NRTL-SAC Model Research Articles

Measurement of the solubility and density of the saturated solution of 3-aminophenol in different pure solvents from 283.1 to 323.1 K: Correlative to pure predictive thermodynamic modeling and molecular dynamic simulation

The solubility of 3-aminophenol was measured in water, isopropanol, ethyl acetate, chloroform, and tert-butyl methyl ether (MTBE) from 283.1 to 323.1 K at atmospheric pressure. In addition, the density of pure solvents and the saturated 3-aminophenol solutions was measured. The experimental solubility data were correlated and predicted using four types of thermodynamic models, including correlative (Wilson, NRTL, and UNIQUAC), semi-predictive (NRTL-SAC, and UNIQAUC-SAC), predictive group contribution methods (UNIFAC, and UNIFAC-DMD), and pure predictive COSMO-SAC model. The NRTL-SAC and UNIQUAC-SAC as semi-predictive models were used to obtain 3-aminophenol conceptual segment numbers, and then, using the NRTL-SAC model, the solubility of 3-aminophenol was predicted in 58 FDA approved solvents in the pharmaceutical industry. The predictive models including UNIFAC and UNIFAC-DMD were also used to predict the 3-aminophenol solubility and compared with the experimental data. The results of the COSMO-SAC model have a large deviation from experimental data. In addition, the experimental solubility data were correlated using the PR equation of state with relative success. The segment-based models such as NRTL-SAC and UNIQUAC-SAC are suggested in the fast solvent screening procedure. Finally, the standard dissolution enthalpy (ΔdisH), the standard dissolution entropy (ΔdisS), and the standard dissolution Gibbs energy (ΔdisG) of 3-aminophenol in the selected solvents were calculated by the Van’t Hoff model and the Gibbs-Helmholtz equation. These values imply that the solubility of 3-aminophenol is an entropy-driven non-spontaneous endothermic process in all chosen single solvents. Using the molecular dynamic (MD) simulation the solvation free energy of 3-aminophenol was calculated. The order of the absolute value of free energy of solvation is as ethyl acetate > isopropanol > MTBE > water > chloroform which is consistent with the order of solubility data.

Application of Thermodynamic Models to Predict the Solubility of Biologically Active Substances

Introduction. The choice of solvents for the processes of extraction of biologically active substances from natural raw materials, the processes of purification of natural and synthesized substances by extraction, crystallization and dissolution methods is an important problem of the modern pharmaceutical industry, because a large number of experiments must be performed to determine the optimal solvent or mixture of solvents. To reduce the cost of developing and optimizing the extraction and purification of substances stages, it is proposed to use thermodynamic models at the stage of preliminary solubility assessment. The article investigates predicting the solubility of pharmaceutical substances issue on the example of the technology for isolating hesperidin and glycyrrhizic acid from plant materials.Aim. Theoretical determination of the dissolving power of various solvents with respect to hesperidin and glycyrrhizic acid.Materials and methods. The PMUNIFAC and NRTL-SAC thermodynamic models were used to predict solubility. The solubility calculation for the NRTL-SAC model was performed using Aspen Properties V14 software, and for the PMUNIFAC model using PTC Mathcad Prime V6. To evaluate the results obtained using thermodynamic models, a number of experiments were carried out, the object of which was the peel of an orange (dried flavedo and albedo, the degree of grinding is 0.2–0.5 mm, the moisture content is 8 %). The quantitative content of hesperidin was determined by direct spectrophotometry at a wavelength of 290 nm. Statistical data processing was performed using Minitab v20 software (Minitab Inc., USA), differences were considered statistically significant at p < 0.05.Results and discussion. On the basis of thermodynamic models, the prediction of the solubility of hesperidin and glycyrrhizic acid was made. It has been shown that the solubility can be assessed both in the presence of solubility data according to the NRTL-SAC model, and in their complete absence according to PMUNIFAC. The correspondence of the theoretically calculated data to the experimental data confirms the correctness of the calculations of thermodynamic models. The results of the calculations are evaluated and solvents are recommended that can be used in the technology of isolating hesperidin and glycyrrhizic for the stages of degreasing, extraction and crystallization with the antisolvent.Conclusion. Using the NRTL-SAC and PMUNIFAC thermodynamic models, the dissolving power of various solvents with respect to hesperidin and glycyrrhizic acid was determined. From the calculation results, a list of solvents was built, ranked by the solubility of the studied substances in them. The resulting list can be used in the development of an industrial technology for the isolation and purification of hesperidin and glycyrrhizic acid. It is shown that the NRTL-SAC and PMUNIFAC models have good prospects for quantitative prediction of the solubility of active substances.

