| Abstract |
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 degrees 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) degrees 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. |
