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Formulation of Ceftriaxone Sodium Under the Guidance of Drug Quality Analysis

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Pharmaceutical Chemistry Journal Aims and scope

Ceftriaxone sodium is an antibiotic used clinically.We have developed a strategy for evaluation of the consistency of ceftriaxone sodium for injection and used it to replicate the formulation. Comparison of the quality of generic and original raw materials and analysis of the process of drug production revealed that the quality of ceftriaxone sodium raw material is the most important factor in replicating the formulation, and a key factor affecting the quality of raw materials is the ceftriaxone sodium crystallisation process. Secondly, the solution clarity of the formulation, another key aspect, was addressed by controlling the leachable components found in rubber closures used in the packaging. The time to achieve therapeutic efficacy of the preparation could be preliminarily evaluated by determining the rates of salt formation and protein binding. Finally, the key quality control index and drug quality standards were evaluated by systematic comparison of the pharmaceutical index of generic products with that of the original preparation, particularly the impurity profile. On this basis, a strategy for the evaluation of ceftriaxone sodium for injection has been developed.

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Funding

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

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Authors and Affiliations

  1. School of Pharmacy, Xi’an Jiaotong University, Xi’an, 710061, China

    Xiaomeng Chong & Langchong He

  2. National Institutes for Food and Drug Control, Beijing, 102629, China

    Lixin Wang & Changqin Hu

Authors
  1. Xiaomeng Chong
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  2. Lixin Wang
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  3. Changqin Hu
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  4. Langchong He
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Xiaomeng Chong and Lixin Wang. The first draft of the manuscript was written by Xiaomeng Chong, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Langchong He.

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CONFLICT OF INTEREST

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SUPPLEMENTARY MATERIAL

SUPPLEMENTARY MATERIAL

Impurities 3 and 7 were analyzed by column switching and high-resolution mass spectrometry. The +enhanced full mass scan (EMS) spectrum and the secondary mass spectrum of +enhanced product ions (EPI) m/z = 372.0402 [M+H]+ of impurity 3 are shown in Fig. 1-1. The ions at m/z = 372.01015, 394.02192 and 409.99565 in the +EMS spectrum were predicted to appear as [M+H]+, [M+Na]+ and [M+K]+ ion peaks, respectively. Therefore, the molecular weight of impurity 3 was expected to be 371.01015 and it was predicted to be impurity E (EP). The structure and mass fragmentation pathway of impurity 3 are shown in Fig. 1-2.

figure a

Fig. 1-1. The +EMS (1) and EPI (2) spectra of impurity 3.

figure b

Fig. 1-2. The structures and mass fragmentation pathways of impurity 3.

The +EMS spectrum and secondary mass spectrum of +EPI m/z = 950.08069 [M+H]+ of impurity 7 are shown in Fig. 2-1. The ions at m/z = 950.08069 and 988.0360 in the +EMS spectrum were predicted to appear as [M+H]+ and [M+K]+ ion peaks, respectively. Therefore, the molecular weight of impurity 7 was expected to be 949.08069. Based on fragment ions in the secondary mass spectrum, it was suggested to be a dimer formed by the hydrolysis of lactone on the 3-side chain of ceftriaxone and the release of the ring with ceftriaxone. The structure and mass fragmentation pathway of impurity 7 are shown in Fig. 2-2.

figure c

Fig. 2-1. The +EMS (1) and EPI (2) spectra of impurity 7.

figure d

Fig. 2-2. The structures and mass fragmentation pathways of impurity 7.

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Chong, X., Wang, L., Hu, C. et al. Formulation of Ceftriaxone Sodium Under the Guidance of Drug Quality Analysis. Pharm Chem J 56, 1512–1525 (2023). https://doi.org/10.1007/s11094-023-02823-2

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