Research on solubility behavior of iminostilbene in twelve mono-solvents: Measurement, modeling, molecular simulation and thermodynamic properties

Iminostilbene (IMB) is an important pharmaceutical intermediate that can be used to prepare the antiepileptic drug omazepine. The measurement of solid–liquid equilibrium solubility parameters in various solvents can be employed for crystallization and separation processes of IMB. In this research, mole-fraction solubility of IMB in twelve individual organic solvents namely: “methyl acetate (MeAC), ethyl acetate (EtAC), n-propyl acetate (NPAC), isopropyl acetate (IPAC), n-butyl acetate (NBAC), isobutyl acetate (IBAC), N-methylpyrrolidone (NMP), acetone (DMK), N,N-dimethylformamide (DMF), acetonitrile (MeCN), N,N- dimethylacetamide (DMAC) and 1,4-dioxane (Diox)” was critically evaluated ranged from 278.15/288.15 K to 323.15 K at 0.1 MPa using laser monitoring method. Experimental solubility data had a general uptrend with the incremental temperature. Simultaneously, IMB solubility in selected mono-solvents showed an obvious order from high to low of: NMP > DMAC > DMF > Diox > DMK > NBAC > NPAC > EtAC > IBAC > IPAC > MeAC > MeCN. In order to explore dissolution behavior, Hirshfeld surface as well as molecular electrostatic potential surface (MEPs) were employed to analyze intermolecular interaction, and result indicated hydrogen bonding was easily formed on >NH group and its opposite position CHCH group. Meanwhile, Hansen solubility parameters (HSPs) were used to investigate solubility order, the result of which suggested that dispersion interaction could be the main factor influenced on solubility order in homologous solvents. Moreover, four activity coefficient models (Margules, UNIQUAC, NRTL, NRTL-SAC model) as well as a combined equation (Jouyban model) were applied for correlation of solubility data with twelve solvents. UNIQUAC model provided the highest regression accuracy among five models in terms of average relative deviation (ARD) lower than 1.178 % and root mean square deviation (RMSD) not higher than 1.176 ‰. Furthermore, based on UNIQUAC equation, thermodynamic properties including dissolution and mixing process were strictly evaluated for further research on solubility behavior. The results demonstrated that both of mixing and dissolution behaviors were spontaneous and entropically driven.

Investigation on solid–liquid equilibrium behavior of 4-cyanobenzoic acid in fourteen mono-solvents: Determination, correlation, molecular simulation and thermodynamic analysis

4-Cyanobenzoic acid (4-CyBZA) is an important pharmaceutical intermediate, and the research on solubility behavior of 4-CyBZA in organic solvents is very necessary for its crystallization and separation processes. Therefore, this study aimed at exploring dissolution behavior of 4-CyBZA in several pure solvents via experiment, calculation, and simulation process. In this study, mole-fraction solubility values of 4-CyBZA in fourteen common solvents including four low alcohols (methanol (MeOH), ethanol (EtOH), n-propanol (NPOH), n-butanol (NBOH)), four acetates (methyl acetate (MeAC), ethyl acetate (EtAC), n-propyl acetate (NPAC), n-butyl acetate (NBAC)), two alcohol ethers (2-ethoxyethanol (EGEE), 2-methoxyethanol (EGME)) as well as four common heteroatom/heterocyclic solvents (acetonitrile (MeCN), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), 1,4-dioxane (Diox)) were critically measured by using laser monitoring method from 278.15/288.15 K to 323.15 K under 100 kPa. Interestingly, experimental results indicated that an increase in temperature facilitated the dissolution of 4-CyBZA in selected 14 solvents. At the same time, the solubility curve underwent a crossover phenomenon. At 298.15 K, the common order of 4-CyBZA solubility was: DMF > EGME > EGEE > NMP > Diox > MeOH > MeAC > EtOH > EtAC > NPAC > NPOH > NBOH > NBAC > MeCN. The Hansen solubility parameter (HSP) was introduced to analyze solubility behavior via molecular similarity between 4-CyBZA and chosen solvents. Molecular modeling including Hirshfeld surface (HS) analysis and molecular electrostatic potential surface (MEPS) were employed to understand internal interactions within 4-CyBZA crystals. Moreover, solubility was fitted by Margules model, NRTL model, NRTL-SAC model, UNIQUAC model as well as a combined model (Jouyban model). Results showed that NRTL and NRTL-SAC model were more suitable for correlating 4-CyBZA solubility with absolute temperature. Furthermore, given the high accuracy of the NRTL model, dissolution thermodynamic characteristics of 4-CyBZA in chosen solvents were analyzed by NRTL model, which revealed that the dissolving process and mixing process were spontaneous and entropy-driven.

