Liquid-assisted grinding of an equimolar amount of pyrazinamide and p-nitrobenzoic acid yields two stoichiometric cocrystals in a 1:1 and 2:1 ratio, respectively. The 2:1 cocrystal was found to be the thermodynamically stable cocrystal based on solid stoichiometric interconversion, solvent-mediated conversion, and solubility studies. M echanochemistry 1,2 is one of the go-to methods for the synthesis and screening of cocrystals. A technique that goes back to the early 19th Century 3 was pioneered in the context of engineering cocrystals by the late Margaret Etter. 4−6 She demonstrated through a series of studies that cocrystals can be formed by grinding two components together in the solid state. Since then, synthesis of cocrystals by mechanochemistry has become widely popular. Mechanochemistry is particularly attractive because it can produce cocrystals not readily accessible by solution or melt synthesis. Moreover, it has been shown to afford control over the polymorphic outcome and stoichiometric composition of cocrystals. 7,8 The technique produces microcrystalline materials, which are primarily characterized by powder X-ray diffraction (PXRD). A unique PXRD pattern that is different from the starting materials generally indicates the formation of a new product. However, unlike in the case of a single component system where variation in the PXRD pattern of the product can be attributed to polymorphism, in a two-component system stoichiometric variation is an additional possibility that has to be taken into consideration. Differentiating between polymorphs and stoichiometrically diverse cocrystals by PXRD alone is not an easy task, and misinterpreting PXRD data can easily confuse polymorphs and stoichiometric cocrystals. A case in point is presented herein with a pair of pyrazinamide (PZA)·p-nitrobenzoic acid (pNBA) cocrystals. The relative thermodynamic stability based on solvent-mediated conversion, solid state stoichiometric interconversion and solubility studies is also discussed.pNBA is a suitable coformer for PZA that was selected to complement our previous study 9 on the effect of electronwithdrawing/-donating substituents on cocrystal formation. Figure 1 depicts the molecular structure of PZA and pNBA and the supramolecular synthons 10 likely to sustain the resulting cocrystal.Equimolar amounts of PZA and pNBA were reacted by liquid-assisted grinding (LAG) in the presence of various solvents. The resulting microcrystalline product was analyzed by PXRD and differential scanning calorimetry (DSC). PXRD data revealed the formation of a new phase, as indicated by a unique PXRD pattern that is different from either of the starting materials. DSC data showed two endotherms at ca. 171 and 183°C suggesting that two phases existed. Influenced by Figure 1. Molecular structures of pyrazinamide (PZA) and pnitrobenzoic acid (pNBA) and the possible supramolecular synthons that could sustain the two in a cocrystal.Communication pubs.acs.org/crystal
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