AAPS PharmSciTech

, 20:8 | Cite as

Solid-State Characterization of Three Polymorphs of an Orally Available Analog of Diethylenetriaminepentaacetic Acid

  • Carla Coste Sanchez
  • Arjun Kalra
  • Tonglei Li
  • Michael JayEmail author
Research Article


The present work investigated the physical and thermal characteristics of three polymorphic forms (namely, PF1, PF2, and PF3) of a diethyl ester analog of diethylenetriaminepentaacetic acid (C2E2) produced under varying conditions. The identity of each form of C2E2 was confirmed by 1H-NMR, 13C-NMR, and mass spectroscopy. The different polymorphic forms exhibited solubilities ranging from 40 to 150 mg/mL. Powder X-ray diffraction (PXRD) and electron microscopy confirmed that all three forms were crystalline, two of which being scaly, and the third being well-formed. Infrared and Raman spectroscopy revealed differences in the C = O bonding region while differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) showed widely different melting points with only one thermal event for each compound. The comparison of the melting points and heats of fusion show that the PF1 is monotropically related to both PF2 and PF3, while PF2 and PF3 are enantropically related. Our finding indicates that PF3 is the thermodynamically stable polymorph and will be used for in vitro and in vivo experiments.


chelator polymorphs physical characterization thermal characterization physical-chemical properties 



  1. 1.
    National Council on Radiation Protection. Development of a biokinetics model for radionuclide-contaminated wounds and procedures for their assessment, dosimetry and treatment. NCRP Report No 156. 2007.Google Scholar
  2. 2.
    Pentetate calcium trisodium [package insert]. Gloucester, U.K.: Hameln; 2013.Google Scholar
  3. 3.
    Aulton M. Aulton’s pharmaceutics: the design and manufacture of medicines 3rd ed. London: Churchill Livingstone Elsevier; 2008. p. 441–82.Google Scholar
  4. 4.
    Huckle JE, Sadgrove MP, Leed MG, Yang YT, Mumper RJ, Semelka RC, et al. Synthesis and physicochemical characterization of a diethyl ester prodrug of DTPA and its investigation as an oral decorporation agent in rats. AAPS J. 2016;18(4):972–80.CrossRefGoogle Scholar
  5. 5.
    Huckle JE, Sadgrove MP, Pacyniak E, Leed MG, Weber WM, Doyle-Eisele M, et al. Orally administered DTPA di-ethyl ester for decorporation of (241)Am in dogs: assessment of safety and efficacy in an inhalation-contamination model. Int J Radiat Biol. 2015;91(7):568–75.CrossRefGoogle Scholar
  6. 6.
    Florence AT, Attwood D. Properties of the solid state. In: Physicochemical principles of pharmacy. London: Palgrave Macmillan Publishing Co; 1998. p. 5–35.CrossRefGoogle Scholar
  7. 7.
    Particle Sciences Technical Brief 2011 Volume 9, Biopharmaceutical Classification System and Formulation Development. Available at: Accessed Nov 2017.
  8. 8.
    Sachin L, Grant DJW. Thermodanymics in polymorphs. In: Hilfiker R, editor. Polymorphism in the Pharmaceutical Industry. Weinheim: WILEY-VCH Verlag GmbH & Co; 2006. p. 21–42.Google Scholar
  9. 9.
    Gong N, Zhang G, Jin G, Du G, Lu Y. Polymorphs and versatile solvates of 7-hydroxyisoflavone. J Pharm Sci. 2016;105(4):1387–97.CrossRefGoogle Scholar
  10. 10.
    Haleblian J, McCrone W. Pharmaceutical applications of polymorphism. J Pharm Sci. 1969;58(8):911–29.CrossRefGoogle Scholar
  11. 11.
    Burger A, Ramberger R. On the polymorphism of pharmaceuticals and other molecular crystals. I. Microchim Acta. 1979;2:259–71.CrossRefGoogle Scholar
  12. 12.
    Kitamura M. Thermodynamic stability and transformation of pharmaceutical polymorphs. Pure Appl Chem. 2005;77(3):581–91.CrossRefGoogle Scholar
  13. 13.
    Sato K. Polymorphic transformations in crystal growth. J Phys D. 1993;26(8B):B77–84.CrossRefGoogle Scholar
  14. 14.
    Smith BT. Remington education: physical pharmacy. London: Pharmaceutical Press; 2016. p. 31–50.Google Scholar
  15. 15.
    Burger A, Ramberger R. On the polymorphism of pharmaceuticals and other molecular crystals. II. Microchim Acta. 1979;72(3–4):273–316.CrossRefGoogle Scholar
  16. 16.
    Erizal CS, Nurono SS, Halim A. Effect of milling on solid state transformation of sulfamethoxazole. Int J Pharmacol. 2008;4:140–4.CrossRefGoogle Scholar
  17. 17.
    Maher A, Croker DM, Seaton CC, Rasmuson AC, Hodnett BK. Solution-mediated polymorphic transformation: form II to form III piracetam in organic solvents. Cryst Growth Des. 2014;14(8):3967–74.CrossRefGoogle Scholar
  18. 18.
    Kadam KP, Chavan RP. Evaluation of various polymorphs by different techniques and their characterization a review. Int J Eng Sci. 2016;5(6):29–34.CrossRefGoogle Scholar
  19. 19.
    Lee EH. A practical guide to pharmaceutical polymorph screening & selection. AJPS. 2014;9(4):163–75.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Carla Coste Sanchez
    • 1
  • Arjun Kalra
    • 2
  • Tonglei Li
    • 2
  • Michael Jay
    • 1
    Email author
  1. 1.Department of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyUniversity of North CarolinaChapel HillUSA
  2. 2.Department of Industrial and Physical Pharmacy, College of PharmacyPurdue UniversityWest LafayetteUSA

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