Modeling the Solubility of Monoterpenoids with Hybrid and Predictive Thermodynamic Tools.

The Abraham and NRTL-SAC semipredictive models were employed to represent the solubility of (-)-borneol, (1R)-(+)-camphor, l-(-)-menthol, and thymol in water and organic solvents, using data measured in this work and collected from the literature. A reduced set of solubility data was used to estimate the model parameters of the solutes, and global average relative deviations (ARDs) of 27% for the Abraham model and 15% for the NRTL-SAC model were obtained. The predictive capability of these models was tested by estimating the solubilities in solvents not included in the correlation step. Global ARDs of 8% (Abraham model) and 14% (NRTL-SAC model) were obtained. Finally, the predictive COSMO-RS model was used to describe the solubility data in organic solvents, with ARD of 16%. These results show the overall better performance of NRTL-SAC in a hybrid correlation/prediction approach, while COSMO-RS can produce very satisfactory predictions even in the absence of any experimental data.

Assessment of solid–liquid equilibrium behavior and thermodynamic analysis of natural plant extracts artemisinin (Form I) in twelve mono-solvents

Solid-liquid equilibrium solubility of artemisinin (ART) Form I in twelve mono-solvents namely N, N-dimethylformamide (DMF), oxolane (THF), n-propanol (NPA), 4-methylpentan-2-one (MIBK), ethyl formate (EF), butyl acetate (BAC), 2-ethoxyethanol (EGEE), 1,4-Dioxane, 2-methoxyethanol (EGME), 2-propoxyethanol (EGPE), propyl acetate (NPAC) and 2-butoxyethanol (EGBE) from 283.15 K to 323.15 K were determined by a laser dynamic method under 0.1 MPa. The minimum solubility of ART (Form I) was found in NPA at 283.15 K (0.004541), the maximum mole fraction solubility of ART (Form I) was observed as 0.2523 in DMF at 323.15 K. At the temperature of 298.15 K, the experimental mole fraction solubility order of ART Form I in the tested solvents was DMF (0.1559) > 1,4-Dioxane (0.09117) > THF (0.08301) > MIBK (0.05054) > EF (0.04902) > NPAC (0.03860) > BAC (0.03658) > EGME (0.02031) > EGEE (0.01859) > EGPE (0.01817) > EGBE (0.01689) > NPA (0.007185). The solubility behavior was computationally correlated by Margules model, Wilson model, NRTL model, NRTL-SAC model, Buchowski-Ksiazczak λh model and UNIQUAC model, the total RMSD was no>0.025 in the selected models. With the help of Hansen solubility parameters (HSPs) analysis, molecular similarities of ART (Form I) in twelve mono-solvents were investigated. Besides, Hirschfeld surface analysis (HSs) was considered to evaluate the intermolecular interaction of artemisinin. Moreover, thermodynamic properties including ΔmixH, ΔmixG, ΔmixS, lnγ1, lnγ1∞ of ART (Form I) in the selected solvents were estimated. All the negative ΔmixG and positive ΔmixS values indicated that the mixing process were spontaneous and entropy-increasing.

Solid-liquid equilibrium of 1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethenone in twelve mono-solvents: Solubility determination, Hansen solubility parameter and thermodynamic analysis

The mole fraction solubility of 1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethenone (1-HPE) in twelve mono-solvent systems namely “2-methoxyethanol (2-ME), methanol (MeOH), ethanol (EtOH), butan-1-ol (n-BuOH), 2-propoxyethanol (2-PE), propan-2-ol (i-PrOH), 2-methylpropan-1-ol (i-BuOH), Acetonitrile (MeCN), ethane-1,2-diol (EG), 2-ethoxyethanol (2-EE), propan-1-ol (n-PrOH), 2-butoxyethanol (2-BE)” were determined from 283.15 K to 323.15 K under 0.1 MPa. The experimental solubility order follows: 2-ME > 2-EE > 2-PE > 2-BE > MeOH > EtOH > n-PrOH > i-PrOH ≈ n-BuOH > i-BuOH ≈ MeCN > EG. The UNIQUAC model, modified Apelblat model, NRTL model, Wilson model, Jouyban model and NRTL-SAC model equation were used to correlate of 1-HPE solubility, and the average 104RMSD of them was 0.89, 1.21, 0.94, 4.72, 0.60 and 1.25, respectively. Furthermore, Hansen solubility parameters analysis (HSP) was used to evaluate the miscibility of 1-HPE in the selected solvents. Hirshfeld surface (HS) analysis was performed to discuss the electrostatic features and the patterns of intermolecular interactions of 1-HPE. Thermodynamic properties (ΔmixG, ΔmixS, ΔmixH, ΔdisG, ΔdisS, ΔdisH) were calculated by the UNIQUAC model. The calculated results indicated that the dissolution and mixing process of 1-HPE in the mono-solvents selected in this work was spontaneous and entropy increment.

