Screening of pyrazinamide polymorphs was carried out by crystallization from solvents differing in polarity and hydrogen bonding ability and also by sublimation and lyophilization. Pure samples of polymorphs α, δ, and γ could be prepared, and mixtures of the β form with one of the other polymorphs were also produced. These forms were fully characterized by infrared spectroscopy and two main profiles registered in the N−H stretching vibration region, clearly distinguishing polymorphs encompassing a dimeric pirazinamide unit, α, β, and δ, and where the dimer does not exist, the γ one. The thermal behavior of pyrazinamide polymorphs was also investigated using differential scanning calorimetry (DSC) and polarized light thermal microscopy, supported by powder X-ray diffraction and infrared spectroscopy. The α, β, and δ forms give rise on heating to the γ form, in endothermic transitions, with some superheating being observed. Also, the DSC peaks display an irregular shape. These observations suggest kinetic hindering of the solid−solid transitions. An endothermic phase transition of the δ form to the α one was observed only for samples seeded with this latter polymorph. The relative stability of the four pyrazinamide polymorphs was derived from the experimental observations.

A screening of naproxen cocrystals with coformers picolinamide, nicotinamide, isonicotinamide, and pyrazinamide is performed by the Kofler contact method and mechanochemistry. The solids obtained by mechanochemistry are characterized by differential scanning calorimetry, DSC, polarized light thermomicroscopy, PLTM, infrared spectroscopy, FTIR, and X-ray powder diffraction, XRPD. No cocrystal could be prepared under the experimental conditions investigated between naproxen and pyrazinamide, which bears two aromatic nitrogen atoms, ortho and meta to the amide group. For the o-, m-, and p-pyridinecarboxamide isomers, regardless of the aromatic nitrogen position, the coformer interacts with naproxen to give rise to new cocrystals: naproxen:picolinamide, naproxen 2 :nicotinamide, and naproxen:isonicotinamide. A supramolecular acid:aromatic nitrogen heterosynthon is found in all these cocrystals. The structure of the new naproxen:isonicotinamide compound was solved by single-crystal X-ray diffraction, SXD. As nicotinamide has FDA/GRAS status the naproxen:nicotinamide (2:1) cocrystal is of special relevance.

A 1:1 co-crystal involving pyrazinamide, one of the first-line drugs recommended by the World Health Organization for tuberculosis treatment, and diflunisal, a nonsteroidal anti-inflammatory substance, has been synthesized for the first time. From a combination drug perspective, this is an interesting pharmaceutical co-crystal because of the known side effects of pyrazinamide therapy. Preliminary studies by computational methods on the relative stability of homodimers versus the two probable heterodimers indicated differences that could easily be overcome by the network of intermolecular interactions in a possible co-crystal structure. The co-crystal synthesis was first attempted by manually grinding equimolar mixtures. This procedure yields a physical mixture of the components, whose differential scanning calorimetry (DSC) curve indicates possible conditions for generating the co-crystal. The pyrazinamide-diflunisal co-crystal can be obtained from an equimolar mortar ground mixture by thermal activation at T = 80 °C. The co-crystal synthesis was also successfully achieved from equimolar mixtures by two other methods: ethanol-assisted ball mill grinding and room temperature annealing of a low crystalline mixture obtained by neat ball mill grinding. The new species was characterized by DSC (T fus = (147.4 ± 0.2) °C, which lies between those of the pure components), polarized light thermal microscopy, X-ray powder diffraction, and Fourier transform infrared spectroscopy. The infrared spectra show evidence of pyridine-acid association.

The structural, vibrational, and photochemical study of 1-methylhydantoin (1-MH, C4H6N2O2) was undertaken by matrix isolation infrared spectroscopy (in argon matrix; 10 K), complemented by quantum chemical calculations performed at the DFT(B3LYP)/6-311++G(d,p) level of approximation. The theoretical calculations yielded the Cs symmetry structure, with planar heavy atom skeleton, as the minimum energy structure on the potential energy surface of the molecule. The electronic structure of this minimum energy structure of 1-MH was then studied in detail by means of the natural bond orbital (NBO) and atoms in molecules (AIM) approaches, allowing for the elucidation of specific characteristics of the molecule's σ and π electronic systems. The infrared spectrum of the matrix-isolated 1-MH was fully assigned, also with the help of the theoretically predicted spectrum of the compound, and its UV-induced unimolecular photochemistry (λ ≥ 230 nm) was investigated. The compound was found to fragment to CO, isocyanic acid, methylenimine, and N-methyl-methylenimine. Finally, a thermal behavior investigation on 1-MH samples was carried out using infrared spectroscopy (10 K until melting), differential scanning calorimetry and polarized light thermal microscopy. A new polymorph of 1-MH was identified. The IR spectra of the different observed phases were recorded and interpreted.

This paper describes an environmentally sustainable synthetic method for the preparation of a set of meso-aryl hydroporphyrins, namely chlorins and bacteriochlorins, via reduction of porphyrins with diimide, in the total absence of solvents and bases. Thermomicroscopy studies clearly showed that the process is a typical solvent-free reaction. † Electronic supplementary information (ESI) available: SI_PLTM_por-phyrin_p_toluenesulfonylhydrazide movie file.