Compreendendo as formas sólidas de 5E-(feniletenil)benzofuroxano com diferente atividade anti-T. cruzi in vivo

5E-Phenylethenylbenzofuroxan (5PhEBfx) was reported as an excellent anti-Chagas drug candidate. However, its oral bioavailability was affected by the crystallization process. Two samples exhibiting variable in vivo activity was investigated: a thin yellow powder (5PhEBfx-Y) and orange needles (5PhEBfx-O). X-ray powder diffraction, differential scanning calorimetry, vibrational spectroscopy, optical and electron scanning microscopies were applied to investigate both solid forms in order to correlate the solid-state properties with the variable bioavailability of 5PhEBfx. It was observed that 5PhEBfx-Y have a better solubility and consequently higher bioavailability when compared with 5PhEBfx-O. This result suggests that the difference of activity between these two 5E-Phenylethenylbenzofuroxanes could be associated with the solid forms, which also cause the coloration variation.CAPESFINEPInstituto de Pesquisa e Desenvolvimento Institucional (IPDI)FUNCAPPrograma Sul-Americano de Apoio às Atividades de Cooperação em Ciência e Tecnologia (PROSUL) - CNPqDrugs for Neglected Diseases initiative (DNDi

Solvothermal Preparation of Drug Crystals: Didanosine

For the first time, crystals of suitable size for X-ray diffractometry structure determination (Dian important anti-HI V drug were prepared under solvothermal conditions. In this study, the crystal structure of didanosine (2`,3`-dideoxyinosine, ddI) in the form of a hydrate was determined using single-crystal X-ray diffractometry. Powder X-ray diffraction analysis revealed that the solid-state phase of the drug incorporated into pharmaceutical solid dosage forms is isostructural to the solvothermally prepared ddI material, even though they do not exhibit an identical chemical composition due to different water fractions occupying hydrophobic channels formed within the crystal lattice. Two ddI conformers are present in the structure, in agreement with a previous structure elucidation attempt. Concerning the keto enol equilibrium of ddI, our crystal data and vibrational characterizations by Fourier transform infrared (FTIR) and FT-Raman spectroscopy techniques were conclusive to state that both conformers exist in the keto form, contrary to solid-state NMR spectroscopic assignments that suggested ddI molecules occur as enol tautomers. In addition, characterizations by thermal (differential scanning calorimetry) and spectroscopic techniques allowed us to understand the structural similarities and the differences related to the hydration pattern of the nonstoichiometric hydrates.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Brazilian Research Council CNPq[477201/2009-1]Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Brazilian Research Council CNPq[302441/2009-3]FAPESP (Fundacao de Amparo Pesquisa do Estado de Sao Paulo)[2007/07185-5]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP (Fundacao de Amparo Pesquisa do Estado de Sao Paulo)[2009/14705-0]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPEMIG (Fundacao de Amparo a Pesquisa do Estado de Minas Gerais)[APQ-2011-5.02/07]Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)FAPEMIG (Fundacao de Amparo a Pesquisa do Estado de Minas Gerais)[APQ-6010-5.02/07]Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)FAPEMIG (Fundacao de Amparo a Pesquisa do Estado de Minas Gerais)[APQ-02685-09]CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)[PNPD2008]Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FUNCAP (Fundacao Cearense de Amparo ao Desenvolvimento Cientifico e Tecnologico)Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP)IPDI (Instituto de Pesquisa, Desenvolvimento e Inovacao)IPDI (Instituto de Pesquisa, Desenvolvimento e Inovacao

The continuum in 5‑fluorocytosine: toward salt formation

5-Fluorocytosine (5-FC) was crystallized with complementary dicarboxylic acids, aiming to achieve a controlled synthesis of structures based on the ΔpKa rule proposed in the salt-cocrystal continuum study and to provide structural information helpful in the comprehension of its supramolecularity. Although 5-FC tends to be basic, pKa = 3.26, only three salts are reported. In this way, new 5-FC salts were obtained, the fumaric, maleic and oxalic ones, all crystallizing in the monoclinic space group P21/c. In the 5- FC oxalate and fumarate cases, the acid molecules are placed on an inversion center in a fashion that each half molecule exhibits one terminal donor-acceptor site, leading to the constitution of a 5-FC- acid-5-FC heterodimer. Such a heterodimer is observed in only one donor-acceptor site of the maleate of 5-FC, whose acid molecule exhibits a closed chain architecture. Infrared and Raman spectra recorded for the three compounds complement the salt characterization on the basis of the extent of proton transfer. Thermal analysis evidence that the salt formation decreases the melting point of the new compounds, ranking this molecule as a coformer candidate to improve the physical properties of other drugs.CAPESCNPqFAPES