Investigation on solubility behavior of 2-chloronicotinamide in ten mono-solvents: Measurement, correlation, molecular simulation and thermodynamic analysis

Solubility behavior as a significant molecular property should be known in the field of crystal form screening, dosage form along with separation and purification in the pharmaceutical industry. In this research work, solubility data of 2-chloronicotinamide (2-CNA) in ten pure solvents including methanol (MeOH), ethanol (EtOH), ethylene glycol (EG), 2-methoxyethanol (EGME), 2-ethoxyethanol (EGEE), methyl acetate (MeAc), water, 1,4-dioxane (Diox), N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMAC) within the range of 278.15/288.15 K to 323.15 K was experimentally determined by laser monitoring method at 0.1 MPa. Solubility of 2-CNA presented a positive correlation with temperature, and increased with incremental temperature. The result was indicative of a common tendency: DMAC > DMF > EGME > EGEE > EG > MeOH > Diox > EtOH > MeAc > water. The solvation free energy, molecular electrostatic potential surface (MEPS) and Hirshfeld surface were used to study the intermolecular interactions. Moreover, six mathematical models namely “Margules, UNIQUAC, NRTL, Wilson, NRTL-SAC and Jouyban model” were utilized to correlate solubility data of 2-CNA in mono-solvents. UNIQUAC model could provide maximum regression accuracy in correlation with solubility data among six models in terms of average relative deviation (ARD) and root mean square deviation (RMSD). Finally, thermodynamic parameters obtained from UNIQUAC equation indicated that all dissolution and mixing process were always entropy-increasing, endothermic and spontaneous.

Solubility, thermodynamic properties and molecular simulation of tinidazole in fourteen mono-solvents at different temperatures

The solubility properties of tinidazole (TNZ) in investigated fourteen mono-solvents were further studied at several temperature points (278.15 K ∼ 323.15 K) under 101.2 kPa using the laser monitoring technique. The selected solvents were acetone, methanol, ethanol, 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, 2-butoxyethanol, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, NMP, DMF, DMAC, respectively. The order of solubility of tinidazole in fourteen mono-solvents at 298.15 K is: NMP > DMAC > DMF > acetone > 2-methoxyethanol > methylacetate > 2-ethoxyethanol > ethyl acetate > 2-propoxyethanol > n-propyl acetate > 2-butoxyethanol > n-butyl acetate > methanol > ethanol. As shown by the solubility data of TNZ in chosen fourteen mono-solvents in this work, TNZ is more soluble in higher temperature. The KAT-LSER model and molecular dynamics simulation were adopted to probe the influence of solvent effects and solute–solvent interaction on TNZ solubility. The obtained solubility data of TNZ was fitted by (λh equation, NRTL model, NRTL-SAC model, two-Suffix Margules model, and UNIQUAC model). The results indicate that five models can fit the experimental values well, in which the NRTL-SAC model gives the best regression effect. Moreover, the apparent thermodynamic properties (△solG°, △solH° and △solS°) of TNZ in various solvents were calculated by Van’t Hoff equation. In accordance with the analysis and calculation of dissolution, the dissolution process is is entropy-motivated and endothermal.

Solubility, MD simulation, thermodynamic properties and solvent effect of perphenazine (Form I) in eleven neat organic solvents ranged from 278.15 K to 318.15 K

Perphenazine has rather effective in the treatment of mental illness. In this work, the solid-liquid equilibrium data of perphenazine in eleven organic neat solvents were determined by laser dynamic method under the atmospheric pressure and temperature range of 278.15 K ∼ 318.15 K. The selected solvents were n-propanol, n-butyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, n-amyl acetate, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), acetone, 2-methoxyethanol, glycol ether, respectively. From the results, the solubility of perphenazine is all positively correlated with temperature. Separately, we have adopted the KAT-LSER model and molecular dynamics simulation to investigate the influence of solvent effects and solute-solvent interaction on solute solubility. Meanwhile, there were four activity coefficient models being used to correlate the solubility data and Average relative deviation of models are 4.13% (Margules model), 3.94% (NRTL model), 4.49% (NRTL-SAC model) and 3.06% (UNIQUAC model), respectively, all of which do not exceed 5%. It manifests that the four activity coefficient models can fit the experimental values well, in which the UNIQUAC model gives the best regression effect. Moreover, the apparent thermodynamic properties(△solG°, △solH° and △solS°) of perphenazine in various solvents were calculated by Van’t Hoff equation. In accordance with the analysis and calculation of dissolution, the dissolution process is an endothermic entropy-driven process. This research can provide basic data for the crystallization process of perphenazine.

