Method for enantiomeric purity of a quinuclidine candidate drug by capillary electrophoresis.

Abstract

A chiral procedure based on EKC was developed and validated for determination of the enantiomeric purity of PHA-543613, a drug candidate that was under development for treatment of the cognitive deficits of Alzheimer's disease and schizophrenia. Separation of enantiomers is accomplished via differential, enantiospecific complexation with a single-isomer, precisely sulfated beta-CD and heptakis-6-sulfato-beta-CD (HpS-beta-CD). Both neutral and sulfated CDs were screened before selecting HpS-beta-CD as the chiral selector. The separation is conducted in a 61 cm x 50 microm uncoated fused silica capillary with 25 mM HpS-beta-CD in pH 2.50, 25 mM lithium phosphate as the separation buffer with detection at 220 nm. Application of reverse polarity at -30 kV results in an elution time of about 12 min for PHA-543613 and 13 min for the undesired S-enantiomer. Quantification is versus an authentic reference S-enantiomer as an external standard in combination with an internal standard. The procedure was validated over the range 0.1-2.0% w/w. The detection limit is 0.01-0.02%. The amount of distomer intrinsic to the drug substance is about 0.1% or less. The developed method was used to generate stability data on multiple lots: in one case for up to 3 years.

• Authors: Tore Ramstad, Rebecca L Johnson
• Journal: Journal of separation science (J Sep Sci) Vol. 29 Issue 13 Pg. 2056-64 (Aug 2006) ISSN: 1615-9306 [Print] Germany
• PMID: 17017019 (Publication Type: Comparative Study, Journal Article, Validation Study)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide
• Nicotinic Agonists
• Nootropic Agents
• Quinuclidines

Topics

• Bridged Bicyclo Compounds, Heterocyclic (chemistry, isolation & purification, standards)
• Chromatography, High Pressure Liquid (methods)
• Chromatography, Micellar Electrokinetic Capillary (methods, standards, statistics & numerical data)
• Electrophoresis, Capillary (methods, standards, statistics & numerical data)
• Nicotinic Agonists (chemistry, isolation & purification, standards)
• Nootropic Agents (chemistry, isolation & purification, standards)
• Quinuclidines (chemistry, isolation & purification, standards)
• Reference Standards
• Stereoisomerism