Proposal of a new degradation mechanism of enalapril maleate and improvement of enalapril maleate stability in tablet formulation with different stabilizers.

Enalapril maleate (EM) is unstable in poorly designed tablet formulations. To improve the stability of EM, the degradation mechanism should be elucidated. In this study, we found that several commonly used excipients promoted the degradants of EM, particularly a diketopiperazine derivative (DKP). We propose two degradation pathways in which both acid and alkali can promote the formation of DKP, although previous reports suggested that DKP is produced mainly in acidic media. Based on the degradation pathways, we believe that subtle control of the microenvironmental pH can inhibit the formation of DKP. This was confirmed by the observation that the degradation rate became slower when certain organic acids were added to the binary mixtures of EM and excipient. The data showed that the stability of EM in the ternary mixtures was much higher than that in binary mixtures. It was further proved that tablets containing these organic acids produced less DKP after the accelerated test. We also found that the formation of DKP in tablets varied with different ratios of tartaric acid, which was used as a model organic acid. This illustrated that an optimum ratio of tartaric acid is required. These results indicated that the stability of EM in tablet formulation is closely associated with microenvironmental pH and the addition of a suitable organic acid based on the reaction mechanism is an effective strategy for improving the stability of EM.