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The polymorphism of apremilast has been investigated. Two polymorphs have been identified and characterized by differential scanning calorimeter, fourier transform infrared spectroscopy, and powder X-ray diffractometer. Solubilities of apremilast forms B and E in three binary solvents of methanol-water, acetonitrile-water, and acetonitrile-methanol have been measured using the static method at a temperature ranging from 288.15 K to 328.15 K under standard atmospheric pressure. Subsequently, the solubility data have been analyzed using the Wilson, NRTL, and UNIQUAC thermodynamic models, respectively. Furthermore, the Gibbs energy of solution and the radial distribution function have been calculated using the molecular simulation method to evaluate the dissolution mechanism. The Gibbs energy of solution reveals that the rank of solute-solvent interaction correlated well with solubility order in binary solvent mixtures, and the radial distribution function indicates that weakening of solvent-solvent interaction led to an increase in solubility., (Copyright © 2021 Elsevier B.V. All rights reserved.)

[Display omitted] • A novel cocrystal of metformin hydrochloride with citric acid was synthesized and obtained. • Physicochemical properties and the single-crystal structure of the cocrystal were investigated and determined. • The binding models of the cocrystal were built, simulated, and calculated to investigate the mechanisms of cocrystal formation. • Hirshfeld surface of cocrystal was analyzed to reveal the intermolecular interactions and the strength of molecular packing. Pharmaceutical cocrystals have matured into an effective technique for tuning the physicochemical and mechanical properties of drugs in solid form simultaneously. Herein, in order to provide a novel cocrystal form of oral medicine metformin hydrochloride (MH), citric acid (CA) was selected as an efficient ligand after screening a variety of inorganic and organic acids. Thus, based on the principle of crystal engineering, we report a novel cocrystal: metformin hydrochloride - citric acid (MHCA) after the systematic screening, which was experimentally proved to be constituted with 1:1 stoichiometry. Compared with pure MH, MHCA has been proved higher solubility in water, methanol, and ethanol from 283.15 to 313.15 K. Through single-crystal X-ray diffraction (SC-XRD), the particular molecular structure of MHCA has been determined as the orthorhombic system and Pbca space group. Besides, the binding model of MH-CA was built for investigating the binding energy and stability between two components at 278, 298, and 318 K, which were found to be essential for the prediction and analysis of cocrystals. The contribution of different intermolecular interactions and the strength of molecular packing in the cocrystal also have been investigated by Hirshfeld surface analysis. It was found that the cocrystal structure was mainly stabilized by intermolecular hydrogen bonds existing as N—H···O between components, which indicated that the diffusion-combination trend of molecules enhanced the regular array of cocrystal. The results revealed that the molecules of MH and CA formed supramolecular cocrystals mainly induced by hydrogen bonds after passive contacts, such as co-crystallization or grind. [ABSTRACT FROM AUTHOR]

• The nucleation behavior of tiamulin hydrogen fumarate methanol solvate (THFMS) was investigated. • The solubility and cosolvency effect of THFMS were studied in methanol-ethyl acetate binary mixtures. • The interfacial energy, the critical nucleation potential, and the critical nucleation parameterswere discussed. To investigate the nucleation behavior of tiamulin hydrogen fumarate methanol solvate (THFMS), the solubility, induction time, and metastable zone width (MSZW) of THFMS in methanol-ethyl acetate binary mixtures were measured. The nucleation potential model, which is based on the classical nucleation theory and correlates the induction time and MSZW, has been employed to deal with the experimental data and estimate the interfacial energy and the critical nucleation potential. The estimated values determined from the nucleation potential model are in accordance with the experimental values. The interfacial energy and the critical nucleation potential of THFMS steadily decrease with the increasing saturation temperature, whereas those of THFMS initially decrease and subsequently increase as the ethyl acetate content increases. The results demonstrate that an increase in saturation temperature leads to enhanced nucleation favorability, while the difficulty of nucleation initially decreases and then increases with increasing ethyl acetate content. Furthermore, the critical nucleation parameters, including the critical Gibbs free energy, the critical nucleus size, and the critical number of molecules in a nucleus, exhibit the same trend in alterations regarding both saturation temperature and ethyl acetate content. [ABSTRACT FROM AUTHOR]