All-Angle Negative Refraction from the Phonon Response in Anisotropic Crystals

We consider how all-angle negative refraction may be induced in anisotropic crystals by making use of the phonon response. We investigate, both theoretically and experimentally, the example of crystal quartz at far infrared wavelengths

Base-Paired and Base-Stacked Structures of the Anti-HIV Drug Lamivudine: A Nucleoside DNA-Mimicry with Unprecedented Topology

We have prepared a DNA-mimicry of nucleosides in which the anti-HIV drug lamivudine (β-l-2′,3′-dideoxy-3′-thiacytidine, 3TC) self-assembles into a base-paired and helically base-stacked hexagonal structure. Face-to-face and face-to-tail stacked 3TC3TC dimers base-paired through two hydrogen bonds between neutral cytosines by either N–H···O or N–H···N atoms give rise to a right-handed DNA-mimicry of lamivudine with an unusual highly symmetric hexagonal lattice and topology. In addition, a base-paired and base-stacked supramolecular architecture of lamivudine hemihydrochloride hemihydrate was also obtained as a result of our crystal screenings. This structure is formed through partially face-to-face stacked lamivudine pairs held together by protonated and neutral fragments. However, no helical stacking occurs in this structure in which lamivudine also adopts unusual conformations as the C1′-<i>endo</i> and C1′-<i>exo</i> sugar puckers and cytosine orientations intermediate between the <i>anti</i> and <i>syn</i> conformations. As a conclusion drawn from the nucleoside duplex, the hexagonal DNA-mimicry of lamivudine reveals that such double-stranded helices can be assembled without counterions and organic solvents but with higher crystallographic symmetry instead, because only water crystallizes together with lamivudine in this structure

The Continuum in 5‑Fluorocytosine. Toward Salt Formation

5-Fluorocytosine (5-FC) was crystallized with complementary dicarboxylic acids, aiming to achieve a controlled synthesis of structures based on the Δp<i>K</i>_a rule proposed in the salt–cocrystal continuum study and to provide structural information helpful in the comprehension of its supramolecularity. Although 5-FC tends to be basic, p<i>K</i>_a = 3.26, only three salts are reported. In this way, new 5-FC salts were obtained, the fumaric, maleic and oxalic ones, all crystallizing in the monoclinic space group <i>P</i>2₁/<i>c</i>. In the 5-FC oxalate and fumarate cases, the acid molecules are placed on an inversion center in a fashion that each half molecule exhibits one terminal donor–acceptor site, leading to the constitution of a 5-FC–acid–5-FC heterodimer. Such a heterodimer is observed in only one donor–acceptor site of the maleate of 5-FC, whose acid molecule exhibits a closed chain architecture. Infrared and Raman spectra recorded for the three compounds complement the salt characterization on the basis of the extent of proton transfer. Thermal analysis evidence that the salt formation decreases the melting point of the new compounds, ranking this molecule as a coformer candidate to improve the physical properties of other drugs

Polymorphism evaluation in generic tablets containing mebendazole by dissolution tests

This study evaluates the incidence of the polymorphic forms of mebendazole (MBZ) in tablets within the Brazilian market by dissolution tests. The indicated dissolution medium by the USP 30 (United States Pharmacopoeia) and a proposed modified medium were duly compared in order to verify whether they are able to discriminate the polymorph A from polymorph C in commercial tablets. Dissolution assay tests of physical mixtures in raw materials of polymorph A and polymorph C, as well as of nine tablets of MBZ (available in the Brazilian market), were properly performed. For the dissolution tests, the USP 30 medium (I) and a modified medium (II) were used. The modified medium allowed a reproducible and reliable quality control of MBZ polymorphism in commercial tablets