Browsing by Author "Diniz, Luan F."
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Item Avoiding irreversible 5-fluorocytosine hydration: Via supramolecular synthesis of pharmaceutical cocrystals(Royal Society of Chemistry, 2018-07-27) Souza, Matheus S.; Diniz, Luan F.; Vogt, Lautaro; Carvalho, Paulo S. Jr.; D’vries, Richard F.; Ellena, JavierThe 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.Item Mechanochemical Synthesis of a Multicomponent Solid Form: The Case of 5-Fluorocytosine Isoniazid Codrug(American Chemical Society, 2018-07-12) Souza, Matheus S.; Diniz, Luan F.; Vogt, Lautaro; Carvalho Jr., Paulo S.; D’vries, Richard F.; Ellena, JavierMechanochemistry synthesis was applied to the supramolecular synthesis and green scale-up production of a 1:1 drug–drug cocrystal involving the antimetabolite prodrug 5-Fluorocytosine (5-FC) and the tuberculostatic drug Isoniazid (INH), namely, 5FC-INH. Crystalline material, also obtained by traditional slow evaporation methods, was analyzed by single-crystal X-ray diffraction (XRD). The crystal packing is stabilized by a classical N–H···N hydrogen-bond interaction between the amine moiety of 5-FC and the INH pyridine nitrogen. IR and Raman data provided spectroscopic evidence about the hydrogen atom positions, thereby confirming the neutral nature of the cocrystal. Furthermore, 5FC-INH codrug was also evaluated by a range of analytical techniques such as powder XRD and thermal (thermogravimetric analysis, differential scanning calorimetry, hot stage microscopy) analyses. A physical stability study was performed in high relative humidity conditions to verify possible 5-FC solid-state hydration and/or INH degradation. The equilibrium solubility of this codrug was compared to the anhydrous 5-FC and INH raw materials, in pH 1.2 buffer media, and it was found to be similar to that of 5-FC, a biopharmaceutics classification system class I drug. The results show that the cocrystal has superior phase stability properties against moisture when compared to the starting pharmaceutical ingredients, so it could be considered as a potential candidate for the treatment of concomitant fungal infections, tuberculosis, and cancer.Item Novel Isoniazid cocrystals with aromatic carboxylic acids: Crystal engineering, spectroscopy and thermochemical investigations(Elsevier B.V., 2017-09-30) Diniz, Luan F.; Souza, Matheus S.; Carvalho Jr, Paulo S.; da Silva, Cecilia C.P.; D'Vries, Richard F.; Ellena, JavierFour novel cocrystals of the anti-tuberculosis drug Isoniazid (INH), including two polymorphs, with the aromatic carboxylic acids p-nitrobenzoic (PNBA), p-cyanobenzoic (PCNBA) and p-aminobenzoic (PABA) were rationally designed and synthesized by solvent evaporation. Aiming to explore the possible supramolecular synthons of this API, these cocrystals were fully characterized by X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR) and thermal (TGA, DSC, HSM) techniques. The cocrystal formation was found to be mainly driven by the synthons formed by the pyridine and hydrazide moieties. In both INH−PABA polymorphs, the COOH acid groups are H-bonded to pyridine and hydrazide groups giving rise to the acid⋯pyridine and acid⋯hydrazide heterosynthons. In INH−PNBA and INH−PCNBA cocrystals these acid groups are only related to the pyridine moiety. In addition to the structural study, supramolecular and Hirshfeld surface analysis were also performed based on the structural data. The cocrystals were identified from the FT-IR spectra and their thermal behaviors were studied by a combination of DSC, TGA and HSM techniques.Item Novel Isoniazid cocrystals with aromatic carboxylic acids: Crystal engineering, spectroscopy and thermochemical investigations(Journal of Molecular Structure, 2017) Diniz, Luan F.; Souza, Matheus S.; Carvalho Jr., Paulo S.; P. da Silva, Cecilia C.; D'Vries, Richard F.; Ellena, JavierFour novel cocrystals of the anti-tuberculosis drug Isoniazid (INH), including two polymorphs, with the aromatic carboxylic acids p-nitrobenzoic (PNBA), p-cyanobenzoic (PCNBA) and p-aminobenzoic (PABA) were rationally designed and synthesized by solvent evaporation. Aiming to explore the possible supramolecular synthons of this API, these cocrystals were fully characterized by X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR) and thermal (TGA, DSC, HSM) techniques. The cocrystal formation was found to be mainly driven by the synthons formed by the pyridine and hydrazide moieties. In both INH−PABA polymorphs, the COOH acid groups are H-bonded to pyridine and hydrazide groups giving rise to the acid⋯pyridine and acid⋯hydrazide heterosynthons. In INH−PNBA and INH−PCNBA cocrystals these acid groups are only related to the pyridine moiety. In addition to the structural study, supramolecular and Hirshfeld surface analysis were also performed based on the structural data. The cocrystals were identified from the FT-IR spectra and their thermal behaviors were studied by a combination of DSC, TGA and HSM techniques.