Determination of the enantiomerization barrier of chlorthalidone by dynamic electrokinetic chromatography and computer simulation.
Dynamic electrokinetic chromatography (DEKC) and computer simulation have been used to determine the enantiomerization barrier of the drug chlorthalidone, which is commonly employed as a diuretic. The separation of enantiomers was performed in an aqueous 100 mM citric acid/phosphate buffer system at pH 5 containing 12.5 mg/mL carboxymethyl-beta-cyclodextrin and dimethyl-beta-cyclodextrin each as a dual chiral recognition system. The enantiomerization that occurred during separation resulted in a peak distortion, i.e., plateau formation and peak broadening. The interconversion profiles were simulated with ChromWin software, which is based on the theoretical plate as well as on the stochastic model using the experimental data plateau height, hplateau; peak width at half height, Wh, and total retention time, tR. Peak form analysis yielded the rate constants, k1 and k(-1) as well as the kinetic activation parameters, deltaG++, deltaH++, and deltaS++ of the enantiomerization reaction of chlorthalidone 1. At 37.5 degrees C, the enantiomerization barrier, deltaG++, was determined to be 100.6 +/- 0.4 kJ/mol(-1); the activation parameters by temperature-dependent measurement, deltaH++ = 69.2 +/- 0.2 kJ/mol , deltaS++ = -101 +/- 6 J K(-1) mol(-1) and the half-life, tau, was found to be approximately 2.5 hr.
Schoetz
G
G
Universität Tüebingen, Institut für Organische Chemie, Germany.
Trapp
O
O
Schurig
V
V
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002752:Chlorthalidone / Q000737:chemistry*; D002845:Chromatography / Q000379:methods*; D003198:Computer Simulation; D003505:Cyclodextrins / Q000737:chemistry; D004355:Drug Stability; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013269:Stochastic Processes; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D047392:beta-Cyclodextrins; C441457:carboxymethyl-beta-cyclodextrin; C038119:heptakis(2,6-O-dimethyl)beta-cyclodextrin; D002752:Chlorthalidone