levobupivacaine (Chirocaine)

Cetirizine(Zyrtec/ Reactine) Levocetirizine(Xyzal)

Citalopram(Celexa/ Cipramil) Escitalopram(Lexapro/ Cipralex)

Methylphinidate(Ritalin) Dexmethylphenidate(Focalin)

Racemic Mixture Single-enantiomer

Modafinil(Provigil) Armodafinil(Nuvigil)

Ofloxacin(Floxin) Levofloxacin(Levaquin)

Omeprazole(Prilosec) Esomeprazole(Nexium)

Salbutamol(Ventolin) Levalbuterol(Xopenex)

Zopiclone(Imovane) Eszopliclone(Lunesta)

Statical data: CHIRAL DRUG SALE SHOW NO SIGN OF SLOWING

$ MILLIONS 1998 1999 2000

Cardio vascular $21,906 $24,805 $26,012

Antibiotics 19,756 20,907 23,265

Cancer 8,006 9,420 13,360

Central Nervous System 7,027 8,592 13,720

Antiviral 6,131 7,540 13,446

Gastrointestinal 1,718 2,998 5,355

TOTAL $6,45,44 $74,262 $95,198

CHIRAL TECHNOLOGY IN COMMERCIALLY

Chiral technology is a rapidly

developing area

Chiral technology represents a huge commercial business opportunity that has yet to be fully realised

MARKET OF CHIRAL DRUGS

Single–enantiomer drug sales show a continuous growth worldwide

and many of the top selling drugs are marketed as single enantiomers

Annual sales of chiral drugs:

$133billion(2000), $172billion(2005)

Conclusion: It is necessary to consider the chiral nature of a com-pound in drug Research.

Enantiomers of all chiral bioactive molecules must be separated and tested.

The FDA and regulatory authorities in Europe, China, and Japan have provided guidelines indicating that only the active enantiomer of a chiral drug should be brought to market.

References:Chiral drug separation

Bingyun LiDonald T. Haynie Engineering and Physics, Bionano systems Engineering Labo Biomedical ratory, Center for Applied Physics Studies, Louisiana Tech University, Ruston, Louisiana, U.S.A

The impact of chiral technology on the pharmaceutical industry

ANDY RICHARDS & RAY McCAGUE

Acknowledgement:

This work was supported by

A.VISWANATH M.pharm (Ph.D)

Dept of Pharamaceutical chemisrty.

My beloved PRINCIPAL

Dr.P.SRINIVASA BABU

Thank you