Initial Rate Analysis of Zoniporide Hydrolysis Degradants Using High-Performance Liquid Chromatography Coupled with Mass Spectrometric Detection

Abstract

Zoniporide, N-(5-Cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine methanesulfonic acid, is a sodium-hydrogen exchanger type 1 (NHE-1) inhibitor. This compound forms two major hydrolysis degradants (Degradants I and II) and therefore was formulated as an IV concentrate lyophile. The purpose of this study was to perform initial rate analysis on formation of Degradants I and II, to determine if a liquid Zoniporide formulation is feasible. Solutions of Zoniporide were placed on stability at ambient temperature (30°C), refrigerated temperature (5°C), and frozen temperature (−20°C). Initial formation rates were determined for Degradants I and II by using high-performance liquid chromatography/mass spectrometry (HPLC/MS). The initial formation rates were used to predict the time required for a degradant level of 0.1% relative to Zoniporide to be reached. The predicted times for Degradant I to reach 0.1% were 9 days, 330 days, and 30,962 days at temperatures of 30°C, 5°C, and −20°C, respectively, indicating that refrigerated or frozen storage would be required for a liquid Zoniporide formulation to be feasible and reach the target shelf life. The initial formation rates of Degradant II were approximately 1-order of magnitude lower. In Addition, samples of the Zoniporide solutions were assayed for concentrations of Degradant I and Zoniporide after 2.5 years of storage at 5°C and −20°C to determine the validity of the initial formation rate predictions. The mean experimentally determined Degradant I concentration at 5°C was within 13% of the predicted concentration, and the mean experimentally determined Degradant I concentration at −20°C was within 37% of the predicted concentration. This agreement between the experimentally determined and predicted Degradant I concentrations indicates that the initial rate method is sufficiently accurate and can be used to rapidly evaluate various formulation conditions with respect to stability.