Avoiding 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 the structural level under storage conditions. The anhydrous form of 5-FC 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 the 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, and hot-stage microscopy) techniques. The physical stabilities of 5-FC and its cocrystals were evaluated in environments with high relative humidity and the equilibrium solubility was measured in a pH 1.2 buffer medium. 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 a high solubility profile. The hydration stabilities of 5-FC and its cocrystals were evaluated in humid environments to confirm the irreversible hydration of 5-FC in contrast with the absence of phase transitions in its cocrystal forms. In this way all 5-FC cocrystals reported herein maintained to a large degree the API solubility and do not undergo the hydration process or phase transition under extreme storage conditions, being more stable than the parent 5-FC.