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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

A New Thermodynamically Favored Flubendazole/Maleic Acid Binary Crystal Form: Structure, Energetics, and in Silico PBPK Model-Based Investigation

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Autor(es):
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de Araujo, Gabriel L. B. [1] ; Ferreira, Fabio Furlan [2] ; Bernardes, Carlos E. S. [3, 4] ; Sato, Juliana A. P. [2] ; Gil, Otavio M. [5] ; de Faria, Dalva L. A. [5] ; Loebenberg, Raimar [6] ; Byrn, Stephen R. [7] ; Ghisleni, Daniela D. M. [1] ; Bou-Chacra, Nadia A. [1] ; Pinto, Terezinha J. A. [1] ; Antonio, Selma G. [8] ; Ferraz, Humberto G. [1] ; Zemlyanov, Dmitry [9] ; Goncalves, Debora S. [1] ; Minas da Piedade, Manuel E. [3]
Número total de Autores: 16
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Fac Ciencias Farmaceut, Dept Farm, Sao Paulo, SP - Brazil
[2] UFABC, Ctr Ciencias Nat & Humanas, Sao Paulo - Brazil
[3] Univ Lisbon, Fac Ciencias, Ctr Quim & Bioquim, P-1748016 Lisbon - Portugal
[4] Univ Lisbon, Fac Ciencias, Ctr Quim Estrutural, P-1748016 Lisbon - Portugal
[5] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, Sao Paulo, SP - Brazil
[6] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2H7 - Canada
[7] Purdue Univ, Dept Ind & Phys Pharm, W Lafayette, IN 47907 - USA
[8] Univ Estadual Paulista, Inst Quim, Dept Fis Quim, Araraquara - Brazil
[9] Purdue Univ, Birck Nanotechnol Ctr, W Lafayette, IN 47907 - USA
Número total de Afiliações: 9
Tipo de documento: Artigo Científico
Fonte: Crystal Growth & Design; v. 18, n. 4, p. 2377-2386, APR 2018.
Citações Web of Science: 3
Resumo

The use of flubendazole (FBZ) in the treatment of lymphatic filariasis and onchocerciasis (two high incidence neglected tropical diseases) has been hampered by its poor aqueous solubility. A material consisting of binary flubendazole/maleic acid crystals (FBZ/MA), showing considerably improved solubility and dissolution rate relative to flubendazole alone, has been prepared in this work through solvent assisted mechanical grinding. The identification of FBZ/MA as a binary crystalline compound with salt character (proton transfer from MA to FBZ) relied on the combined results of powder X-ray diffraction, Raman spectroscopy, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), thermogravimetry (TG), and differential scanning calorimetry (DSC). Isothermal solution microcalorimetry studies further suggested that the direct formation of FBZ/MA from its precursors in the solid state is thermodynamically favored. A comparison of the in silico pharmacokinetic performance of the FBZ/MA with that of pure FBZ based on a rat fasted physiology model indicated that the absorption rate, mean plasma peak concentration, and absorption extension of FBZ/MA were similar to 2.6 times, similar to 1.4 times, and 60% larger, respectively, than those of FBZ. The results here obtained therefore suggest that the new FBZ/MA salt has a considerable potential for the development of stable and affordable pharmaceutical formulations with improved dissolution and pharmacokinetic properties. Finally, powder X-ray diffraction studies also led to the first determination of the crystal structure of FBZ. (AU)

Processo FAPESP: 15/05685-7 - Cristalização e polimorfismo do Flubendazol e outros fármacos mal caracterizados
Beneficiário:Gabriel Lima Barros de Araujo
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 15/26233-7 - Síntese e caracterização estrutural de cocristais para aplicações em protetores solares e antioxidantes de uso tópico
Beneficiário:Fabio Furlan Ferreira
Linha de fomento: Auxílio à Pesquisa - Regular