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.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/isolation & purification , Electrophoresis, Capillary/methods , Quinuclidines/isolation & purification , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/standards , Chromatography, High Pressure Liquid/methods , Chromatography, Micellar Electrokinetic Capillary/methods , Chromatography, Micellar Electrokinetic Capillary/standards , Chromatography, Micellar Electrokinetic Capillary/statistics & numerical data , Electrophoresis, Capillary/standards , Electrophoresis, Capillary/statistics & numerical data , Nicotinic Agonists/chemistry , Nicotinic Agonists/isolation & purification , Nicotinic Agonists/standards , Nootropic Agents/chemistry , Nootropic Agents/isolation & purification , Nootropic Agents/standards , Quinuclidines/chemistry , Quinuclidines/standards , Reference Standards , StereoisomerismABSTRACT
Nicotine replacement therapy (NRT) is an effective treatment for smoking cessation, but as with all such pharmacotherapies, the majority of smokers who use NRT products do not stop smoking or remain abstinent long term. Treatment outcome is affected by a range of individual-specific factors, as well as the pharmacokinetic profile of each NRT formulation. This has led to speculation that abstinence rates could be improved if NRT treatments were individually tailored to best match each individual's needs and preferences. There are also populations for whom special product and dosage considerations are warranted to maximise treatment safety.This paper reviews the rationale for NRT treatment, standard dose recommendations and recommendations for how to best match NRT treatment to the specific needs of individual smokers. We also review emerging evidence that genetic profiling may one day be a useful consideration for tailoring NRT treatment.
