Experimental and theoretical screening of multi-component crystal forms of miconazole (MCL), an antifungal drug, with ten aliphatic dicarboxylic acids was performed. Seven multi-component molecular crystals were isolated and identified by...

In this work, three new cocrystals of the nonsteroidal anti-inflammatory drug flurbiprofen with salicylamide, benzamide, and picolinamide have been discovered using thermodynamic analysis of solid–liquid binary phase diagrams, and their crystal structures have been determined from the high-resolution synchrotron powder diffraction data. Periodic density functional theory calculations have been carried out to gain additional insight into energy differences between the cocrystal structures. The pH–solubility behavior and solubility advantage of the cocrystals have been examined via eutectic concentrations of the components, and the thermodynamic stability relationships between different solid phases have been rationalized in terms of Gibbs energies of the formation reactions. In addition, a new model has been proposed for estimating the solubility product (K sp) of a cocrystal, based on the experimental intrinsic solubility of the drug and coformer complemented by calculated physicochemical HYBOT descriptors. The relationship between the change in Gibbs free energy and the molecular volume of cocrystal formation has been observed and discussed.

Miconazole shows low oral bioavailability in humans due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as antifungal, anti-tubercular and anti-tumor effects. Cocrystal/salt formation is one of the effective methods for solving this problem. In this study, different methods (liquid-assisted grinding, slurrying and lyophilization) were used to investigate their impact on the formation of the miconazole multicomponent crystals with succinic, maleic and dl-tartaric acids. The solid state of the prepared powder was characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. It was found that lyophilization not only promotes partial amorphization of both salts but also allows obtaining a new polymorph of the miconazole salt with dl-tartaric acid. The lyophilized salts compared with the same samples prepared by two other methods showed better dissolution rates but low stability during the studies due to rapid recrystallization. Overall, it was determined that the preparation method of multicomponent crystals affects the solid-state characteristics and miconazole physicochemical properties significantly. The in vivo studies revealed that the miconazole multicomponent crystals indicated the higher peak blood concentration and area under the curve from 0 to 32 h values 2.4-, 2.9- and 4.6-fold higher than the pure drug. Therefore, this study demonstrated that multicomponent crystals are promising formulations for enhancing the oral bioavailability of poorly soluble compounds.

Formation thermodynamic parameters for three cocrystals of carbamazepine (CBZ) with structurally related coformers (benzamide (BZA), para-hydroxybenzamide (4-OH-BZA) and isonicotinamide (INAM)) were determined by experimental (cocrystal solubility and competitive reaction methods) and computational techniques. The experimental solubility values of cocrystal components at eutectic points and solubility product of cocrystals [CBZ + BZA], [CBZ + 4-OH-BZA], and [CBZ + INAM] in acetonitrile at 293.15 K, 298.15 K, 303.15 K, 308.15 K, and 313.15 K were measured. All the thermodynamic functions (Gibbs free energy, enthalpy, and entropy) of cocrystals formation were evaluated from the experimental data. The crystal structure of [CBZ + BZA] (1:1) cocrystal was solved and analyzed by the single crystal X-ray diffractometry. A correlation between the solubility products and pure coformers solubility values has been found for CBZ cocrystals. The relationship between the entropy term and the molecular volume of the cocrystal formation has been revealed. The effectiveness of the estimation of the cocrystal formation thermodynamic parameters, based on the knowledge of the melting temperatures of active pharmaceutical ingredients, coformers, cocrystals, as well as the sublimation Gibbs energies and enthalpies of the individual components, was proven. A new method for the comparative assessment of the cocrystal stability based on the H-bond propensity analysis was proposed. The experimental and theoretical results on the thermodynamic parameters of the cocrystal formation were shown to be in good agreement. According to the thermodynamic stability, the studied cocrystals can be arranged in the following order: [CBZ + 4-OH-BZA] > [CBZ + BZA] > [CBZ + INAM].

New multicomponent crystals of climbazole (CLB) with fumaric acid (FumAc) and tioconazole (TCL) with oxalic (OxlAc), malonic (MlnAc), fumaric, and DL-tartaric (TartAc) acids were obtained by liquid-assisted grinding. The single crystals of CLB were obtained for the first time, and the crystal structure was characterized. The crystal structures of the four multicomponent crystals studied[CLB + FumAc] cocrystal (2:1), [TCL + MlnAc] salt (1:1), [TCL + FumAc] salt (1:1), and [TCL + TartAc + H 2 O] salt (1:1:1)the single crystals of which were obtained by slow evaporation form solution were determined. The influence of the coformer structure of the multicomponent crystals on CLB and TCL conformational flexibility was discussed. A thermal analysis of the studied multicomponent crystals was carried out. The [TCL + TartAc + H 2 O] salt (1:1:1) dehydration mechanism was analyzed by differential scanning calorimetry, a thermogravimetric method, and thermomicroscopy. It was established that the completion of the [TCL + TartAc + H 2 O] salt (1:1:1) dehydration process was followed by melting of the eutectic mixture and crystallization of the [TCL + TartAc] salt (1:1). A study of the multicomponent crystal solubility was carried out in a phosphate buffer solution at pH 6.8. Cocrystallization/salt formation of the studied active pharmaceutical ingredients with dicarboxylic acids not only significantly improved their solubility but also maintained the level of supersaturation in the solution for quite a long time.