Studies on the formation and forming mechanism of the related substance E in potassium clavulanate production by HPLC-MS/MS
Open accessAbstract
The objective of this study was to investigate the formation and forming mechanism of the related substance E in potassium clavulanate production. The impurity with retention time of 11.1 min in potassium clavulanate final product was confirmed as the related substance E by high performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS).The related substance E analysis during the production of clavulanic acid showed that this impurity could be formed during both the fermentation and purification processes, especially in the later fermentation stage, filtration concentration and back-extraction procedure. Clavulanic acid was the precursor of the related substance E. Studies on its forming mechanism showed that the related substance E was formed by the combination of the imino group of one molecule of clavulanic acid with the carboxyl group of another molecule of clavulanic acid with the opening of β-lactam ring. Results of a multi-factor orthogonal test confirmed that the concentration of clavulanic acid was the dominant factor to accelerate the reaction, while the temperature was another contributing factor. The pH 5.0-6.5 had little impact on the generation of the related substance E.
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Zhong et al. proposed a mechanism of formation of the degradation product known as substance E involving several steps, including the irreversible reaction of an active intermediate with an additional molecule of CA.
“In this regard, Zhong et al. [30] proposed a mechanism of formation of the degradation product known as substance E; this mechanism involves several steps, including the irreversible reaction of an active intermediate with an additional molecule of CA leading to the reported decomposition product.”
From Degradation Kinetics of Clavulanic Acid in Fermentation Broths at Low Temperatures (2019) · cites this paper as [30]
The “Inference for the forming mechanism” section proposes a multistep route in which an active intermediate reacts with another molecule of clavulanic acid to form substance E. The Conclusions likewise describe formation of a new amide bond. Neither passage says the reaction is irreversible; page numbers are unavailable in our copy. (LLM, conf=0.86)
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Saudagar, P. S., & Singhal, R. S. (2007) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-007-9030-x · Cited by 26 · see citing works
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Research works printed but not linked: 1
- PARAG, S.; SAUDAGAR, S.A.; SURVASE, R.; SINGHAL, S. Clavulanic acid: a review. Biotechnol. Adv., v.26, p.335- 351, 2008.
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Degradation Kinetics of Clavulanic Acid in Fermentation Broths at Low Temperatures
Gómez-Ríos, D., Ramírez-Malule, H., Neubauer, P., Junne, S., & Ríos-Estepa, R. (2019) · Antibiotics · doi:10.3390/antibiotics8010006 · Cited by 17 · see citing works
“[30] proposed a mechanism of formation of the degradation product known as substance E; this mechanism involves several steps, including the irreversible reaction of an active intermediate with an additional molecule of CA leading to the reported decomposition product.”
Background
- Authors
- Zhong, C., Cao, G., Jin, X., & Wang, F.
- Affiliations
- Shandong Jianzhu University (CN)
- Shandong Medicinal Biotechnology Centre, China; Lunan Pharmaceutical Group Corporation, China
- Lunan Pharmaceutical Group Corporation, China
- Shandong University (CN)
- Venue
- Brazilian Journal of Pharmaceutical Sciences
- Publisher
- FapUNIFESP (SciELO)
- Published
- 2014-04
- Volume
- 50
- Issue
- 2
- Pages
- 391-399
- ISSN
- 1984-8250 (ISSN-L)
- OpenAlex
- W2087340259
- Cited by
- 6
- References
- 1
- Citations by year
- 2025: 1 · 2019: 2 · 2018: 1 · 2016: 1 · 2015: 1
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by-nc
- Locations
- Brazilian Journal of Pharmaceutical Sciences (publishedVersion, cc-by-nc)
- Americanae (AECID Library) (publishedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- Funders
- Chinese Academy of Sciences
- Topics
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Keywords
- potassium clavulanate, impurity formation mechanism, clavulanic acid, β-lactam ring opening, stripping, orthogonal experimental design
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