Solid-liquid equilibrium of 2,3-dimethoxybenzoic acid in fifteen mono-solvents: Determination, Correlation, Hansen solubility parameter, molecular dynamic simulation and thermodynamic analysis

This current research work was devoted to investigating solid–liquid equilibrium solubility, Hansen solubility parameters (HSPs), intermolecular interaction and thermodynamic analysis of 2,3-dimethoxybenzoic acid (o-veratric acid) in fifteen mono-solvent systems namely “water, methanol (MtOH), ethanol (EtOH), n-propanol (NPOH), isopropanol (IPOH), n-butanol (NBOH), methyl acetate (MtAC), ethyl acetate (EtAC), n-propyl acetate (NPAC), isopropyl acetate (IPAC), n-butyl acetate (NBAC), ethylene glycol monomethyl ether (EGME), ethylene glycol monoethyl ether (EGEE), 1,4-dioxane (Diox) and acetonitrile (MeCN)” by experimentation, mathematical relationships and molecular simulations. The measurement of solubility of o-veratric acid was conducted by laser monitoring method under 0.1 MPa, and corresponding measuring temperature range was 278.15 K to 323.15 K in most mono-solvents except Diox (288.15 K ∼ 323.15 K). The maximum of o-veratric acid solubility expressed in mole faction was found in Diox at 323.15 K (0.1717), while the minimum of solubility value was observed as 4.791e-3 in water at 278.15 K. At 298.15 K, o-veratric acid solubility in selected solvents had a general order of: Diox ≈ EGME > EGEE > MtOH > MtAC > EtOH > EtAC > MeCN > NPOH > NPAC > IPOH > NBOH > IPAC ≈ NBAC > water. Molecular similarities between o-veratric acid and fifteen selected mono-solvents were deeply considered with the help of HSPs concept. Moreover, solubility values were computationally expressed by Margules, Wilson, NRTL, NRTL-SAC and UNIQUAC model with the average relative deviation (ARD) of no higher than 5.365%. For explaining solubility behavior of o-veratric acid, molecular electrostatic potential surface, Hirschfeld surface as well as solvation free energy of o-veratric acid were analyzed by molecular simulation. Furthermore, the dissolution thermodynamic properties (ΔdisG, ΔdisH and ΔdisS) of o-veratric acid dissolving in selected solvents and mixing thermodynamic properties (ΔmixG, ΔmixH and ΔmixS) of o-veratric acid with fifteen solvents were estimated by UNIQUAC model, the results of which indicated the dissolution processes were spontaneous, endothermic as well as entropy increasing and mixing processes were spontaneous as well as entropy-increasing.

Pressure drop particle precipitation from a quasi-incompressible, ternary and liquid mixture

We found a quasi-incompressible and liquid mixture of ibuprofen, water and acetone, that enables the crystallization of ibuprofen particles by decreasing the pressure from 15MPa to ambient pressure (~0.1MPa). We measured the solubility of ibuprofen in the mixture as a function of the acetone/water-ratio for pressures of 0.1MPa, 5.5MPa and 15MPa and at 308K using the cloud point method. Based on the solubilities, binodal compositions of the ternary system were modelled using the NRTL-SAC model. The solubility of the drug in the mixture increases with increasing pressure at constant acetone/water-ratio. This pressure sensitive solubility can be exploited for the crystallization of ibuprofen particles via a pressure-drop approach. A pressure-drop from 15MPa to ambient pressure ~0.1MPa can result in a supersaturation of up to 1.43.

Thermodynamic analysis and molecular simulation of solid–liquid phase equilibrium of isoprenaline hydrochloride in eleven pure solvents at saturation

In this research, the solubility of isoprenaline hydrochloride (IPN) in eleven neat solvents was investigated by using experimental and molecular dynamic (MD) simulation analysis approaches. The experimental solubility data of IPN in eleven neat solvents of methanol, 2-methoxyethanol, ethanol, 2-ethoxyethanol, n-propanol, 2-propoxyethanol, n-butanol, 2-butoxyethanol, N, N-dimethylformamide (DMF), N-N-Dimethylacetamide (DMAC) and 1-Methyl-2-pyrrolidinone (NMP) were determined by laser monitoring method at temperature range of (278.15 K–323.15 K) under atmospheric pressure. The solubility values were sensitive to temperature, namely, increased monotonously with increasing temperature. The order of IPN solubility at each temperature point in selected solvents is: DMAC > DMF > NMP > methanol > 2-methoxyethanol > ethanol > 2-ethoxyethanol > 2-propoxyethanol > n-propanol > 2-butoxyethanol > n-butanol. Then, the measurement solubility data was correlated by Two-Suffix Margules model, NRTL-SAC model, Yaws model, λh equation and Apelblat equation, respectively. The derived apparent thermodynamic parameters (ΔdisGo, ΔdisHo, ΔdisSo, ζH, ζTS) shown an entropy-driven, endothermic and spontaneous process of dissolution of IPN in all chosen solvents. And the main contribution of ΔdisGo comes from the positive enthalpy according the larger ζH than ζTS. Furthermore, the results of molecular dynamic simulation revealed using radial distribution function (RDF) analysis, which indicated that interactions of solvent–solute have well fitted with solubility order of IPN in selected solvents.

