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Avoiding the Irreversible 5-Fluorocytosine Hydration via Supramolecular Synthesis of Pharmaceutical Cocrystals

Abstract

The antimetabolite 5-Fluorocytosine (5-FC) was used to form pharmaceutical cocrystals in order to modulate its poor physicochemical stability in humid environments, which leads to the irreversible incorporation of a water molecule at structural level under storage conditions. 5-FC anhydrous form is a well-known fluorinated analog of cytosine with antifungal activity and it has become one of the most used medications for cancer treatment via gene therapy approach. In this study, novel 5-FC cocrystals were obtained from the reaction of 5-FC with three nontoxic coformers: caffeine (CAF), p-aminobenzoic acid (PABA) and caprylic acid (CA). These cocrystals namely 5FC-CAF, 5FC-PABA and 5FC-CA were characterized by single-crystal and powder X-ray diffraction (SCXRD and PXRD), spectroscopic (FT-IR and FT-Raman) and thermal (thermogravimetric analysis, differential scanning calorimetry, Hot-Stage microscopy) techniques. The physical stability of 5-FC and its cocrystals were evaluated in environment with high relative humidity as well as the equilibrium solubility was measured in pH 1.2 buffer media. These studies show that the prodrug 5-FC is able to form different homo and heterosynthons that lead to cocrystal formation. Additionally, the solubility profiles of the novel multicomponent solid forms were found to be similar to the API raw material, a BCS class I drug, exhibiting high solubility profile. The hydration stability of 5-FC and its cocrystals were evaluated in humid environment to confirm the irreversible hydration of 5-FC in contrast with the absence of phase transitions in it cocrystals forms. In this way all 5-FC cocrystals reported herein maintained to a large degree the API solubility and do not undergo hydration process or phase transition under extreme storage conditions, being more stable than the parent 5-FC.

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Publication details

The article was received on 30 May 2018, accepted on 26 Jul 2018 and first published on 27 Jul 2018


Article type: Paper
DOI: 10.1039/C8NJ02647E
Citation: New J. Chem., 2018, Accepted Manuscript
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    Avoiding the Irreversible 5-Fluorocytosine Hydration via Supramolecular Synthesis of Pharmaceutical Cocrystals

    M. S. Souza, L. F. Diniz, L. Vogt, P. D. S. de Sousa Carvalho, Jr., R. F. D'Vries and J. A. Ellena, New J. Chem., 2018, Accepted Manuscript , DOI: 10.1039/C8NJ02647E

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