Characterization and Kinetic Studies of the Thermal Degradation of Mebendazole Polymorphs A and C

  • Roxana Lili Roque-FloresEmail author
  • Juliana Ferreira de Oliveira
  • Flavio Machado de Souza Carvalho
  • Jivaldo do Rosário Matos
Original Article



Mebendazole is an anthelmintic drug of low solubility, which exhibits three polymorphic forms (A, B, and C) with different thermodynamic stability (A > C > B). Form C is the most appropriate for pharmaceutical development due to its adequate bioavailability and lower toxicity. This form is stable between room temperature ± 180 °C. The aim of this work was to characterize and study the thermal degradation kinetics of Mebendazole polymorphs A and C by isothermal and non-isothermal (Ozawa method) thermogravimetric methods.


Thermogravimetry (TG), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR), and elementary analysis (EA) were used to identify Mebendazole polymorphs A and C. Isothermal and non-isothermal thermogravimetric methods were used to study the thermal degradation kinetics of Mebendazole polymorphs.


The results showed that form C converts to the polymorphic form A after heating at 200 °C, exhibiting both exothermic and endothermic events before the first mass loss. Subsequent to this transformation, CO2 was released and the formation of a solid product occurred, which was characterized by EA and FTIR. These results suggested the presence of a Mebendazole impurity. The degradation kinetics studies of polymorphs A and C obtained by both methods indicated activation energy (Ea) values greater for polymorph C.


In fact, part of the energy provided to the polymorph C was used for the transformation to polymorph A, which explains its greater thermal stability. This indicates that polymorph C is very stable under ambient conditions, but at high temperatures (above 180 °C) the stability of polymorph A predominates.


Mebendazole Phase-transformation Physicochemical properties Thermal analysis Kinetic study Isothermal Non-isothermal 



The authors thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) of Brazil for financial support. Roxana L. Roque-Flores thanks Dr. Zoraida López Murgueytio for helpful discussions.

Funding Information

This study is supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) of Brazil.


