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Solubility and permeability of nitrofurantoin (NITRO) were compared with those of its cocrystals containing isoniazid (ISO), bipyridyl (BIP), or phenanthroline (PHE) as coformers, and their parent mixtures. NITRO dissolution profiles were evaluated via HPLC; we resorted to molecular dynamics (MD) simulations to rationalize the experimental data on the basis of nitrofurantoin−coformers and nitrofurantoin−water intermolecular interactions. Permeation studies were performed by using an in vitro model of the small intestine based on IEC-6 cells. The NITRO water solubility was reduced by its mixture with PHE and BIP but not with ISO. Cocrystallization with BIP induced a slight increase of NITRO solubility; cocrystallization with PHE induced its solubility decrease, even if lower than the physical mixture. The solubility changes were attributed to NITRO solvation shell alterations (MD simulations). Cocrystallization with ISO allowed an increase of the NITRO solubility in the first 30 min of the dissolution pattern. Permeation measurements showed that the NITRO− PHE mixture was detrimental for the monolayer integrity, whereas no alterations were induced by the cocrystal. No effects on NITRO permeability and monolayer integrity were observed either for NITRO−ISO or for NITRO−BIP mixtures. The NITRO− ISO cocrystal increased the NITRO permeability across the monolayer without reducing its integrity.

Several studies showed that D-Limonene can improve metabolic parameters of obese mice via various mechanisms, including intestinal microbiota modulation. Nevertheless, its effective doses often overcome the acceptable daily intake, rising concerns about toxicity. In this study we administered to C57BL/6 mice for 84 days a food supplement based on D-Limonene, adsorbed on dietary fibers (FLS), not able to reach the bloodstream, to counteract the metabolic effects of a high-fat diet (HFD). Results showed that daily administration of D-Limonene (30 and 60 mg/kg body weight) for 84 days decreased the weight gain of HFD mice. After 84 days we observed a statistically significant difference in weight gain in the group of mice receiving the higher dose of FLS compared to HFD mice (35.24 ± 4.56 g vs. 40.79 ± 3.28 g, p < 0.05). Moreover, FLS at both doses tested was capable of lowering triglyceridemia and also fasting glycemia at the higher dose. Some insights on the relevant fatty acid changes in hepatic tissues were obtained, highlighting the increased polyunsaturated fatty acid (PUFA) levels even at the lowest dose. FLS was also able to positively modulate the gut microbiota and prevent HFD-associated liver steatosis in a dose-dependent manner. These results demonstrate that FLS at these doses can be considered non-toxic and could be an effective tool to counteract diet-induced obesity and ameliorate metabolic profile in mice.

The therapeutic efficacy of orally administered drugs is strictly dependent on their bioavailability [1, 2]. The solubility and dissolution of drugs in Gastrointestinal (GI) tract, related to their ability to permeate through GI membrane, appear as the key parameters essential for the bioavailability control. This concept constitutes the basis of the Biopharmaceutics Classification System (BCS) [3], where drugs classified in classes II (low solubility-high permeability), III (high solubility-low permeability) or IV (low solubility-low permeability) are often characterized by poor oral bioavailability [2]. Unfortunately, about 40% of marked drugs are poorly water soluble, with a main distribution in Class II (30%) and class IV (10%) [2, 4]; moreover, the percentages in classes II and IV considerably increases to about 70% and 20%, respectively, among the drug candidates in discovery pipelines [5]. Drugs in amorphous form exhibit higher solubility than in crystalline form, even if they are of limited use in pharmaceutical industry being characterized by poor stability with the tendency to recrystallize over time [6]. On the contrary, salts are widely used (representing more than 50% of administered drugs) [7], even if they cannot be used for non-ionisable drugs. New crystal engineering strategies are required in order to modify the physicochemical properties of pharmaceutical solids and, among these, co-crystallization appears promising to increase the oral bioavailability of poorly water soluble drugs [8]. The European Medicine Agency (EMA) defines co-crystals as "homogenous crystalline structures made up of two or more components in a defined stoichiometric ratio where the arrangement in the crystal lattice is not based on ionic bonds" [9]. US Food and Drug Administration (FDA) defines co-crystals as crystalline materials which are composed of two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent bonds [10].