• The solubility of Favipiravir in twelve solvents was determined and correlated with the Modified Apelblat, λh, NRTL, and Wilson models. • The dissolution order of Favipiravir was revealed by HSP and solvent effect analysis. • MEPS, Hirshfeld surface, and solvation free energy were applied to investigate Intermolecular interactions. • Thermodynamic properties of Favipiravir in twelve solvents were calculated and discussed by van't Hoff equation. The solubility of Favipiravir in twelve pure solvents, including methanol (MeOH), ethanol (EtOH), n-propanol (NPOH), isopropanol (IPOH), n-butanol (NBOH), acetone (DMK), acetonitrile (MeCN), dichloromethane (DCM), N , N -Dimethylformamide (DMF), methyl acetate (MtAC), ethyl acetate (EtAC), butyl acetate (NBAC) was measured by gravimetric method at a temperature range of 293.15 to 333.15 K at 0.1 MPa. The maximum and minimum of Favipiravir solubility were obtained in DMF at 333.15 K (0.02599 mol·mol−1) and MeOH at 293.15 K (0.00147 mol·mol−1), respectively. At 298.15 K, the order of solubility in different solvents is: DMF > NBAC > DMK > MtAC > EtAC > NBOH > DCM > EtOH > NPOH > IPOH > MeCN > MeOH. The Hansen solubility parameter (HSP) was used to analyze the miscibility of Favipiravir in selected solvents. In addition, the solvent effect was studied by analyzing solvent properties, which indicate that the solubility of Favipiravir in selected solvents is influenced by the synergistic effect of multiple factors. The Modified Apelblat model, λh model, NRTL model, and Wilson model were employed to correlate the solubility data, indicating the Apelblat model provides the highest regression accuracy corresponding to the lowest average value of average relative deviation (ARD, 0.017459) and root mean square deviation (RMSD, 0.00012). In order to explain the dissolution behavior of Favipiravir in different solvents, the intermolecular interactions were analyzed by using Hirshfeld surface (HS), Molecular electrostatic potential surface (MEPS), and solvation free energy. The thermodynamic parameters derived from van't Hoff equation including Δ dis G 0 (10.71–16.57 kJ·mol−1), Δ dis H 0 (6.33–18.67 kJ·mol−1), and Δ dis S 0 (−32.77–25.47 J·mol−1·K−1) indicate that the dissolution of Favipiravir is endothermic, entropy-driven or has no driving force, and non-spontaneous. [ABSTRACT FROM AUTHOR]

The solubility of dabigatran etexilate mesylate (DEM) Forms I, II, M, and Hemihydrate in pure water, methanol, ethanol, n-propanol, and n-butanol was determined by a dynamic method in the temperature range of 278.15–298.15 K under 0.1 MPa. The measured solubility data were then correlated by the modified Apelblat equation, λh equation, and van't Hoff equation, with the best fitting from the modified Apelblat equation. It is found that the dissolution process of DEM is endothermic, entropy-driven, and non-spontaneous by calculating the thermodynamic properties. Further, the molecular simulation was used to investigate the interaction between solute and solvent molecules. The results show that the absolute value of the solvation free energy of DEM is positively correlated with the experimental solubility. • A systematic solubility of dabigatran etexilate mesylate (DEM) polymorphs in five mono-solvents was firstly measured. • Experimental solubility data were correlated by Modified Apelblat equation, λh equation and van't Hoff equation. • Molecular simulation was performed to reveal the solubility behavior of the same crystal form in different mono-solvents. [ABSTRACT FROM AUTHOR]

Solubility is important in designing the delivery of the pharmaceuticals and in designing the crystallization process for purification. It is significant to understand the thermodynamics of the stable polymorph and the metastable polymorphs. Lenalidomide can be used for the treatment of multiple myeloma and myelodysplastic syndromes. The lenalidomide solubility of metastable hydrate forms B and E were determined at 0.1 MPa with phosphoric acid solutions in the temperature ranging from 303.15 to 343.15 K. The solubility increased from 8.00 × 10−6 (B) to 9.99 × 10−3 (E) with the rise of temperature and the concentration of phosphoric acid. The solubility has been correlated by the UNIQUAC model, and the molecular interactions between different components in the solution were estimated. To further explain the solubility and understand the molecular interactions in the solutions, the molecular dynamics simulation was used to calculate lattice energy, solvation free energy, and Gibbs energy of solution during the dissolution process. • Phosphoric acid effectively improves the poor solubility of lenalidomide. • Solubility of lenalidomide polymorph was measured in phosphoric acid solution. • Thermodynamic analyses of polymorph were performed based on UNIQUAC model. • Molecular simulation revealed the solubility data of lenalidomide polymorph. [ABSTRACT FROM AUTHOR]

Solubility of d -glucosamine 2-sulfate sodium salt in water and binary aqueous mixtures with methanol, ethanol or n-propanol were firstly reported from 288.15 K to 318.15 K under 0.1 MPa. The results showed that the solubility of GS in water is about three orders of magnitude higher than its solubility in alcohols, and the solubility increases with increasing temperature and the composition of the alcohols. Thermodynamic properties of d -glucosamine 2-sulfate sodium salt, such as melting temperature, and decomposition temperature were determined by DSC and TGA. The solubility in various pure and binary solvents was correlated and compared by the modified Apelblat equation, Jouyban-Acree model, Wilson model, and NRTL model. Mixing thermodynamic properties, such as the mixing Gibbs energy, mixing enthalpy, and the mixing entropy of d -glucosamine 2-sulfate sodium salt in these solvents were estimated and analyzed. • Solubility of GS at 288.15 K to 318.15 K, increasing with T • Solubility at same temperature: in water > in methanol > in ethanol > in propanol • Composition of alcohols (antisolvent) increased: solubility in mixtures decreased • Modified Apelblat equation, Jouyban-Acree, Wilson, and NRTL model applied • Melting, combining with decomposition, started at 466.15 K. [ABSTRACT FROM AUTHOR]