Highly Water-Soluble Orotic Acid Nanocrystals Produced by High-Energy Milling

Jéssica de Cássia Zaghi Compri, Veni Maria Andres Felli, Felipe Rebello Lourenço, Takayuki Takatsuka, Nikoletta Fotaki, Raimar Löbenberg, Nádia Araci Bou-Chacra, Gabriel Lima Barros de Araujo

Research output: Contribution to journalArticle

Abstract

Orotic acid (OA), a heterocyclic compound also known as vitamin B13, has shown potent antimalarial and cardiac protection activities; however, its limited water solubility has posed a barrier to its use in therapeutic approaches. Aiming to overcome this drawback, OA freeze-dried nanocrystal formulations (FA, FB, and FC) were developed by using the high-energy milling method. Polysorbate 80 (FA) and povacoat® (FC) were used alone and combined (FB) as stabilizers. Nanocrystals were fully characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, thermal analysis (thermogravimetry and derivative thermogravimetry, and differential scanning calorimetry), and X-ray powder diffraction revealing an acceptable polydispersity index, changes in the crystalline state with hydrate formation and z-average of 100-200 nm, a remarkable 200-time reduction compared to the OA raw material (44.3 μm). Furthermore, saturation solubility study showed an improvement of 13 times higher than the micronized powder. In addition, cytotoxicity assay revealed mild toxicity for the FB and FC formulations prepared with povacoat®. OA nanocrystal platform can deliver innovative products allowing untapped the versatile potential of this drug substance candidate.

Original languageEnglish
Pages (from-to)1848-1856
JournalJournal of Pharmaceutical Sciences
Early online date30 Dec 2018
DOIs
Publication statusPublished - 1 May 2019

Keywords

  • formulation
  • nanocrystal(s)
  • nanotechnology
  • physical characterization
  • physicochemical
  • polymer(s)
  • solubility
  • stability
  • stabilization
  • surfactant(s)

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

de Cássia Zaghi Compri, J., Andres Felli, V. M., Lourenço, F. R., Takatsuka, T., Fotaki, N., Löbenberg, R., ... Barros de Araujo, G. L. (2019). Highly Water-Soluble Orotic Acid Nanocrystals Produced by High-Energy Milling. Journal of Pharmaceutical Sciences, 1848-1856. https://doi.org/10.1016/j.xphs.2018.12.015

Highly Water-Soluble Orotic Acid Nanocrystals Produced by High-Energy Milling. / de Cássia Zaghi Compri, Jéssica; Andres Felli, Veni Maria; Lourenço, Felipe Rebello; Takatsuka, Takayuki; Fotaki, Nikoletta; Löbenberg, Raimar; Bou-Chacra, Nádia Araci; Barros de Araujo, Gabriel Lima.

In: Journal of Pharmaceutical Sciences, 01.05.2019, p. 1848-1856.

Research output: Contribution to journalArticle

de Cássia Zaghi Compri, J, Andres Felli, VM, Lourenço, FR, Takatsuka, T, Fotaki, N, Löbenberg, R, Bou-Chacra, NA & Barros de Araujo, GL 2019, 'Highly Water-Soluble Orotic Acid Nanocrystals Produced by High-Energy Milling', Journal of Pharmaceutical Sciences, pp. 1848-1856. https://doi.org/10.1016/j.xphs.2018.12.015
de Cássia Zaghi Compri J, Andres Felli VM, Lourenço FR, Takatsuka T, Fotaki N, Löbenberg R et al. Highly Water-Soluble Orotic Acid Nanocrystals Produced by High-Energy Milling. Journal of Pharmaceutical Sciences. 2019 May 1;1848-1856. https://doi.org/10.1016/j.xphs.2018.12.015
de Cássia Zaghi Compri, Jéssica ; Andres Felli, Veni Maria ; Lourenço, Felipe Rebello ; Takatsuka, Takayuki ; Fotaki, Nikoletta ; Löbenberg, Raimar ; Bou-Chacra, Nádia Araci ; Barros de Araujo, Gabriel Lima. / Highly Water-Soluble Orotic Acid Nanocrystals Produced by High-Energy Milling. In: Journal of Pharmaceutical Sciences. 2019 ; pp. 1848-1856.
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abstract = "Orotic acid (OA), a heterocyclic compound also known as vitamin B13, has shown potent antimalarial and cardiac protection activities; however, its limited water solubility has posed a barrier to its use in therapeutic approaches. Aiming to overcome this drawback, OA freeze-dried nanocrystal formulations (FA, FB, and FC) were developed by using the high-energy milling method. Polysorbate 80 (FA) and povacoat{\circledR} (FC) were used alone and combined (FB) as stabilizers. Nanocrystals were fully characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, thermal analysis (thermogravimetry and derivative thermogravimetry, and differential scanning calorimetry), and X-ray powder diffraction revealing an acceptable polydispersity index, changes in the crystalline state with hydrate formation and z-average of 100-200 nm, a remarkable 200-time reduction compared to the OA raw material (44.3 μm). Furthermore, saturation solubility study showed an improvement of 13 times higher than the micronized powder. In addition, cytotoxicity assay revealed mild toxicity for the FB and FC formulations prepared with povacoat{\circledR}. OA nanocrystal platform can deliver innovative products allowing untapped the versatile potential of this drug substance candidate.",
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