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. 2015 Aug;5(4):256-268.
doi: 10.1016/j.jpha.2015.02.001. Epub 2015 Feb 13.

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

Esen Bellur Atici  1 , Bekir Karlığa  1
Affiliations

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

Esen Bellur Atici et al. J Pharm Anal. 2015 Aug.

Abstract

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-benzylpiperidin-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.

Keywords: Benidipine; Characterization; Impurities; Stability; Synthesis; Validation.

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Figures

Fig. 1
Fig. 1
Chemical structure of α-benidipine hydrochloride.
Scheme 1
Scheme 1
Synthesis of benidipine hydrochloride.
Fig. 2
Fig. 2
HPLC analysis of benidipine spiked with impurities.
Fig. 3
Fig. 3
Structures of benidipine and its impurities.
Scheme 2
Scheme 2
Synthesis of Ben-ox impurity.
Scheme 3
Scheme 3
Synthesis of Ben-bis impurity.
Scheme 4
Scheme 4
Synthesis of Ben-desbenzyl impurity.
Fig. 4
Fig. 4
Chromatograms of HPLC method validation for determination of Ben-2 in benidipine: (A) blank solution, (B) test solution spiked with Ben-2 at specification limit (0.10%), (C) LOD solution (Ben-2 conc. 0.03 μg/mL (0.003%)), and (D) LOQ solution (Ben-2 conc. 0.09 μg/mL (0.01%)).
Fig. 5
Fig. 5
Assay chromatograms (UPLC) of stress-testing studies: (A) untreated sample, (B) thermal, (C) day-light, (D) UV-light, (E) neutral hydrolysis (boiling), (F) acidic hydrolysis (HCl), (G) basic hydrolysis (NaOH), and (H) oxidation (H2O2).
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