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Structure Elucidation and Mechanistic Study of a New Dimer Impurity in Mirabegron Extended-Release Tablets

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Abstract

An unknown peak with a relative retention time (RRT) of 1.47 was noticed in HPLC chromatograms for related substances of mirabegron extended-release tablets. The level of this unknown peak under the accelerated stability condition for 6 months was as high as 0.19%, which had a trend to exceed the identification threshold of 0.2% from ICH Q3B. The purpose of this study was to identify the RRT 1.47 impurity, and we studied its degradation mechanism to control its content to a lower level. The structure of the RRT 1.47 impurity was identified as a mirabegron dimer bridged by methylene via LC–MS and NMR. Investigation on compatibility of drug-excipients indicated that this impurity formed by Mannich reaction between mirabegron and residual formaldehyde in excipients polyethylene glycol (PEG), polyoxyethylene (PEO). Moreover, the determination of formaldehyde content in excipients further proved this speculation. There was a linear relationship between the amount of formaldehyde and the content of generated dimer impurity within a certain range. The reaction between mirabegron and formaldehyde at different temperatures demonstrated that the higher the temperature, the faster the reaction rate and the higher level of this impurity were generated. To understand the kinetics of the reaction, we calculated the rate of dimerization and also the activation energy of the process based on the stability data. During the development of pharmaceutical formulation on mirabegron or similar structure, appropriate excipients should be selected or the formaldehyde content in excipients could be controlled to avoid such reactions to improve the quality of the product.

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Acknowledgements

We acknowledge Yuting Liu and Yanhua Li for their support in performing NMR analysis, LC-MS analysis, and the structure elucidation.

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No funding was received to assist with the preparation of this manuscript.

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Authors and Affiliations

  1. Dongguan HEC Generic Drug R&D Co., Ltd., Dongguan, 523871, China

    Xinghua Lin, Gugu Hao, Guobin Xu, Fuzhou Sun, Libo Xin, Shuming Wu, Zhongqing Wang, Jinsong You, Fangfang Huang & Xuezhi Song

  2. State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd., Dongguan, 523871, China

    Xinghua Lin, Gugu Hao, Guobin Xu, Fuzhou Sun, Libo Xin, Shuming Wu, Zhongqing Wang, Jinsong You, Fangfang Huang & Xuezhi Song

Authors
  1. Xinghua Lin
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  2. Gugu Hao
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  9. Fangfang Huang
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Contributions

Methodology: XL and GH; formal analysis and investigation: XL, GX, and ZW; formal analysis: LX and SW; writing—original draft: XL; writing—review and editing: GH and FS; resources and funding acquisition: FH; conceptualization: JY and XS; supervision: JY and XS.

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Correspondence to Fangfang Huang or Xuezhi Song.

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All authors receive salaries and research funding from Sunshine Lake Pharmaceutical Company Ltd.

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Lin, X., Hao, G., Xu, G. et al. Structure Elucidation and Mechanistic Study of a New Dimer Impurity in Mirabegron Extended-Release Tablets. Chromatographia 86, 185–197 (2023). https://doi.org/10.1007/s10337-022-04231-2

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