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Novel Pharmaceutical Cocrystals of Tegafur: Synthesis, Performance, and Theoretical Studies

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Abstract

Purpose

Tegafur (TF) is one of the most important clinical antitumor drugs with poor water solubility, severely reducing its bioavailability. This work develops new cocrystals to improve the solubility of TF and systematically investigates the intermolecular interactions to provide new insights into the formation of cocrystal and changes in physicochemical properties.

Method

In this paper, two new 1:1 cocrystals of TF with 2,4 dihydroxybenzoic acid (2,4HBA) and p-nitrophenol (PNP) were synthesized. The cocrystal products were identified and characterized by various solid state analysis techniques. And the high performance liquid chromatography (HPLC) was conducted to determine the solubility and dissolution rate of TF and cocrystals. Moreover, the quantum chemistry calculations of crystal structure provided theoretical support for the results.

Result

Compared with pure TF, the solubility and dissolution rate of TF-2,4HBA is significantly increased in a pH 6.8 buffer at 37°C. Under accelerated storage conditions (40°C, 75% RH), all cocrystal exhibits excellent stability over 8 weeks. Hirshfeld surface (HS) analysis, atoms in molecules (AIM) analysis, interaction region indicator (IRI) analysis, molecular electrostatic potential surface (MEPS) analysis and frontier molecular orbital (HOMO–LUMO) analysis were integrated to understand the hydrogen bonding interaction more comprehensively. The simulation results are in good agreement with the experimental data. The results show that the analysis of physical and chemical properties of TF-PNP cocrystal and TF crystal by quantum chemistry method is reliable at molecular level.

Conclusion

These results are helpful to provide guiding methods in the cocrystal development and theoretical study of tegafur.

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Data Availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China [No.21978201] and [No. 22108196].

Funding

This work was supported by National Natural Science Foundation of China, 21978201, 22108196.

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Authors and Affiliations

  1. National Engineering Research Center of Industrial Crystallization Technology, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, People’s Republic of China

    Haoran Mei, Na Wang, Di Wu, Qi Rong, Xue Bai, Xin Huang, Lina Zhou, Ting Wang & Hongxun Hao

  2. Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, 300072, People’s Republic of China

    Na Wang, Xin Huang, Lina Zhou, Ting Wang & Hongxun Hao

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  1. Haoran Mei
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  2. Na Wang
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  6. Xin Huang
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  7. Lina Zhou
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  8. Ting Wang
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  9. Hongxun Hao
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Contributions

Haoran Mei: conceptualization, writing – review & editing. Na Wang: writing – review & editing. Di Wu: software. Qi Rong: investigation. Xue Bai: investigation. Xin Huang: funding acquisition. Lina Zhou: funding acquisition. Ting Wang: funding acquisition. Hongxun Hao: resources, writing – review & editing.

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Correspondence to Na Wang or Hongxun Hao.

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Mei, H., Wang, N., Wu, D. et al. Novel Pharmaceutical Cocrystals of Tegafur: Synthesis, Performance, and Theoretical Studies. Pharm Res 41, 577–593 (2024). https://doi.org/10.1007/s11095-024-03668-4

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