Identification, synthesis and characterization of process related impurities of benidipine hydrochloride, stress-testing/stability studies and HPLC/UPLC method validations☆

摘要

Benidipine hydrochloride, used as an antihypertensive agent and long-acting calcium antagonist, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of benidipine, process related impurities were detected. These impurities were identified, synthesized and characterized and mechanisms of their formation were discussed in detail. After all standardization procedures, they were used as reference standards for analytical studies. In addition, a separate HPLC method was developed and validated for detection of residual 1-benzylpi-peridin-3-ol (Ben-2), which is used during benidipine synthesis and controlled as a potential process related impurity. As complementary of this work, stress-testing studies of benidipine were carried out under specified conditions and a stability-indicating UPLC assay method was developed, validated and used during stability studies of benidipine.