Uridine in twelve pure solvents: Equilibrium solubility, thermodynamic analysis and molecular simulation

in this work, the solubility of uridine in twelve neat solvents was investigated by using experimental laser monitoring method and molecular dynamic (MD) simulation analysis approach. The experimental solubility data of uridine in twelve neat solvents, including methanol, 2-methoxyethanol, ethanol, 2-ethoxyethanol, n-propanol, 2-propoxyethanol, isopropanol, n-butanol, 2-butoxyethanol, ethylene glycol, N, N-dimethylformamide (DMF) and water, was measured at temperature range of (278.15 K–323.15 K) under atmospheric pressure. The solubility of uridine was sensitive to temperature in tested solvents, namely, increased monotonously with rising temperature. The order of uridine solubility at 298.15 K in selected solvents is DMF (0.1780) > water (0.04061) > 2-methoxyethanol (0.01565) > ethylene glycol (0.01399) >2-ethoxyethanol (0.006413) > methanol (0.003195) > 2-propoxyethanol (0.003005) > 2-butoxyethanol (0.002241) > isopropanol (0.001238) > ethanol (0.001086) > n-propanol (0.001047) > n-butanol (0.0009806). the measurement solubility data was correlated by NRTL model, NRTL-SAC model, UNIQUAC model, λh equation and Apelblat equation, respectively. The derived apparent thermodynamic parameters (ΔdisGo, ΔdisHo, ΔdisSo, ζH, ζTS) shown an entropy-driven, endothermic and spontaneous process of dissolution of uridine in all chosen solvents, and the main contribution of ΔdisGo comes from the positive enthalpy. Hansen solubility parameters (HSPs) were employed to reveal the solubility phenomenon of uridine in selected solvents. Furthermore, the results of molecular dynamic simulation revealed using radial distribution function (RDF) analysis, which indicated that interactions of solvent-solute have well fitted with solubility order of uridine in selected solvents.

Solid-liquid phase equilibrium of nimesulide (Form I) in twelve mono-solvents: Solubility determination, molecular dynamic simulation, solvent effect, model correlation and thermodynamic analysis

The equilibrium solubility of nimesulide (NIMS) in twelve single solvents was accurately measured by a laser monitoring method. It was indicated that the positive impact of experimental temperature on the solubility data of NIMS (Form I) in twelve mono-solvents within the investigated temperature range of 278.15–323.15 K under 101.3 KPa. The solubility shows a clear non-linear trend and decreased in the order methyl acetate > ethyl acetate >2-methoxyethanol > n-propyl acetate > n-butyl acetate >2-ethoxyethanol >2-propoxyethanol >2-butoxyethanol > methanol > ethanol > n-propanol > n-butanol. NIMS (Form I) has the highest solubility (x1 = 5.223e-2) in methyl acetate at 323.15 K and the smallest solubility (x1 = 6.800e-6) in n-butanol at 278.15 K. And then, the solvent polarity, radial distribution function obtained from molecular dynamic simulation and solvent effect (KAT-LSER model) were implemented to investigate the effect of solute-solvent interactions on solid-liquid phase equilibrium of NIMS (Form I). The results demonstrated that the whole dissolution behavior of NIMS (Form I) in organic solvents was a complicated process, and the solvent-solute interactions are mainly affected by the dipolarity/polarizability. Moreover, five widely used activity coefficient models including NRTL, NRTL-SAC, Wilson, Two-Suffix Margules, and UNIQUAC models had been fitted to experimental solubility data. Deviation analysis reveals that the UNIQUAC model reflects the best agreement between the measured data and calculated values, with the minimum mean values of 100ARD (0.89) and RMSD (1.22e-4). Finally, the thermodynamic parameters (ΔdisGo, ΔdisHo, ΔdisSo, ζH and ζTS) of NIMS (Form I) dissolution process in investigated 12 single solvents were evaluated based on the van't Hoff equation. The positive ΔdisGo, ΔdisHo and ΔdisSo indicate that the dissolution process of NIMS (Form I) is an entropy-driven non-spontaneous endothermic process in all chosen single solvents, and the ζH is the main contributor of ΔdisGo.

