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Polymorphism of Pradofloxacin: Crystal Structure Analysis, Stability Study, and Phase Transformation Behavior

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Abstract

Purpose

Pradofloxacin is an important antibiotic with poor physical stability. At present, there is no systematic study on its polymorphic form. The purpose of this study is to develop new crystal forms to improve the stability of Pradofloxacin and systematically study the crystal transformation relationships to guide industrial production.

Method

In this work, three solvent-free forms (Form A, Form B and Form C), a new dimethyl sulfoxide solvate (Form PL-DMSO) and a new hydrate (Form PL-H) were successfully obtained and the single crystal data of Form A, Form B and Form PL-DMSO were solved for the first time. Various solid state analysis techniques and slurry experiments have been used to evaluate the stability and determine phase transformation relationships of five crystal forms, the analysis of crystal structure provided theoretical support for the results.

Result

The water vapor adsorption and desorption experiences of Forms A, B, C and Form PL-H were studied, and the results show that the new hydrate has good hygroscopic stability and certain development potential. The thermal stability of different forms was determined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and the crystal structure shows that there are more hydrogen bonds and C − H···π interactions in form B, which is the reason why Form B is more stable than form A. Finally, the phase transformation relationships of the five crystal forms were systematically studied and discussed.

Conclusion

These results are helpful to provide guiding methods in the production and storage of pradofloxacin.

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Data Availability

Data generated for this study are available upon request to the corresponding author.

References

  1. Shi Q, Chen H, Wang Y, Xu J, Liu Z, Zhang C. Recent advances in drug polymorphs: aspects of pharmaceutical properties and selective crystallization. Int J Pharm. 2022;611: 121320.

    Article  CAS  PubMed  Google Scholar 

  2. Xuan B, Wong SN, Zhang Y, Weng J, Tong HHY, Wang C, et al. Extended release of highly water soluble isoniazid attained through cocrystallization with curcumin. Cryst Growth Des. 2020;20:1951–60.

    Article  CAS  Google Scholar 

  3. Lévesque A, Maris T, Wuest JD. ROY reclaims its crown: new ways to increase polymorphic diversity. J Am Chem Soc. 2020;142:11873–83.

    Article  PubMed  Google Scholar 

  4. Zhang Z, Wang Y, Huang X, Ding S, Chen K, Wang N, et al. Formation and growth mechanism of ceftezole sodium monohydrate ring-banded spherulites. Cryst Growth Des. 2021;21:5967–75.

    Article  CAS  Google Scholar 

  5. Aitipamula S, Shan LP, Gupta KM. Polymorphism and distinct physicochemical properties of the phloretin–nicotinamide cocrystal. CrystEngComm. 2022;24:560–70.

    Article  CAS  Google Scholar 

  6. Zhou Y, Wang J, Xiao Y, Wang T, Huang X. The effects of polymorphism on physicochemical properties and pharmacodynamics of solid drugs. CPD. 2018;24:2375–82.

    Article  CAS  Google Scholar 

  7. Shi Q, Moinuddin SM, Wang Y, Ahsan F, Li F. Physical stability and dissolution behaviors of amorphous pharmaceutical solids: role of surface and interface effects. Int J Pharm. 2022;625: 122098.

    Article  CAS  PubMed  Google Scholar 

  8. Censi R, Di Martino P. Polymorph impact on the bioavailability and stability of poorly soluble drugs. Molecules. 2015;20:18759–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lee AY, Erdemir D, Myerson AS. Crystal polymorphism in chemical process development. Annu Rev Chem Biomol Eng. 2011;2:259–80.

    Article  CAS  PubMed  Google Scholar 

  10. Guo M, Sun X, Zhang S, Cai T. Modulation of solid-state chemical stability of gabapentin by pyridinecarboxylic acid. Pharm Res. 2022;39:2305–14.

    Article  CAS  PubMed  Google Scholar 

  11. Chemburkar SR, Bauer J, Deming K, Spiwek H, Patel K, Morris J, et al. Dealing with the impact of ritonavir polymorphs on the late stages of bulk drug process development. Org Process Res Dev. 2000;4:413–7.

