Matheus da Silva Souza

Indolizines fused with a seven-member lactone ring were identified as a promising scaffold in the search for new anticancer agents. Through a modular synthetic sequence, a library of cis and trans indolizines lactones had their antiproliferative activity evaluated against hormone-refractory prostate DU-145 and triple-negative breast MDA-MB-231 cancer cell lines. A methoxylated analogue was identified as an initial hit against MDA-MB-231 and late-stage functionalization of the indolizine core led to analogues within potencies up to twenty times higher than the parent precursor.

Two novel multicomponent crystal forms of the prodrug 5-fluorocytosine (5-FC), an ionic cocrystal and a monohydrate salt, with 2,4,6-trinitrophenol (picric acid, PA) and 3,5-dinitrosalicylic acid (DNSA), respectively, were rationally designed and synthesized. Nitro compounds are used to treat many diseases, such as cancer, one of the 5-FC targets via gene-directed prodrug therapy. In addition, within the wide range of applications for nitro compounds is the formation of charge-transfer complexes with organic molecules. Among all 5-FC crystalline structures depicted, only two contain nitro compounds: a salt with PA and a dihydrate cocrystal with 5-nitrouracil. Therefore, the two new single translucent pale gold prism crystals of 5FC-PA and 5FC-DNSA were successfully obtained by slow evaporation from aqueous solution and characterized by X-ray diffraction (single crystal and powder), Fourier Transform Infrared (FT-IR), and Raman (FT-Raman) spectroscopies. In both crystal structures, the 5-FC pyrimidine ring is protonated at the N3 atom and the respective packings are mainly stabilized by N–H⋯O H-bonds. For the 5FC-PA ionic cocrystal, the formation of triple H-bonds (two N–H⋯O and one charge assisted N–H⁺⋯N H-bonds) among the 5-FC molecules was observed. This is consistent with the expected stability of the duplex structure, which is considered the strongest association between two species. In addition to the structural study, Hirshfeld surface analysis was carried out based on the single crystal X-ray diffraction data. Thermal stability was assessed through thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and hot-stage microscopy (HSM), indicating that these compounds are stable up to approximately 200 °C. The results contribute to the diversity of new 5-FC solid forms and introduce two novel compounds, with possible application in fungal/cancer medicine formulations or to better understand the behavior of cytosine in DNA/RNA base pairing.

Paroxetine hydrochloride, PRX HCl, is an important and widely prescribed antidepressant drug for anxiety and depression treatment. Since hydrochloride salts can cause problems in their manufacture, we have designed organic salts with oxalic, fumaric, maleic and L-tartaric acids based on the NH₂ ⁺⋯COO⁻ synthon. All the salts were obtained from an innovative anion exchange method: selective crystallization from a mixture of PRX HCl and an acid in a certain ratio. The crystal structures of paroxetine (PRX) salts with dicarboxylic acids were determined by the single-crystal X-ray diffraction (SCXRD) method and were also analysed by thermogravimetric analysis, differential scanning calorimetry and FT-IR spectroscopy. Except for FUM and MAL acids, all the carboxylic acids form hydrate salts. Oxalate and tartrate salts are formed through the complete protonation of the anion and exhibit a 1 : 2 stoichiometry. All structures have a Z′ > 1 and different conformations are found for the PRX molecules. In general, the ionic units in the salts extend into chains that pack cohesively, via CH⋯O and CH⋯π interactions, into layers. The oxalate salt forms a channel structure where H₂O molecules are hosted. On the other hand, the presence of water molecules in the tartrate salt allows the packing of ionic layers. The organic salts are thermally more stable than the commercial PRX form, m.p. > 143 °C. They exhibit lower solubility compared to the hydrochloride form. The scientific contributions of this study show the diversity of the PRX solid forms and identify candidates for use in new antidepressant API solid formulations.

Fluconazole (FLZ) is one of the most used antifungal drugs worldwide and has been the focus of various investigations with the aim of enhancing its biomedical application. Most of the new solid forms achieved for this drug were determined by powder X-ray diffraction, and a few reports on polymorphs, solvates, cocrystals, and one salt–cocrystal by single-crystal X-ray diffraction (SCXRD) are available. By considering that FLZ is a very weak base (pK_a = 1.76, when protonated), salt formation with this drug is expected with the use of very strong organic acids, in order to dislocate the proton from the acid to the FLZ. To the best of our knowledge, only one organic salt of FLZ with picric acid (pK_a = 0.38) and one salt–cocrystal (maleate–maleic, pK a₁ = 1.92) were reported by SCXRD until now. Having in mind all the advantages that pharmaceutical salts have in drug delivery, in this work we depict the methodology and techniques employed to synthesize a new salt of FLZ using oxalic acid (pK a₁ = 1.23). The screening process was initially monitored using Raman spectroscopy, while further characterization by X-ray diffraction (powder and single crystal) and thermal analysis (DSC and TG) was performed to confirm the new salt fluconazolium oxalate (1 : 1). Finally, salt equilibrium solubility studies confirmed an improvement, about 7-fold, when compared to the commercialized active pharmaceutical ingredient (polymorph II). In addition, this is the first reported GRAS (generally regarded as safe) salt of the antifungal drug fluconazole.

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.