Solution Stability of Factor Xa Inhibitors as a Function of pH

Abstract

The stability of two factor Xa inhibitors (MLN1021 and CT54004) as a function of pH was investigated in order to better characterize the compounds and to locate the optimum pH for a stable formulation that might be used in a first‐in‐person (FIP) clinical study. The compounds prepared in buffer solutions over a pH range of 1–10 were stored at 60°C, and assayed for pH and purity at different time points. The pH‐rate profiles indicated that both compound was quite stable in the middle pH range, and least stable at pH < 3 and > 8. The optimum pH for stability of the compounds was around 6, which is consistent with the theoretical predictions by a mathematical model. The mechanism of the reaction is not a specific‐acid/base‐catalyzed reaction. Based on the experience of this study, an ideal experimental design is proposed, which will be useful for future study on similar drug candidate.

Key Words:

• Factor Xa
• pH
• Stability
• Degradation rate