    Article  CAS  Google Scholar 

  12. Bučar D-K, Lancaster RW, Bernstein J. Disappearing polymorphs revisited. Angew Chem Int Ed. 2015;54:6972–93.

    Article  Google Scholar 

  13. Rascol O, Perez-Lloret S. Rotigotine transdermal delivery for the treatment of Parkinson’s disease. Expert Opin Pharmacother. 2009;10:677–91.

    Article  CAS  PubMed  Google Scholar 

  14. Li D, Wang Y, Zong S, Wang N, Li X, Dong Y, et al. Unveiling the self-association and desolvation in crystal nucleation. IUCrJ. 2021;8:468–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zong S, Wang J, Huang X, Wu H, Liu Q, Hao H. Formation and stabilization mechanism of mesoscale clusters in solution. IUCrJ. 2022;9:215–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu Y, Wang Y, Huang X, Li X, Zong S, Wang N, et al. Conformational selectivity and evolution affected by the desolvation process. Cryst Growth Des. 2022;22:1283–91.

    Article  CAS  Google Scholar 

  17. Cedeno R, Cruz-Cabeza A, Drummond-Brydson R, K. Dudek M, Edkins K, Fichthorn K, et al. Controlling polymorphism: general discussion. Faraday Discuss. 2022;235:508–35.

  18. Chakraborty J, Subash M, Thorat BN. Drying induced polymorphic transformation of pharmaceutical ingredients: a critical review of recent progresses and challenges. Drying Technol. 2022;40:2817–35.

    Article  Google Scholar 

  19. Yadav K, Sachan AKr, Kumar S, Dubey A. Techniques for increasing solubility: a review of conventional and new strategies. Asian J Pharm Res Dev. 2022;10:144–53.

  20. Park H, Kim J-S, Hong S, Ha E-S, Nie H, Zhou QT, et al. Tableting process-induced solid-state polymorphic transition. J Pharm Investig. 2022;52:175–94.

    Article  CAS  Google Scholar 

  21. Sykes JE, Blondeau JM. Pradofloxacin: a novel veterinary fluoroquinolone for treatment of bacterial infections in cats. Vet J. 2014;201:207–14.

    Article  CAS  PubMed  Google Scholar 

  22. Lapointe G, Skepper CK, Holder LM, Armstrong D, Bellamacina C, Blais J, et al. Discovery and optimization of DNA gyrase and topoisomerase IV inhibitors with potent activity against fluoroquinolone-resistant gram-positive bacteria. J Med Chem. 2021;64:6329–57.

    Article  CAS  PubMed  Google Scholar 

  23. Penn-Nicholson A, Georghiou SB, Ciobanu N, Kazi M, Bhalla M, David A, et al. Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study. Lancet Infect Dis. 2022;22:242–9.

    Article  CAS  PubMed  Google Scholar 

  24. Jia Y, Zhao L. The antibacterial activity of fluoroquinolone derivatives: an update (2018–2021). Eur J Med Chem. 2021;224: 113741.

    Article  CAS  PubMed  Google Scholar 

  25. Mathur P, Sanyal D, Callahan DL, Conlan XA, Pfeffer FM. Treatment technologies to mitigate the harmful effects of recalcitrant fluoroquinolone antibiotics on the environ- ment and human health. Environ Pollut. 2021;291: 118233.

    Article  CAS  PubMed  Google Scholar 

  26. Osman M, Albarracin B, Altier C, Gröhn YT, Cazer C. Antimicrobial resistance trends among canine Escherichia coli isolated at a New York veterinary diagnostic laboratory between 2007 and 2020. Prev Vet Med. 2022;208: 105767.

    Article  PubMed  Google Scholar 

  27. Merino-Gutierrez V, Puig J, Feo-Bernabe L. Successful treatment of 3 dogs with fluoroquinolone-resistant escherichia coli associated granulomatous colitis. Top Companion Anim Med. 2022;47: 100621.

    Article  PubMed  Google Scholar 

  28. Thomas H, Werner H, Hubert R. Crystal modification A of 8-cyano-1-cyclopropyl-7-(1s,6s-2,8-diazabicylo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. CN1328558A. 2001.

  29. Thomas H, Werner H, Hubert R. Crystal modification B of 8-cyano-1-cyclopropyl-7-(1s,6s-2,8-diazabicylo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. CN1328556A. 2001.

