title: Preparative Scale Resolution of Enantiomers Enables Accelerated Drug Discovery and Development.
abstract: The provision of pure enantiomers is of increasing importance not only for the pharmaceutical industry but also for agro-chemistry and biotechnology. In drug discovery and development, the enantiomers of a chiral drug depict unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of the chiral drugs determines their pharmacokinetic, pharmacodynamic and toxicological properties. We present a number of challenging case studies of up-to-kilogram separations of racemic or enriched isomer mixtures using preparative liquid chromatography and super critical fluid chromatography to generate individual enantiomers that have enabled the development of new candidate drugs within AstraZeneca. The combination of chromatography and racemization as well as strategies on when to apply preparative chiral chromatography of enantiomers in a multi-step synthesis of a drug compound can further facilitate accelerated drug discovery and the early clinical evaluation of the drug candidates.
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 431 83 Molndal, Sweden. hanna.leek@astrazeneca.com.
authors.forename: Hanna
authors.initials: H
authors.lastname: Leek
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, 431 83 Molndal, Sweden. shalini.andersson@astrazeneca.com.
authors.forename: Shalini
authors.initials: S
authors.lastname: Andersson
mesh_terms: D000577:Amides / Q000302:isolation & purification*; D002264:Carboxylic Acids / Q000302:isolation & purification*; D002845:Chromatography / Q000295:instrumentation / Q000379:methods*; D055808:Drug Discovery; D015507:Drugs, Investigational / Q000302:isolation & purification*; D006801:Humans; D013237:Stereoisomerism
chemical_list: D000577:Amides; D002264:Carboxylic Acids; D015507:Drugs, Investigational
keywords: active pharmaceutical ingredient; chiral resolution; chiral stationary phases; drug development; drug discovery; preparative chromatography; racemization; supercritical fluidchromatography