Stability of phenobarbital N-glucosides: identification of hydrolysis products and kinetics of decomposition.
The two diastereomers of 1-(1-beta-D-glucopyranosyl)phenobarbital, (1A) and (1B), decompose to 1-(1-beta-D-glucopyranosyl)-3-(2-ethyl-2-phenylmalonyl)urea (2A or 2B) followed by decarboxylation to 1-(1-beta-D-glucopyranosyl)-3-(2-phenylbutyryl)urea (3A and 3B) under physiological conditions of temperature and pH. The sigmoidal pH-rate profile and the Arrhenius parameters indicate that degradation takes place by hydroxide ion attack on the undissociated and monoanion forms of 1A and 1B. The rates of hydrolysis of the nonionized species of 1A and 1B are more than two orders of magnitude faster than those of common 5,5-disubstituted or 1,5,5-trisubstituted barbiturates. Molecular modeling studies suggest that rate enhancement is due to intramolecular hydrogen bonding in the transition state of the C2' hydroxyl with the tetrahedral hydrated C6 carbonyl as well as hindered rotation around the N1-C1' of phenobarbital and glucose. Based on these studies it is recommended that any data related to the quantitation of 1A and 1B be reevaluated depending on how the samples were collected, stored, and analyzed.
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond 23298-0581.
F B
FB
Vest
W H
WH
Soine
R B
RB
Westkaemper
P J
PJ
Soine
D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D006027:Glycosides; D006868:Hydrolysis; D007202:Indicators and Reagents; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D010634:Phenobarbital / Q000031:analogs & derivatives* / Q000032:analysis; D013696:Temperature
D006027:Glycosides; D007202:Indicators and Reagents; D010634:Phenobarbital