Mechanism of hydrolysis of a novel indolocarbazole topoisomerase I inhibitor.
The degradation kinetics and reaction product profile of the antitumor agent 1 in aqueous solution was studied. Hydrolysis of the pendant imide ring of 1 is the primary mode of thermal degradation in aqueous solution, and the pH rate profile of 1 has a V-shape indicating that hydrolysis of the imide ring can be catalyzed by either acid or base. Hydrolysis of 1 to the anhydride derivative 3 or the dicarboxylic acid derivative 4 is stepwise and the intermediates 2a and 2b formed by initial hydrolytic attack have been observed under alkaline conditions. An overall mechanism for the hydrolysis of 1 in aqueous solution has been proposed. Extrapolating Arrhenius behavior to the hydrolysis reaction of 1 in aqueous solution maintained at a pH value of 4 suggests an aqueous buffered formulation has sufficient thermal stability to be considered a robust room temperature drug product.
Breslin
David
D
Pharmaceutical Research and Development, Merck Research Laboratories, West Point, PA 19486, USA.
Sato
Yuichi
Y
Karki
Shyam B
SB
D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000494:pharmacology*; D019075:Electrophoresis, Capillary; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics
D002227:Carbazoles; D004791:Enzyme Inhibitors; D004264:DNA Topoisomerases, Type I