Solubility determination, model evaluation, Hansen solubility parameter and thermodynamic properties of N-hydroxyphthalimide in eleven neat solvents

The equilibrium solubility and thermodynamic properties of N-hydroxyphthalimide (NHPI) in n-propanol, 2-methoxyethanol, 1,4-dioxane, n-propyl acetate, ethanol, acetonitrile, methyl acetate, 2-ethoxyethanol, acetone, methanol and ethyl acetate were reported. Solubility determinations were performed through laser monitoring method in the temperature range of (278.15–323.15) K (except 1,4-dioxane at 288.15–323.15 K). It is found that the mole fraction solubility of NHPI increases apparently with augmented experimental temperature. The measured data is observed highest in 2-methoxyethanol (0.3807), followed by 2-ethoxyethanol (0.2601), 1,4-dioxane (0.2307), acetone (0.1260), methanol (0.06572), ethanol (0.06138), methyl acetate (0.05282), n-propanol (0.04670), acetonitrile (0.04141), ethyl acetate (0.03992), n-propyl acetate (0.03286) at “T = 298.15 K”. Various properties of materials including solvent polarity and Hansen solubility parameter of NHPI as well as selected solvents were summarized to analyze the solubility order of NHPI in studied solvents. The analysis consequence shows that solubility of NHPI in selected solvents is affected by multiple factors. Moreover, all recorded solubility was regressed by the modified Apleblat equation, Wilson model, NRTL model and NRTL-SAC model, attaining the average 100ARD (average relative deviation) value lower than 1.200 and average 104RMSD (root-mean square deviation) value lower than 1.550. Furthermore, analysis of thermodynamic properties indicates that the mixing and dissolution of NHPI in all considered cases are entropy-driven and spontaneous processes.

Solid-liquid phase equilibrium of busulfan in fifteen pure solvents: Solubility determination, solvent effect, model correlation and thermodynamic analysis

The equilibrium solubility and thermodynamic properties of busulfan in fifteen organic single solvents were reported. Solubility determinations were performed through the laser monitoring method at T = (278.15–323.15) K (except DMSO at 298.15–323.15 K) and p = 101.3 kPa. It can be found that the mole fraction solubility of busulfan increases apparently with the augmented experimental temperature. The solubility of busulfan in single solvents exhibits the following order from maximum to minimal at 303.15 K: NMP (4.870e−2) > DMSO (4.591e−2) > DMF (3.966e−2) > methyl acetate (4.502e−3) > 2-methoxyethanol (3.105e−3) > ethyl acetate (2.090e−3) > n-propyl acetate (1.367e−3) > 2-ethoxyethanol (1.280e−3) > n-butyl acetate (9.618e−4) > 2-propoxyethanol (6.930e−4) > 2-butoxyethanol (5.219 e−4) > methanol (3.787e−4) > ethanol (1.423e−4) > n-propanol (6.680e−5) > n-butanol (6.350e−5). The maximum value in busulfan solubility profile is related to DMSO at 323.15 K (x1 = 1.035 e−1) and the minimum one is obtained for n-butanol (6.800e−6, T = 278.15 K). The results of using KAT-LSER model to study the solvent effect of busulfan solubility in fifteen single solvents show that solute-solvent interactions are principally attributed to the dipolarity/polarizability interaction and the hydrogen bonding basicity. And then, the determined solubility values of busulfan have been fitted to five widely used thermodynamic models, namely, λh, modified Apleblat, NRTL, NRTL-SAC and UNIQUAC models. The calculated results via the five models were all consistent with the solubility values, indicating that all models could provide high fitting accuracy. Moreover, according to the results of apparent thermodynamic properties calculated by Van’t Hoff equation, it can be stated that the dissolution process of busulfan in all selected solvents is recorded as an endothermic, non-spontaneous process driven by entropy.

