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Synthesis, establishment of reference standard impurity A of ramipril and assessment of impurities in ramipril products

Introduction: Ramipril, which is an angiotensin-converting enzyme (ACE) inhibitor, is prescribed to treat heart failure, diabetic kidney diseases and high blood pressure. The United States Pharmacopeia 43 (USP 43) and British Pharmacopoeia 2020 (BP 2020) require testing ramipril methyl ester (impurity A) in ramipril pharmaceutical substances as well as corresponding finished products. This study was conducted with the aim of synthesis and standardization of impurity A as related substance and using established reference impurity A in impurity test of ramipril pharmaceutical products.

Method: Impurity A was synthesized from ramipril by transesterification reaction with methanol and potassium hydroxide. The synthesized product chemical structure was elucidated from its spectroscopic data. High performance liquid chromatography (HPLC) method was utilized to determine its purity and establish it as reference standard. Finally, the assay of impurities in ramipril pharmaceuticals was determined by HPLC method, using the established impurity A standard.

Results: Ramipril methyl ester was successfully synthesized and purified with 39.2% yields (about 1.08 g). Impurity A purity determined was over 98% and conformed to establish reference standard. The assigned purity value of impurity A is 99.01%. Additionally, the assay of impurities in available ramipril pharmaceuticals by application of a HPLC method referred from USP 43 was conducted.