It has been traditionally suggested that polymorphism of cocrystals is a phenomenon seen less frequently than in monocomponent crystals. However, since the research on cocrystals has recently experienced a big growth, the number of solved structures of polymorphic cocrystals in the Cambridge Structural Database has increased, which can help to understand better whether a lower impact of this phenomenon exists or not in multicomponent crystals. In this paper we describe the cocrystal landscape of agomelatine, a particularly promiscuous drug able to cocrystallize with up to nine different coformers. Interestingly, two of those coformers have produced polymorphic cocrystals during the screening, which converts agomelatine into a new example that questions the traditional belief of the lesser impact of polymorphism in cocrystals and highlights the importance of polymorphism studies in cocrystal screening. Our work is completed with the determination of the crystal structures of the new forms from combined single crystal/ laboratory X-ray powder diffraction data.
Formulation of solids as cocrystals offers an opportunity to modulate physical properties, so identification of cocrystal formers (CCFs) for an active pharmaceutical ingredient is an area of significant interest. Exhaustive experimental screening would be time-consuming, but we have developed a computational method for identifying CCFs that have a high chance of success based on calculated functional group interaction energies. This virtual screening tool has been applied to nalidixic acid cocrystals. Calculations on a library of 310 compounds identified the 44 most promising CCFs for formation of nalidixic acid cocrystals. Six of these compounds were already known to form cocrystals, and experimental work was undertaken on the remaining 38 compounds. X-ray powder diffraction (XRPD) of mixtures obtained from grinding experiments identified seven CCFs that form new solid phases with nalidixic acid. Infrared spectroscopy and differential scanning calorimetry confirm that these new solid phases are different from the pure components. Further structural characterization was not possible for the skatole, 2,4-dihydroxybenzoic acid, and 3,4-dihydroxybenzoic acid cocrystals, but X-ray crystal structures were obtained from single crystals of the 1:1 tert-butylhydroquinone cocrystal and of the 1:1 propyl gallate cocrystal and from the XRPD pattern for the 1:1 2-phenylphenol cocrystal and for the 1:2 indole cocrystal. The results suggest that success rates in cocrystal screening can be significantly improved by application of computational filters to select the most appropriate CCFs for experimental study.
Two different types of monodimensional crystalline aggregates formed by squaramides, chains and ribbons, have been studied both in the solid state and ab initio with four model compounds. Although ribbons are a priori possible, only covalently forced syn conformations have been observed. Cooperative induction is postulated to explain the preference for chains instead of ribbons in squaramide crystals.
Using a dipyridyl squaramide derivative as a model, we have shown that cooperativity in hydrogen-bonded catemers plays a crucial role in defining the solid-state synthon of disecondary squaramides, overriding the preferred association mode in solution.
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