Advertisement

Simultaneous measurements of X-ray diffraction–differential scanning calorimetry

The investigation of the phase transition of ganciclovir and characterization of its polymorphic forms
  • Roxana Lili Roque-FloresEmail author
  • Jivaldo do Rosário Matos
Article

Abstract

Ganciclovir (GCV) is an antiviral drug for treating cytomegalovirus infections. This drug is reported to exist in four crystal forms in the solid state, with I and II being anhydrous and III and IV hydrates. Of particular interest about its thermal behavior, we performed simultaneous measurements of X-ray diffraction and differential scanning calorimetry (DSC) from a GCV commercial sample. The results showed that GCV Form III was stable between room temperature and ± 180 °C, and it transformed to Form I around 189 °C. Furthermore, the crystallization studies by slow solvent evaporation led to four GCV polymorphic forms (Form I, III, IV, and V), one anhydrous and three hydrated, respectively. GCV crystal forms were characterized by X-ray powder diffraction, thermogravimetry/derivative thermogravimetry, DSC, Fourier transform infrared spectroscopy and elemental analysis. Notable differences in the peak positions, shapes and intensities were detected. Slurry conversion experiments found that all recrystallized forms of GCV converted to Form I over time, consistent with Form I being the thermodynamically stable form. These results are relevant for the pharmaceutical development of GCV.

Keywords

Ganciclovir Phase transformation Polymorphism Solid-state stability Combined XRD–DSC Slurry conversion 

Notes

Acknowledgements

The authors thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) of Brazil (Project No 141395/2013-3) for financial supported. Roxana L. Roque-Flores thanks Eurofarma Pharmaceutical Company (Brazil) and Matheus Costa for the donation of the sample and use of the equipment hot-stage microscopy.

References

  1. 1.
    Kawamura T, Hirayama N. Crystal structure of ganciclovir. X-Ray Struct Anal Online. 2009;25:51–2.CrossRefGoogle Scholar
  2. 2.
    Biron KK. Antiviral drugs for cytomegalovirus diseases. Antivir Res. 2006;71:154–63.CrossRefGoogle Scholar
  3. 3.
    Sarbajna RM, Preetam A, Devi AS, Suryanarayana MV, Sethi M, Dutta D. Studies on crystal modifications of ganciclovir. Mol Cryst Liq Cryst. 2011;537:141–54.CrossRefGoogle Scholar
  4. 4.
    Fernandes JA, Galli S, Palmisano G, Volante P, Mendes RF, Paz FAA, Masciocchi N. Reviewing the manifold aspects of ganciclovir crystal forms. Cryst Growth Des. 2016;16:4108–18.CrossRefGoogle Scholar
  5. 5.
    Roque-Flores RL, Guzei IA, Matos JDR, Yu L. Polymophs of the antiviral drug ganciclovir. Acta Crystallogr C. 2017;73:1116–20.CrossRefGoogle Scholar
  6. 6.
    Roque-Flores RL, Ávila SG, Oliveira JF, Carvalho FMS, Araújo GLB, Matos JR. Caracterização físico-química e analítica do ganciclovir. In: Associação Brasileira de Análise Térmica e Calorimetria (ABRATEC). Serra Negra; 2014.Google Scholar
  7. 7.
    Guillory JK. Generation of polymorphs, hydrates, solvates, and amorphous solids. In: Brittain HG, editor. Polymorphism in pharmaceutical solids. New York: Marcel Dekker; 1999. p. 183–226.Google Scholar
  8. 8.
    Remenar JF, MacPhee JM, Larson BK, Tyagi VA, Ho JH, McIlroy DA, Hickey MB, Shaw PB, Almarsson Ö. Salt selection and simultaneous polymorphism assessment via high-throughput crystallization: the case of sertraline. Org Proc Res Dev. 2003;7:990–6.CrossRefGoogle Scholar
  9. 9.
    Stahly GP. Diversity in single- and multiple-component crystals. The search for and prevalence of polymorphs and cocrystals. Cryst Growth Des. 2007;7:1007–26.CrossRefGoogle Scholar
  10. 10.
    Campeta AM, Chekal BP, Abramov YA, Meenan PA, Henson MJ, Shi B, Singer RA, Horspool KR. Development of a targeted polymorph screening approach for a complex polymorphic and highly solvating API. J Pharm Sci. 2010;99:3874–86.CrossRefGoogle Scholar
  11. 11.
    Burger A, Ramberger R. On the polymorphism of pharmaceuticals and other molecular crystals. I Theory of thermodynamic rules. Mikrochim Acta. 1979;72:259–71.CrossRefGoogle Scholar
  12. 12.
    Burger A, Ramberger R. On the polymorphism of pharmaceuticals and other molecular crystals. II Applicability of thermodynamic rules. Mikrochim Acta. 1979;72:273–316.CrossRefGoogle Scholar
  13. 13.
    Yu L. Inferring thermodynamic stability relationship of polymorphs from melting data. J Pharm Sci. 1995;84:966–74.CrossRefGoogle Scholar
  14. 14.
    Silverstein RM, Webster FX, Kiemle DJ. Spectrometric identification of organic compounds. 7th ed. New Jersey: Wiley; 2005.Google Scholar

Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2019

Authors and Affiliations

  1. 1.Departamento de Farmácia, Faculdade de Ciências FarmacêuticasUniversidade de São PauloSão PauloBrazil
  2. 2.Departamento de Química Fundamental, Instituto de QuímicaUniversidade de São PauloSão PauloBrazil

Personalised recommendations