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 crystal structures of two important marketed pharmaceuticals, namely, ramelteon (RAM) and tolvaptan (TOL), were determined for the first time using 3D precession electron diffraction tomography (PEDT) on 500 nm-sized crystals. The results were compared with the same structures determined by single-crystal X-ray diffraction on subsequently grown 50−200 μm single crystals, indicating a good match of molecular conformation, crystal packing, and unit cell parameters. The X-ray crystal structures were used to validate the developed workflow of data acquisition and structure solution with electron diffraction. This study highlights that 3D PEDT alone is able to provide accurate crystal structures from pharmaceutical nanocrystals that will suffice for most practical applications when no larger crystals can be grown.

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.

Determination of the first crystalline structures of the antihistaminic drug promethazine hydrochloride (PTZ) by single crystal X-ray diffraction revealed a possible case of intergrowth of polymorphic domains that requires further experimentation for confirmation. The two crystal structures of PTZ are characterized by high similarity of both molecular conformation and crystal packing and slight variations of the unit cell parameters induced by two distinct disorder levels in the PTZ aliphatic chain. These unit cell variations lead to small displacements of the molecules in the crystal structures and, consequently, to slight energy, density, and melting point differences between the forms. Although highly similar, the two crystalline forms of PTZ are clearly distinct disordered forms: they were repeatedly and reproducibly obtained, no intermediate disorder levels were found so far, and solvent-mediated transformation between them was evidenced by slurry experiments. In addition, the two distinct disorder levels were confirmed by solid-state nuclear magnetic resonance. Our study emphasizes the benefit of single-crystal structure data for the judgment of the phase purity and of solid forms exhibiting subtle structural differences. The newly discovered effect of disorder on the unit cell dimensions contributes to understanding the similarity limits between distinct disordered forms and, consequently, may provide important clues for crystal structure prediction.

On the basis of high-resolution synchrotron powder diffraction data, crystal structures have been solved for 1,3-distearoyl-2-oleoylglycerol, a major cis-mono-unsaturated triglyceride fraction of cocoa butter, and cocoa butter itself in the β(V) phase. The latter implies that in fact a crystal structure model of chocolate in the β(V) phase has been obtained. The results clarify the metastability of the β(V) phase and explain why fat bloom may develop on β(V)-type chocolate that has been stored at temperatures that are too high.