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Preparation, Crystal Structures and Hirshfeld Surface Analyses of Two Impurities of Azilsartan

  • Liping Zhou
  • Rongkai Du
  • Xianrui Zhang
  • Hua Chen
  • Su Guan
  • Jing Li
  • Lei Zhang
Original Paper

Abstract

Two impurities of azilsartan (1·EtOH and 2) have been prepared and the structures have been identified by 1H-NMR, IR and single crystal X-ray diffraction. Impurity 1·EtOH (C25H22N4O6, Mr = 474.46) crystallizes in triclinic, space group P-1 with a = 9.0425(15), b = 10.5498(18), c = 12.826(2) Å, α = 76.329(3), β = 79.086(3), γ = 76.763(3)°, V = 1145.4(3) Å3, Z = 2, F(000) = 496, Dc = 1.376 g/cm3, and µ = 0.100 mm− 1. Impurity 2 (C25H20N4O5, Mr = 456.45) is triclinic space group P-1 with a = 9.356(7), b = 9.490(8), c = 13.562(10) Å, α = 72.173(13), β = 73.864(12), γ = 82.628(15)°, V = 1099.9(15) Å3, Z = 2, F(000) = 476, Dc = 1.378 g/cm3, and µ = 0.098 mm−1. 1·EtOH shows a heteronuclear R 2 2 (8) dimeric structure through two N–H···O hydrogen bonds constructed by one 1,2,4-oxadiazol and one 2-oxo-benzimidazole groups, and ethanol molecule is attached by O–H···O hydrogen bond. Impurity 2 shows one-dimensional chain structure through two homonuclear R 2 2 (8) N–H···O hydrogen bonds constructed by two 1,2,4-oxadiazols and by two 2-oxo-benzimidazoles, respectively. Hirshfeld surface analysis shows that the hydrogen bonds are important to stabilize the conformation.

Graphical Abstract

Two impurities of azilsartan (1 EtOH and 2) have been prepared and the crystal structures show different molecular configurations and assembly which are predominantly stabilized by the classical hydrogen bonds as well as C–H···N and C–H···O interactions.

Keywords

Azilsartan Hirshfeld surface Impurity Crystal structure 

Notes

Acknowledgements

We thank the Guangdong Provincial Department of Science and Technology (Grant Nos.: 2016A010121004 and 2016B090918075) for financial support of this research.

References

  1. 1.
    Nozawa J, Uda S, Naradate Y, Koizumi H, Fujiwara K, Toyotama A, Yamanaka J (2013) Impurity partitioning during colloidal crystallization. J Phys Chem B 117:5289–5295CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Rai BP, Tewari N, Nizar H, Prasad M, Joseph S (2014) Commercial synthesis of cefprozil: development and control of process impurity. Org Process Res Dev 18:662–664CrossRefGoogle Scholar
  3. 3.
    Mortensen MA, Guo C, Reynolds NT, Wang L, Helle MA, Keefe DK, Haney BP, Paul BJ, Bruzinski PR, Wolf MA, Malinowski NL, Yang Q (2012) Process development, impurity control, and production of a novel tubulin inhibitor. Org Process Res Dev 16:1811–1817CrossRefGoogle Scholar
  4. 4.
    Scott C, Black S (2005) In-line analysis of impurity effects on crystallisation. Org Process Res Dev 9:890–893CrossRefGoogle Scholar
  5. 5.
    Martins PM, Rocha FA, Rein P (2006) The influence of impurities on the crystal growth kinetics according to a competitive adsorption model. Cryst Growth Des 6:2814–2821CrossRefGoogle Scholar
  6. 6.
    Ottens M, Lebreton B, Zomerdijk M, Rijkers MPWM, Bruinsma OSL, Wielen LAM (2004) Impurity effects on the crystallization kinetics of ampicillin. Ind Eng Chem Res 43:7932–7938CrossRefGoogle Scholar
  7. 7.
    Ye Q, Huang Y, Rusowicz A, Palaniswamy VA, Raglione TV (2010) Understanding and controlling the formation of an impurity during the development of muraglitazar, a PPAR dual agonist. Org Process Res Dev 14:238–241CrossRefGoogle Scholar
  8. 8.
    Wirth DD, Stephenson GA (1997) Purification of dirithromycin. Impurity reduction and polymorph manipulation. Org Process Res Dev 1:55–60CrossRefGoogle Scholar
  9. 9.
    Lam S (2011) Azilsartan: a newly approved angiotensin II receptor blocker. Cardiol Rev 19:300–304CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Rakugi H, Enya K (2012) Azilsartan: a new angiotensin II receptor blocker. Nihon Rinsho 70:1615–1620PubMedPubMedCentralGoogle Scholar
  11. 11.
    Matsumoto S, Shimabukuro M, Fukuda D, Soeki T, Yamakawa K, Masuzaki H, Sata M (2014) Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser1177/Thr497 of endothelial nitric oxide synthase in diabetic mice. Cardiovasc Diabetol 13:30CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Gu WJ, Hou YT, Yang MH, Sun XM, Sui Q, Tang C (2014) HPLC determination of azilsartan content and its related substances. Chin J Pharm Anal 34:2185–2191Google Scholar
  13. 13.
    Kohara Y, Kubo K, Imamiya E, Wada T, Inada Y, Naka T (1996) Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres. J Med Chem 39:5228–5235CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Sheldrick GM (1997) SHELXS-97, program for crystal structure refinement. University of Götingen, GötingenGoogle Scholar
  15. 15.
    Sheldrick GM (1997) SHELXS-97, program for crystal structure solution. University of Götingen, GötingenGoogle Scholar
  16. 16.
    Dolomanov OV, Bourhis LJ, Gildea RJ, Howard JAK, Puschmann H (2009) OLEX2: a complete structure solution, refinement and analysis program. Appl Cryst 42:339–341CrossRefGoogle Scholar
  17. 17.
    Wolff SK, Grimwood DJ, McKinnon JJ, Jayatilaka D, Spackman MA (2015) CrystalExplorer 3.1. University of Western Australia, PerthGoogle Scholar
  18. 18.
    Spackman MA, McKinnon JJ (2002) Fingerprinting intermolecular interactions in molecular crystals. CrystEngComm 4:378–392CrossRefGoogle Scholar
  19. 19.
    Seth SK, Maity GC, Kar T (2011) Structural elucidation, Hirshfeld surface analysis and quantum mechanical study of para-nitro benzylidene methyl arjunolate. J Mol Struct 1000:120–126CrossRefGoogle Scholar
  20. 20.
    Spackman MA, Jayatilaka D (2009) Hirshfeld surface analysis CrystEngComm 11:19–32Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Liping Zhou
    • 1
  • Rongkai Du
    • 1
  • Xianrui Zhang
    • 1
  • Hua Chen
    • 2
  • Su Guan
    • 1
  • Jing Li
    • 1
  • Lei Zhang
    • 1
  1. 1.School of Biology and Biological EngineeringSouth China University of TechnologyGuangzhouChina
  2. 2.Guangdong Institute for Drug ControlGuangzhouChina

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