Solubility measurement, solubility behavior analysis and thermodynamic modelling of melatonin in twelve pure solvents from 278.15 K to 323.15 K

Solubility of melatonin in twelve mono-solvents including seven alcohols {methanol (MT), ethanol (ET), n-propanol (n-PrA), n-butanol (n-BT), i-butanol (i-BT), n-pentanol (n-PT) and n-hexanol (n-HeA)} and five esters {methyl acetate (MeAC), ethyl acetate (EtAC), n-propyl acetate (n-PrAC), n-butyl acetate (n-BtAC) and n-pentyl acetate (n-PtAC)} was determined by laser monitoring approach from 278.15 K to 323.15 K under 0.1 MPa. The experimental results indicate that the mole solubility of melatonin shows a positive relation with temperature variation. The solubility of melatonin in the twelve pure solvents at 298.15 K has order: MT (0.03570) > ET (0.02536) > n-PrA (0.01965) > n-BT (0.01524) > n-PT (0.01450) > i-BT (0.01267) > n-HeA (0.01136) > MeAC (0.008498) > EtAC (0.006587) > n-PrAC (0.004280) > n-BtAC (0.003410) > n-PtAC (0.02990). Moreover, the miscibility behavior of melatonin was further analyzed by the Hansen solubility parameter (HSP). The solvent effect of melatonin in tested pure solvents was investigated by using the KAT-LSER model. The four thermodynamic models including two-Suffix Margules, NRTL, NRTL-SAC and UNIQUAC models were applied to correlate the experimental solubility data of melatonin. Furthermore, the dissolution thermodynamic properties including the apparent standard dissolution enthalpy (ΔdisHo), the apparent standard dissolution entropy (ΔdisSo) and the apparent standard Gibbs energy change (ΔdisGo) of melatonin in investigated solvents were calculated by van't Hoff equation.

Solid-liquid phase equilibrium of trans-cinnamic acid, p-coumaric acid and ferulic acid in water and organic solvents: Experimental and modelling studies

The solubility of the trans isomers of cinnamic acid, p-coumaric acid and ferulic acid was measured in water and seven organic solvents (methanol, ethanol, 1-propanol, 2-propanol, 2-butanone, ethyl acetate and acetonitrile), at 298.2 K and 313.2 K, using the analytical shake-flask technique. The melting temperatures and enthalpies of the solutes were studied by differential scanning calorimetry, while solute solid structures were identified by powder and single X-ray diffraction.The NRTL-SAC model was applied to calculate the solubility of trans-cinnamic acid and trans-ferulic acid in pure solvents. For trans-p-coumaric acid, the NRTL-SAC was combined with the Reference Solvent Approach, as the solute melting properties could not be determined. The global average relative deviations (ARD) were 32% and 41%, in the correlation and prediction stages, respectively. The Abraham solvation model was also applied. The global ARD were 20% for correlation and 29% for predictions, which can be considered very satisfactory results for these semi-predictive models.

Piperonylonitrile solubility in thirteen pure solvents: Determination, Correlation, Hansen solubility parameter, solvent effect and thermodynamic analysis

This work was to investigate piperonylonitrile in terms of its solid–liquid equilibrium solubility in thirteen pure solvents by employing laser monitoring technique. Solubility measurements were completed in range of temperature at (288.15–323.15) K in 1,4-dioxane and at (278.15–323.15) K in isopropanol, 2-methoxyethanol, ethanol, ethyl acetate, methanol, n-propanol, n-propyl acetate, N,N-dimethylformamide (DMF), isopropyl acetate, methyl acetate, acetone as well as acetonitrile under 0.1 MPa. The holistic solubility profile showed that piperonylonitrile solubility in all measured solvents was proportional to the increasing of test temperature. It was also found that the mole-fraction solubility values of piperonylonitrile in measured solvents at 298.15 K exhibited a sequence of: DMF (0.2636) > 1,4-dioxane (0.2212) > methyl acetate (0.1838) > acetone (0.1813) > ethyl acetate (0.1657) > n-propyl acetate (0.1486) > acetonitrile (0.1435) > isopropyl acetate (0.1295) > 2-methoxyethanol (0.1010) > methanol (0.01915) > ethanol (0.01664) > n-propanol (0.01594) > isopropanol (0.01268). The miscibility and solubility order of piperonylonitrile were further revealed by the means of Hansen solubility parameter, demonstrating that solubility behaviors could be well explained by the comprehensive action of various solubility parameters. Besides, the influence on the piperonylonitrile solubility of solute–solvent interaction and solvent–solvent interaction was illustrated via the KAT-LSER model. It was figured out that hydrogen bonding acidity and hydrogen bonding basicity exerted unfavorable influence on piperonylonitrile solubility. Moreover, the measured piperonylonitrile solubility was fitted with Wilson, NRTL, UNIQUAC, Two-Suffix Margules and NRTL-SAC model, and correlation of experimental results with the use of five activity coefficient models showed that sufficient agreement with the calculated data. Finally, the thermodynamic quantities (ΔmixH, ΔmixG and ΔmixS) of the mixing process in different solvents were computed based on measured solubility values and UNIQUAC model. The results demonstrated that the mixing process was entropy-driven and spontaneous.