The 1:1 cocrystal of the antifungal agent ketoconazole with p-aminobenzoic acid was successfully crystallized and systematically characterized by a physical and pharmacological point of view. Crystal structure determination confirmed the cocrystal identity, giving full insight in its crystal packing and degree of disorder. Powder dissolution measurements revealed a 10-fold aqueous solubility increase that induces a 6.7-fold oral bioavailability improvement compared to ketoconazole. In vitro cell assays showed a good toxicity profile of the cocrystal with lower oxidative stress and inflammation and enhanced antifungal activity against several Candida species. The in vivo study of the cocrystal indicated similar pharmacokinetic profiles and liver toxicity with increased transaminases, as reported for ketoconazole. Notably, besides minor signs of inflammation, no morphological changes in liver parenchyma or signs of fibrosis and necrosis were detected. The enhanced solubility and oral bioavailability of the cocrystal over ketoconazole, together with the improved antifungal activity and good in vitro/in vivo toxicity, indicate its potential use as an alternative antifungal agent to the parent drug. Our results bring evidence of cocrystallization as a successful approach for bioavailability improvement of poorly soluble drugs.

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Supramolecular assemblies of 2,7-dipyridylfluorene with diiodotetrafluorobenzene isomers were obtained by mechanochemical synthesis and their structures were determined by single crystal X-ray diffraction. The contribution of specific non-covalent interactions between different building blocks to the stability and solid-state packing behaviors of the supramolecular catemers was evaluated by theoretical methods, which confirm the geometries and interactional bonding observed in single crystal X-ray diffraction structures.

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The nature of intermolecular interactions in different molecular crystal configurations formed by pyridinium cations, chloride or bromide anions as well as β-hexachlorocyclohexane (β-HCH) molecules has been investigated using high level ab initio quantum chemistry methods. Several molecular subsystems taken from the crystal unit cell were considered and their supramolecular energy stability was analyzed in detail using high level density-fitting local electron correlation (DF-LMP2 and DF-LCCSD(T)) methods together with the aug-cc-pVTZ basis set. In order to elucidate the nature of the intermolecular interactions between different fragments, the symmetry adapted perturbation theory (SAPT) method up to "2+3" truncation expansion was applied. The SAPT analysis has shown that the "simple" pair model of a halide anion-β-HCH complex is not adequate to properly describe the stability of the crystals, since the charge polarization induced by the cation counterpart on the halide anion significantly changes the nature and the magnitude of the anion-β-HCH interaction.

The formation of highly ordered supramolecular architectures via cooperative C(aliphatic)-H·anion contacts between β-HCH and various anions (Cl, Br, I and HSO) was investigated by single crystal X-ray diffractometry, molecular modelling, ESI-MS and H-NMR titrations.

Single-crystal X-ray diffraction studies on Halogen-Bonded Organic Frameworks (XBOF) formed by N---I contacts of 2,2′,7,7′-tetrapyridyl-9,9′-spirobifluorene with pentafluoroiodobenzene or the isomers of diiodotetrafluorobenzene revealed the formation by F---I, F---F, and I---I halogen bonds of unique tetrameric superstructures of the halogenated derivatives in which the position of I atoms is mimicking the orientation of pyridyl groups in the 9,9′-spirobifluorene derivative resulting in the 1/4 molar ratio coordination of the halogenated compounds to the tetrapyridyl spiro derivative.