Kinetics and Mechanism of the Base-Catalyzed Rearrangement and Hydrolysis of Ezetimibe

The pH-rate profile of the pseudo-first-order rate constants for the rearrangement and hydrolysis of Ezetimibe giving (2R,3R,6S)-N,6-bis(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxamide (2) as the main product at pH of less than 12.5 and the mixture of 2 and 5-(4-fluorop...

Full description

Saved in:
Bibliographic Details
Published in:Journal of pharmaceutical sciences 2014-08, Vol.103 (8), p.2240-2247
Main Authors: Baťová, Jana, Imramovský, Aleš, HájÍček, Josef, Hejtmánková, Ludmila, Hanusek, Jiří
Format: Article
Language:English
Subjects:
acid-base catalysis
Anticholesteremic Agents - chemistry
Azetidines - chemistry
azetidinone
Buffers
Catalysis
chemical stability
degradation products
Drug Stability
Ezetimibe
Hydrogen-Ion Concentration
Hydrolysis
Kinetics
Liquid chromatography
NMR
Osmolar Concentration
pH rate profile
rearrangement
UV-VIS spectroscopy
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The pH-rate profile of the pseudo-first-order rate constants for the rearrangement and hydrolysis of Ezetimibe giving (2R,3R,6S)-N,6-bis(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxamide (2) as the main product at pH of less than 12.5 and the mixture of 2 and 5-(4-fluorophenyl)-5-hydroxy-2-[(4-fluorophenylamino)-(4-hydroxyphenyl)methyl]-pentanoic acid (3) at pH of more than 12.5 in aqueous tertiary amine buffers and in sodium hydroxide solutions at ionic strength I = 0.1mol L−1 (KCl) and at 39°C is reported. No buffer catalysis was observed and only specific base catalysis is involved. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple β-lactams and it contains several breaks. Up to pH 9, the log kobs linearly increases with pH, but between pH 9 and 11a distinct break downwards occurs and the values of log kobs slightly decrease with increasing pH of the medium. At pH of approximately 13, another break upwards occurs that corresponds to the formation of compound 3 that is slowly converted to (2R,3R,6S)-6-(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxylic acid (4). The kinetics of base-catalyzed hydrolysis of structurally similar azetidinone is also discussed. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2240–2247, 2014
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.24070