The Influence of pH and Preservative Agents on Physicochemical and Microbiological Stability of a Flexible Dose/Age-Appropriate Formulation of Enalapril Maleate. A Quality by Design‑Based Optimization.

Enalapril (ENA) is indicated for the management of heart failure, hypertension, and asymptomatic left ventricular dysfunction, while pediatric patients also benefit from its use in treating hypertension and congestive heart failure. ENA is commercially available as tablets with doses ranging from 2.5 to 20 mg. However, achieving the typical starting dose of 0.1 mg kg-1 day-1 for infants and children can be challenging due to the limitations of available tablet strengths. This limitation is compounded by patients with dysphagia or those who are averse to swallowing tablets. Liquid oral formulations would facilitate adherence to treatment in these patients. The purpose of this study was to develop and optimize an oral liquid scalable-dose formulation of Enalapril Maleate at 2 mg mL-1 following a Quality by Design approach. Quality Target Product Profiles, Critical Process Parameters, and Critical Quality Attributes (CQAs) were identified. CQAs with a higher level were further evaluated through a Design of Experiments (DoE) approach, including pH, physical stability, microbiological quality, and chemical stability. Chemical stability of ENA showed variation depending on the specific formulation conditions and the influence of pH, buffer type, preservative agent, and storage temperature on the stability of the active ingredient was determined by DoE. The final selected formulation: enalapril 2 mg mL-1, pH 3.5, containing 10% v/v glycerin, 10 mM citrate buffer, and 0.2% w/v sodium benzoate, demonstrated to be physically, chemically, and microbiologically stable for at least six months under refrigerated conditions, with drug recoveries exceeding 95%, and a robust Design Space was established for its manufacture and storage.