The impact of ionic excipients on stabilization of enalapril tablets by the formation of alkaline salt “in situ”

Abstract

The formation of salts is one of the possibilities of stabilizing medicinal substances. Salts can be prepared during the manufacture of the dosage form, saving time, reducing cost and environmental impact. Several studies have documented significant enalapril maleate (EM) instability. EM decomposes into diketopiperazine (DKP) and diacid (DA) impurities at elevated temperature and humidity. Notably, toxic DKP is preferentially formed at pH 2 – 3, and DA formation dominates at pH values above 5. This instability raises concerns about the therapeutic efficacy and safety of the drug. The proposed stabilization strategy involves the “in situ” conversion of EM into a stable sodium salt. This is achieved by incorporating suitable ionic excipients, specifically alkali metal salts and an ethanol-based hydrolysis inhibitor, into the granulation solution. This method effectively inhibits the deethylation to DA and provides uniform tablets with minimal DKP content to ensure long-term five-year stability. In general, these tablets show a lower content of degradation products compared to the stability results reported so far in various generics, and the amount of impurities meets the ICH Q3B (R2) requirements.