Hot-melt extrudability of amorphous solid dispersions of flubendazole-copovidone: An exploratory study of the effect of drug loading and the balance of adjuvants on extrudability and dissolution

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de Assis, Joao M. C. ; Barbosa, Eduardo J. ; Bezzon, Vincius D. N. ; Lourenco, Felipe R. ; Carvalho, Flavio M. . S. ; Matos, J. R. ; Bou-Chacra, Nadia Araci ; Benmore, Chris J. ; Byrn, Stephen R. ; Costa, Fanny N. ; de Araujo, Gabriel L. B.

• Document type: Journal article
• Source: International Journal of Pharmaceutics; v. 614, p. 10-pg., 2022-02-25.

Abstract

The FDA-approved anthelmintic flubendazole has shown potential to be repositioned to treat cancer and dry macular degeneration; however, its poor water solubility limits its use. Amorphous solid dispersions may overcome this challenge, but the balance of excipients may impact the preparation method and drug release. The purpose of this study was to evaluate the influence of adjuvants and drug loading on the development of an amorphous solid dispersion of flubendazole-copovidone by hot-melt extrusion. The drug, copovidone, and adjuvants (magnesium stearate and hydroxypropyl cellulose) mixtures were statistically designed, and the process was performed in a twin-screw extruder. The study showed that flubendazole and copovidone mixtures were highly extrudable, except when drug loading was high (>40%). Furthermore, magnesium stearate positively impacted the extrusion and was more effective than hydroxypropyl cellulose. The extruded materials were evaluated by modulated differential scanning calorimetry and X-ray powder diffraction, obtaining positive amorphization and physical stability results. Pair distribution function analysis indicated the presence of drug rich domains with medium-range order structure and no evidence of polymer-drug interaction. All extrudates presented faster dissolution (HCl, pH 1.2) than pure flubendazole, and both adjuvants had a notable influence on the dissolution rate. In conclusion, hot-melt extrusion may be a viable option to obtain stable flubendazole: copovidone amorphous dispersions. (AU)

• FAPESP's process: 18/11990-5 - Local structure characterization and stability of amorphous systems
• Grantee: Vinícius Danilo Nonato Bezzon
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/04998-2 - Nanocrystalline and amorphous solid dispersions formulations for improvement of antitumor therapies
• Grantee: Gabriel Lima Barros de Araujo
• Support Opportunities: Regular Research Grants