Novel 1-indanone Thiosemicarbazone Antiviral Candidates: Aqueous Solubilization and Physical Stabilization by Means of Cyclodextrins

ABSTRACT

Purpose

To investigate cyclodextrin-mediated solubilization and physical stabilization of novel 1-indanone thiosemicarbazone (TSC) candidate drugs that display extremely high self-aggregation and precipitation tendency in water.

Methods

TSC/CD complexes were produced by co-solvent method, and TSC/CD phase-solubility diagrams were obtained by plotting TSC concentration as a function of increasing CD concentration. Size, size distribution, and zeta-potential of the different TSC/CD complexes and aggregates were fully characterized by dynamic light scattering. The morphology of the structures was visualized by atomic force microscopy.

Results

Results indicated the formation of Type A inclusion complexes; the solubility of different TSCs was enhanced up to 215 times. The study of physical stability revealed that, as opposed to free TSCs that self-aggregate, crystallize, and precipitate in water very rapidly, complexed TSCs remain in solution for at least 1 week. On the other hand, a gradual size growth was observed. This phenomenon stemmed from the self-aggregation of the TSC/CD complex.

Conclusions

1-indanone TSC/CD inclusion complexes improved aqueous solubility and physical stability of these new drug candidates and constitute a promising technological approach towards evaluation of their activity against the viruses hepatitis B and C.

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ACKNOWLEDGMENTS & DISCLOSURES

R.J. Glisoni thanks the Ph.D. scholarship of CONICET. AS, AM and DC are staff members of CONICET. The authors thank Dr. Gloria Bonetto (Universidad Nacional de Córdoba, Córdoba, Argentina) for 1D-NMR analysis and Dr. Daniel R. Vega (Departamento Física de la Materia Condensada, CNEA, Buenos Aires, Argentina) for X-ray analysis.

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Correspondence to Alejandro Sosnik.

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Glisoni, R.J., Chiappetta, D.A., Moglioni, A.G. et al. Novel 1-indanone Thiosemicarbazone Antiviral Candidates: Aqueous Solubilization and Physical Stabilization by Means of Cyclodextrins. Pharm Res 29, 739–755 (2012). https://doi.org/10.1007/s11095-011-0599-y

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KEY WORDS

  • 1-indanone thiosemicarbazone antiviral candidates
  • inclusion complexes
  • native and modified cyclodextrins
  • self-assembly
  • water-solubilization