The Stability of Nicorandil in Aqueous Solution. I. Kinetics and Mechanism of Decomposition of N-(2-Hydroxyethyl) nicotinamide Nitrate (Ester) in Aqueous Solution

The extent and mechanism of decomposition of Nicorandil [N-(2-hydroxyethyl) nicotinamide nitrate (ester)] (I) in aqueous solution at various pH values were clarified. Four products derived from (I) were isolated and identified as 2-(3-pyridyl)-2-oxazoline (II), 2-aminoethyl nicotinate nitrate (III), N-(2-hydroxyethyl) nicotinamide (IV) and nicotinic acid (V). The decomposition products and (I) were quantitated by high performance liquid chromatography. The decompositions of (I), (II) and (III) followed pseudo first-order kinetics, while (IV) and (V) did not decompose further in the range of pH 4 to 11. Arrhenius plots of the rate constant for (I) were linear and the apparent activation energy for (I) was 25kcal/mol at pH 7.0. The decomposition in aqueous solution was found to occur by a stepwise mechanism, with (I) cyclizing to form (II), which undergoes ring-opening to give (III), followed by competitive reactions, that is, rearrangement and hydrolysis, to form (IV) and (V) in the pH range of 4 to 11.