Identification and characterization of process-related substances and degradation products in apremilast: Process optimization and degradation pathway elucidation

Background: Regadenoson is an A2A adenosine receptor agonist that is a coronary vasodilator and commonly used as a pharmacologic cardiac stressing agents. Methods: HPLC method was used for the analysis of related substances. The degraded impurities during the process were isolated and characterized by IR, Mass and NMR spectral analysis. Results: Forced degradation study of regadenoson under conditions of hydrolysis (neutral, acidic and alkaline) and oxidations suggested in the ICH Q1A(R2) was accomplished. The drug showed significant degradation under all the above conditions. On the whole, five novel degradation products were found under diverse conditions along with process related impurities which were not reported earlier. Conclusion: All the degradation products were well characterized by using advanced spectroscopic techniques like IR, 1H NMR, 13C NMR and Mass spectra. The identification of these impurities will be productive for the quality control during the production and stability behavior of the regadenoson drug substance.

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Identification, Characterization, and Quantification of Impurities of Safinamide Mesilate: Process-Related Impurities and Degradation Products

Journal of AOAC International ◽

10.5740/jaoacint.16-0218 ◽

2017 ◽

Vol 100 (4) ◽

pp. 1029-1037 ◽

Cited By ~ 1

Author(s):

Liang Zou ◽

Lili Sun ◽

Hui Zhang ◽

Wenkai Hui ◽

Qiaogen Zou ◽

...

Keyword(s):

Degradation Products ◽

Hplc Method ◽

Formation Mechanisms ◽

Stability Indicating ◽

Related Impurities ◽

Related Substances ◽

Water Ph ◽

Bulk Drug ◽

First Time

Abstract The characterization of process-related impurities and degradation products of safinamide mesilate (SAFM) in bulk drug and a stability-indicating HPLC method for the separation and quantification of all the impurities were investigated. Four process-related impurities (Imp-B, Imp-C, Imp-D, and Imp-E) were found in the SAFM bulk drug. Five degradation products (Imp-A, Imp-C, Imp-D, Imp-E, and Imp-F) were observed in SAFM under oxidative conditions. Imp-C, Imp-D, and Imp-E were also degradation products and process-related impurities. Remarkably, one new compound, identified as (S)-2-[4-(3-fluoro-benzyloxy) benzamido] propanamide (i.e., Imp-D), is being reported here as an impurity for the first time. Furthermore, the structures of the aforementioned impurities were characterized and confirmed via IR, NMR, and MS techniques, and the most probable formation mechanisms of all impurities proposed according to the synthesis route. Optimum separation was achieved on an Inertsil ODS-3 column (250 × 4.6 mm, 5 μm), using 0.1% formic acid in water (pH adjusted to 5.0) and acetonitrile as the mobile phase in gradient mode. The proposed method was found to be stability-indicating, precise, linear, accurate, sensitive, and robust for the quantitation of SAFM and its process-related substances, including its degradation products.

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