Enhancement of dissolution rate through eutectic mixture and solid solution of posaconazole and benznidazole

[Display omitted] Benznidazole (BNZ), the only commercialized antichagasic drug, and the antifungal compound posaconazole (PCZ) have shown synergistic action in the therapy of Chagas disease, however both active pharmaceutical ingredients (APIs) exhibit low aqueous solubility potentially limiting th...

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Bibliographic Details
Published in:International journal of pharmaceutics 2017-06, Vol.525 (1), p.32-42
Main Authors: Figueirêdo, Camila Bezerra Melo, Nadvorny, Daniela, de Medeiros Vieira, Amanda Carla Quintas, Soares Sobrinho, José Lamartine, Rolim Neto, Pedro José, Lee, Ping I., de La Roca Soares, Monica Felts
Format: Article
Language:English
Subjects:
Amorphous solid solution
Apparent solubility
Chagas disease
Drug Combinations
Drug Compounding
Eutectic system
Nitroimidazoles - chemistry
Solubility
Triazoles - chemistry
Trypanosoma cruzi
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Summary:[Display omitted] Benznidazole (BNZ), the only commercialized antichagasic drug, and the antifungal compound posaconazole (PCZ) have shown synergistic action in the therapy of Chagas disease, however both active pharmaceutical ingredients (APIs) exhibit low aqueous solubility potentially limiting their bioavailability and therapeutic efficacy. In this paper, we report for the first time the formation of a eutectic mixture as well as an amorphous solid solution of PCZ and BNZ (at the same characteristic ratio of 80:20wt%), which provided enhanced solubility and dissolution rate for both APIs. This eutectic system was characterized by DSC and the melting points obtained were used for the construction of a phase diagram. The preservation of the characteristic PXRD patterns and the IR spectra of the parent APIs, and the visualization of a characteristic eutectic lamellar crystalline microstructure using Confocal Raman Microscopy confirm this system as a true eutectic mixture. The PXRD result also confirms the amorphous nature of the prepared solid solution. Theoretical chemical analyses indicate the predominance of π-stacking interactions in the amorphous solid solution, whereas an electrostatic interaction between the APIs is responsible for maintaining the alternating lamellar crystalline microstructure in the eutectic mixture. Both the eutectic mixture and the amorphous solid solution happen to have a characteristic PCZ to BNZ ratio similar to that of their pharmacological doses for treating Chagas disease, thus providing a unique therapeutic combination dose with enhanced apparent solubility and dissolution rate.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2017.04.021