  30. Rast H, Himmler T. Crystal modification C of 8-cyano-1-cyclopropyl-7-(1s,6s-2,8-diazabicylo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. CN1342160A. 2002.

  31. Himmler T, Rast H. Crystal modification D of 8-cyano-1-cyclopropyl-7-(1s,6s-2,8-diazabicylo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. CN1341116A. 2002.

  32. Rast H, Heep I, Grunenberg A, Hallenbach W, Benet-Buchholz J. New crystalline form of 8-cyano-1-cyclopropyl-7-(1s,6s-2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. CN1938304A. 2007.

  33. Himmler T, Rast H. Semi-hydrochloride of 8-cyano-1-cyclopropyl-7-(1s,6s-2,8-diazabicylo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. CN1328557A. 2001.

  34. Sheldrick GM. A short history of SHELX. Acta Cryst A. 2008;64:112–22.

    Article  CAS  Google Scholar 

  35. Dolomanov OV, Bourhis LJ, Gildea RJ, Howard JAK, Puschmann H. OLEX2: a complete structure solution, refinement and analysis program. J Appl Cryst. 2009;42:339–41.

  36. Connor LE, Delori A, Hutchison IB, Nic Daeid N, Sutcliffe OB, Oswald IDH. The ecstasy and the agony; compression studies of 3,4-methylenedioxymethamphetamine (MDMA). Acta Crystallogr B Struct Sci Cryst Eng Mater. 2015;71:3–9.

    Article  CAS  PubMed  Google Scholar 

  37. Krause L, Herbst-Irmer R, Sheldrick GM, Stalke D. Comparison of silver and molybdenum microfocus X-ray sources for single-crystal structure determination. J Appl Cryst. 2015;48:3–10.

    Article  CAS  Google Scholar 

  38. Thomas SP, Spackman PR, Jayatilaka D, Spackman MA. Accurate lattice energies for molecular crystals from experimental crystal structures. J Chem Theory Comput. 2018;14:1614–23.

    Article  CAS  PubMed  Google Scholar 

  39. Martin AD, Hartlieb KJ, Sobolev AN, Raston CL. Hirshfeld surface analysis of substituted phenols. Cryst Growth Des. 2010;10:5302–6.

    Article  CAS  Google Scholar 

  40. Spackman MA, McKinnon JJ. Fingerprinting intermolecular interactions in molecular crystals. CrystEngComm. 2002;4:378–92.

    Article  CAS  Google Scholar 

  41. Liu W, Hou B, Huang X, Zong S, Zheng Z, Li S, et al. Influence of intermolecular interactions and crystal structure on desolvation mechanisms of solvates. CrystEngComm. 2021;23:3557–68.

    Article  CAS  Google Scholar 

  42. A B. On the polymorphism of pharmaceuticals and other molecular crystals. I, Microchim Acta. 1979;72:259–71.

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Acknowledgements

This research is financially supported by National Natural Science Foundation of China (21908159).

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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, China

    Wenlei Li, Lina Zhou, Beiqian Tian, Kui Chen, Yaoguang Feng, Ting Wang, Na Wang, Xin Huang & Hongxun Hao

  2. State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin, 30072, China

    Ting Wang, Na Wang, Xin Huang & Hongxun Hao

  3. Zhejiang Institute of Tianjin University, Ningbo, 315200, China

    Xin Huang

  4. School of Chemical Engineering and Technology, Hainan University, Haikou, 570208, China

    Hongxun Hao

Authors
  1. Wenlei Li
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Contributions

Wenlei Li: conceptualization, writing-review & editing. Lina Zhou: software. Beiqian Tian: conceptualization, software. Kui Chen: software. Yaoguang Feng: investigation. Ting Wang: supervision. Na Wang: supervision. Xin Huang: writing-review & editing. Hongxun Hao: resources, writing-review & editing.                                                                                                                                                                                

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Correspondence to Xin Huang or Hongxun Hao.

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Li, W., Zhou, L., Tian, B. et al. Polymorphism of Pradofloxacin: Crystal Structure Analysis, Stability Study, and Phase Transformation Behavior. Pharm Res 40, 999–1012 (2023). https://doi.org/10.1007/s11095-023-03509-w

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