Degradation studies of levosimendan isolation, identification, and structure confirmation of stress degradation products using LCMS, mass mediated Prep-HPLC, NMR, HRMS, SFC and FTIR

The present work describes the stress degradation behavior of Levosimendan as per ICH guidelines. Under thermal and photolytic conditions drug had a fair stability and in other stress conditions degradation products (DP) were observed. Initial identification of the DP was performed by UPLC-MS and is...

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Published in:Journal of liquid chromatography & related technologies 2020-01, Vol.43 (1-2), p.17-28
Main Authors: Reddy, G. Mahesh Kumar, Singamsetti, Jcmknn Murty, Kaliyaperumal, Muralidharan, Doddipalla, Raju, Ivaturi, Ramu, Rumalla, Chidananda Swamy, Korupolu, Raghu Babu, Babu, B. Kishore
Format: Article
Language:English
Subjects:
Aromatic compounds
Benzene
Characterization
Cyanides
Degradation
Degradation products
forced degradation
High-performance liquid chromatography
HRMS
Hydrazine
Hydrazines
identification
Impurities
isolation
levosimendan
Liquid chromatography
Nitrogen
NMR
Nuclear magnetic resonance
Peroxide
Stress
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Summary:The present work describes the stress degradation behavior of Levosimendan as per ICH guidelines. Under thermal and photolytic conditions drug had a fair stability and in other stress conditions degradation products (DP) were observed. Initial identification of the DP was performed by UPLC-MS and isolation by MDAP. Various 1 D and 2 D NMR experiments along with supporting FT-IR and HRMS data were performed to characterize the DP. A novel degradant product observed in acidic conditions was isolated and characterized as (R,Z)-2(2-(4-(4-amino-2-methyl-4-oxobutanoyl) phenyl) hydrazono)-2-cyanoacetic acid (DP-1) with molecular formula C 14 H 14 N 4 O 4 . Additionally, two more DP were observed in both basic and peroxide conditions which are basically reported impurities. (R,E)-2-amino-N'-(4-(4-methyl-6-oxo-1,4,-5,6-tetrahydropyridazin-3-yl)phenyl)-2-oxoaceto hydrazonoyl cyanide (DP-2), a Cyano to amide converted product and (R)-5-methyl-6-phenyl-4,5-dihydropyridazin-3(2H)-one (DP-3) formed as result of cleavage of aryl nitrogen bond of benzene substituted dicyano hydrazine. Highlights Levosimendan was subjected to force degradation under acidic, basic, oxidative, photolytic and thermal conditions as per ICH guidelines. In Acid, base and oxidative conditions three degradant products were observed. DP-1 is identified and is novel. It is not reported in any literature. DP-2 and DP-3 are known and reported earlier, however this known degradation products only identified by LCMS. In present paper all the three degradation products have been identified and characterized by using various high-end analytical techniques such as HRMS, NMR, SFC and FT-IR.
ISSN:1082-6076
1520-572X
DOI:10.1080/10826076.2019.1613429