Crystallization of salts and co-crystals of Ketoconazole with aliphatic dicarboxylic acids was investigated by using solution-based and grinding methods. Salt/co-crystal preparation by grinding Solvent drop grinding (SDG) experiments were performed by mechanical grinding using a Retsch MM400 mixer mill (90 min at 30 Hz) using stainless steel grinding jars (1.5 or 5 mL). Before starting, drops of solvent (methanol or 2,2,2-trifluororethanol) were added to approximately 130 mg of mixtures corresponding to (1:1.1) or (1:1) stoichiometric ratios of Ketoconazole and the corresponding cocrystal former (oxalic acid, fumaric acid, succinic acid and adipic acid). The resulting powder was distributed on a filter paper and air-dried. The experimental details and the resulting forms are presented in Table S1. Solution-based salt/co-crystallization The experiments were based on slow evaporation of solutions in which ketoconazole was combined with one of four dicarboxylic acids (oxalic acid, fumaric acid, succinic acid and adipic acid) in 1:1.1 stoichiometric molar ratio. Each experiment was realized in several solvents and solvent mixtures as shown in Table S1. Table S1. Results of the solution-based co-crystalization and solvent-drop grinding experiments for the crystallization of salts / co-crystals of Ketoconazole with aliphatic dicarboxylic acids Co-former Co-former pK a values Solution-based method SDG

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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