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Development of a Novel and Stable Indicating RP-HPLC Method for the Simultaneous Analysis of 12 Impurities in Midazolam and Midazolam Injection Products

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Abstract

Midazolam, a gamma-aminobutyric acid receptor agonist, is among the benzodiazepines that are generally used in clinical practice. Through studying the detection methods of midazolam raw materials and injections related substances in the multinational pharmacopoeias, it was found that these methods have several defects, such as incomplete elution impurities and poor impurity separation. Accordingly, an efficient, rugged, and novel reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed to simultaneously detect 12 related substances in midazolam active pharmaceutical ingredients (APIs) and injections. The detection of related impurities was realized at a detection wavelength of 254 nm by gradient elution at a flow rate of 1.0 mL/min on a YMC Triart-C18 column (250 × 4.6 mm, 5 µm) that was maintained at 35 °C. Mobile phase A was composed of disodium hydrogen phosphate solution. Acetonitrile and methanol were mobile phase B and mobile phase C, respectively. The recoveries of all impurities were in the range of 97–101%, and the precision RSD was less than 1%. The limit of quantitation (LOQ) for impurity A was equivalent to 0.09% of the midazolam test concentration. The LOQ for other impurities was 0.02%. The forced degradation research, which was carried out under acidic, basic, oxidative, thermal, and photolytic stress degradation conditions, showed the stability-indicating capacity of the method. Validation study results indicated that the sensitivity and selectivity of the developed HPLC method are satisfactory. In summary, this research can promote midazolam quality control to better protect the health of patients and can provide a reference for researchers studying midazolam.

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Acknowledgements

This work was supported by Chongqing Plan for High Level Talents project of CQ CSTC (No.: cstc2021ycjh-bgzxm0315) and the National Major Scientific and Technological Special Project of the Ministry of Science and Technology of China (2017ZX09101001).

Funding

Chongqing Plan for High Level Talents project of CQ CSTC (No.: cstc2021ycjh-bgzxm0315); the National Major Scientific and Technological Special Project of the Ministry of Science and Technology of China (2017ZX09101001).

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Authors and Affiliations

  1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China

    Dandan Chen, Li Huang & Jianhua Wang

  2. Chemistry Laboratory, Chongqing Institute for Food and Drug Control, Chongqing, 401121, China

    Dandan Shen, Lixin Hou, Youming Xiong & Linggao Zeng

  3. NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing, 401121, China

    Dandan Shen, Lixin Hou, Youming Xiong & Linggao Zeng

Authors
  1. Dandan Chen
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  2. Dandan Shen
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  3. Li Huang
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  4. Lixin Hou
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  5. Youming Xiong
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  6. Linggao Zeng
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  7. Jianhua Wang
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Contributions

The first draft of the manuscript was written by DC. The experimental protocol was formulated by DS. Data collection and analysis were done by DC and LH. Material and reagent preparation were performed by LH, YX, and LZ. Writing guidance and advice were provided by JW. All authors read and approved the final manuscript.

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Correspondence to Linggao Zeng or Jianhua Wang.

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Chen, D., Shen, D., Huang, L. et al. Development of a Novel and Stable Indicating RP-HPLC Method for the Simultaneous Analysis of 12 Impurities in Midazolam and Midazolam Injection Products. Chromatographia 85, 949–958 (2022). https://doi.org/10.1007/s10337-022-04193-5

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  • DOI: https://doi.org/10.1007/s10337-022-04193-5

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