  1. 1.
    Geary TG, Woo K, Mccarthy JS, Mackenzie CHD, Horton J, Prichard RK, et al. Unresolved issues in anthelmintic pharmacology for helminthiases of humans. Int J Parasitol. 2010;40:1–13.CrossRefGoogle Scholar
  2. 2.
    Calvo NL, Kaufman TS, Maggio RM. Mebendazole crystal forms in tablets formulations. An ATR-FTIR/chemometrics approach to polymorph assignment. J Pharm Biomed Anal. 2016;122:157–65.CrossRefGoogle Scholar
  3. 3.
    Garbuio AQP, Hanashiro T, Markman BEO, Fonseca FLA, Perazzo FF, Rosa PCP. Evaluation and study of mebendazole polymorphs present in raw materials and tables available in the Brazilian pharmaceutical market. J Appl Pharm Sci. 2014;4:1–7.Google Scholar
  4. 4.
    Brits M, Liebenberg W, De Villiers MM. Characterization of polymorph transformations that decrease the stability of tablets containing the WHO essential drug mebendazole. J Pharm Sci. 2010;99:1138–51.CrossRefGoogle Scholar
  5. 5.
    Agatonovic-Kustrin S, Glass BD, Mangan M, Smithson J. Analysing the crystal purity of mebendazole raw material and its stability in a suspension formulation. Int J Pharm. 2008;361:245–50.CrossRefGoogle Scholar
  6. 6.
    Brusau EV, Camí GE, Narda GE, Cuffini S, Ayala AP, Ellena J. Synthesis and characterization of a new mebendazole salt: Mebendazole hydrochloride. J Pharm Sci. 2008;97:542–52.CrossRefGoogle Scholar
  7. 7.
    Kumar S, Chawla G, Sobhia ME, Bansal AK. Characterization of solid-state forms of mebendazole. Pharmazie. 2008;63:136–43.Google Scholar
  8. 8.
    De Villiers MM, Terblanche RJ, Liebenberg W, Swanepoel E, Dekker TG, Song M. Variable temperature X-ray powder diffraction analysis of de crystal transformation of the pharmaceutically preferred polymorphism C of mebendazole. J Pharm Biomed Anal. 2005;38:435–41.CrossRefGoogle Scholar
  9. 9.
    Swanepoel E, Liebenberg W, Devarakonda B, De Villiers MM. Developing a discriminating dissolution test for three mebendazole polymorphs based on solubility differences. Pharmazie. 2003;58:117–21.Google Scholar
  10. 10.
    Liebenberg W, Dekker TG, Lӧtter AP, De Villiers MM. Identification of the mebendazole polymorphic form present in raw materials and tablets available in South Africa. Drug Dev Ind Pharm. 1998;24:485–8.CrossRefGoogle Scholar
  11. 11.
    Costa J, Fresco M, Guzmán L, Igual A, Oliva J, Vidal P, et al. Polymorphic forms of mebendazole: analytical aspects and toxicity. Circ Farm. 1991;312:415–24.Google Scholar
  12. 12.
    Himmelreich M, Rawson BJ, Watson TR. Polymorphic forms of mebendazole. Aust J Pharm Sci. 1977;6:123–5.Google Scholar
  13. 13.
    Singhal D, Curatolo W. Drug polymorphism and dosage form design: a practical perspective. Adv Drug Deliv Rev. 2004;56:335–47.CrossRefGoogle Scholar
  14. 14.
    Vippagunta SR, Brittain HG, Grant DJW. Crystalline solids. Adv Drug Deliv Rev. 2001;48:3–26.CrossRefGoogle Scholar
  15. 15.
    Rodante F, Vecchio S, Tomassetti M. Multi-step decomposition processes for some antibiotics a kinetic study. Thermochim Acta. 2002;394:7–18.CrossRefGoogle Scholar
  16. 16.
    Šimon P, Veverka M, Okuliar J. New screening method for the determination of stability of pharmaceuticals. Int J Pharm. 2004;270:21–6.CrossRefGoogle Scholar
  17. 17.
    Ozawa T. Kinetic analysis of derivative curves in thermal analysis. J Therm Anal. 1970;2:301–24.CrossRefGoogle Scholar
  18. 18.
    Šimon P. The single-step approximation: attributes, strong and weak sides. J Thermal Anal Calorim. 2007;88:709–15.CrossRefGoogle Scholar
  19. 19.
    Tang TB, Chaudhri MM. Analysis of dynamic kinetic data from solid-state reactions. J Therm Anal. 1980;18:247–61.CrossRefGoogle Scholar
  20. 20.
    Órfão JJM. Review and evaluation of the approximations to the temperature integral. AICHE J. 2007;53:2905–15.CrossRefGoogle Scholar
  21. 21.
    Marini A, Berbenni V, Flor G. Kinetic parameters from thermogravimetric data. Z Naturforsch A. 1979;34:661–3.CrossRefGoogle Scholar
  22. 22.
    Zsacó J. Kinetic analysis of thermogravimetric data. J Thermal Anal Calorim. 1970;2:145–9.CrossRefGoogle Scholar
  23. 23.
    Doyle CD. Series approximations to equation of thermogravimetric data. Nature. 1965;207:290–1.CrossRefGoogle Scholar
  24. 24.
    Coats AW, Redfern JP. Kinetic parameters from thermogravimetric data. Nature. 1964;20:68–9.CrossRefGoogle Scholar
  25. 25.
    Gomes AJ, Nagaraju V. High-performance liquid chromatographic separation and determination of the process related impurities of mebendazole, fenbendazole and albendazole in bulk drugs. J Pharm Biomed Anal. 2001;26:919–27.CrossRefGoogle Scholar

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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
  3. 3.Departamento de Mineralogia e Petrologia, Instituto de GeociênciasUniversidade de São PauloSão PauloBrazil

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