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.

The detailed characterization of several subambient solid state transitions occurring in the pharmaceutical ingredient Ciclopirox between −20 °C and −85 °C was performed by using a combination of DSC, cold-stage optical microscopy, vibrational spectroscopies, solid state NMR at controlled temperature, structural analyses by single crystal X-ray diffraction, and temperature-resolved X-ray powder diffraction. The global analysis of the available data reveals that the mechanisms of these reversible transitions involve a subtle compromise between phenomena related to molecular disorder, cooperative release of strains induced by cooling, and structural reorganization associated with topotactic changes in crystal lattice and symmetry. However, no major change in the main features of crystal packings is observed during the successive single crystal-to-single crystal transitions, which highlights the difficulty to classify such transitions in the frame of conventional theoretical frameworks. The successive thermal events and related structural changes or relaxations can be seen as the consequences of a deconvolution phenomenon for the global phase transition between the dynamically disordered room temperature form (C2/c, Z = 8, Z′ = 1) and the ordered low-temperature form (P2 1 /c, Z = 48, Z′ = 12). In this respect, the intermediate form(s) can be seen as transient states of kinetic origin with a questionable genuine crystallographic relevance.

X-ray diffraction analysis of (R,S)-and S-atenolol crystalline forms was performed. The crystals studied were grown from evaporation of an ethanol/water solution. (R,S)-Atenolol crystallizes in the centrosymmetric space group C2/c, and S-atenolol crystallizes in a noncentrosymmetric space group C2. There is one symmetry independent molecule in (R,S)-atenolol crystals and two symmetry independent molecules in S-atenolol. However, due to disorder, two different molecular conformations were identified in the (R,S)-atenolol, and three different conformations were isolated in S-atenolol. Flexibility of molecular segments of the carbon chain is seen in conformational isomorphism and in the atomic position uncertainty. The molecular conformations given by X-ray diffraction were fully relaxed at the HF/6-31G* level of theory. The optimized structure was used as reference in comparison with molecular conformation in the solid state.

The crystallization behavior and morphological features of particles obtained from amorphous diprophylline (DPL) are reported. After fast cooling of the melt, progressive heating above the glass transition (T g ≈ 37 °C) induces the nucleation and growth of well-shaped crystals: PC for primary crystals. The combination of differential scanning calorimetry, hot stage optical microscopy, powder X-ray diffraction, and Raman spectroscopy revealed that these PC are kinetically favored and can form spontaneously in the supercooled melt whatever the enantiomeric composition, although their development and relative stability are influenced by the presence of theophylline, the main impurity in DPL samples. Specific crystal surfaces of the PC act as favorable areas and support for the subsequent formation of previously known metastable crystal forms consisting of solid solutions of the two DPL enantiomers. This study demonstrates the complex multistep mechanism that can occur during the temperature-induced crystallization of chiral amorphous drugs, and their strong sensitivity to enantiomeric composition and chemical purity.