Development of Stereoisomers (Chiral) Drugs: A Brief Review Of Scientific and Regulatory Considerations
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0092-8615/97 Copyright 0 1997 Drug lnformation Association Inc.
DEVELOPMENT OF STEREOISOMERIC (CHIRAL) DRUGS: A BRIEF REVIEW OF SCIENTIFIC AND REGULATORY CONSIDERATIONS JONATHAN M. DANIELS, PHD Senior Scientist
EARLER. NESTMANN, PHD Principal and Vice President CanTox Inc., Consultants in Toxicology, Mississauga, Ontario, Canada
R R BSc ,
ALEX~
Toxicologist 11, CanTox Inc., Consultants in Toxicology, Bridgewater, New Jersey
Stereoisomers are molecules that are identical to one another in terms of atomic constitution and sequence of covalent bonds, but which differ in the three dimensional arrangement of atoms. There is a growing belief that enantioselectivity in the pharmacodynumic and pharmacokinetic properties of a drug is not a rare phenomenon, but occurs rather frequently. Because of differences in pharmacological activity between enantiomers, racemic mixtures can, in theory, be seen as combination products. Recognition of potential differences of pharmaceutical enantiomers has led to increasing attention by regulatory agencies to developments with such compounds. This paper will briefly review the scientifc and regulatory guidance provided for the development and approval of chiral drugs in Canada, and relate this to the requirements currently in place in the United States and Europe. Key Words: Chiral; Pharmaceuticals; Guidelines; Regulatory; Stereoisomers
INTRODUCTION STEREOISOMERS ARE MOLECULES that are identical to one another in terms of atomic constitution and sequence of covalent bonds, but which differ in the three dimensional arrangement of atoms (not to be confused with structural isomers which differ from one another in their sequence or type of covalent bonds). Stereoisomers may have more than one asymmetric (chiral) center.
Reprint address: Dr. Jon Daniels, Pharmaceutical & Healthcare Group, CanTox Inc., 2233 Argentia Road, Suite 308, Mississauga. Ontario, Canada LSN 2x7, E-Mail:[email protected].
For a molecule with n chiral centers, there may be up to 2" stereoisomers. Within stereoisomer classification, there are molecules that are nonsuperimposable mirror images of one another and are called enantiomers. Enantiomer pairs of a particular molecule have identical physical properties except for optical rotation, that is to say, when planepolarized light is passed through a solution or crystal of one enantiomer, the resulting rotation of light is equal in magnitude but opposite in direction than that of its enantiomeric counterpart. For this reason, enantiomers are also called optical isomers. The prefixes + or - and dexrro or levo (DL), which designate the direction of the
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Jonathan M . Daniels, Earle R. Nestmann, and Alex Kerr
angle of rotation, are used to distinguish enantiomers. Another classification system, the R/S system, designates the absolute configuration of a stereoisomer. It has largely replaced the D/L notation and should be used for molecules other than amino acids. A racemic mixture, or racem
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