Solute-solvent Intermolecular Interactions Research Articles

Assessment of intermolecular interaction of mefenamic acid (Form II) in acetone and dimethylformamide (DMF) solution using molecular modelling technique

Solvent plays an important role in the solute-solvent intermolecular interactions of crystal morphology to regulate the crystal shape. Therefore, this work aims to assess the role of functional groups of solvents on the preferential sites on mefenamic acid (Form II) crystal surfaces, namely {001}, {011}, and {010} using the computational molecular modelling interactions techniques. The crystal morphology was successfully predicted as a plate-like crystal morphology using the BFDH method, and the molecular interactions of solutesolvent were assessed using the surface-docking method via Biovia Materials Studio software. The solute and solvent interactions along with surfaces used in this study disclosed that the {001} surfaces had the most negative non-bonded energy, followed by the {010} and {011} surfaces, ranging from −2036 to −2994 kcal/mol. Meanwhile, the binding energy values of acetone on all facets of interest were stronger compared to the binding energy of DMF, which possessed the binding energy of only less than −10 kcal/mol. Nevertheless, the results showed that acetone as a small molecule interacted most strongly with all facets of mefenamic acid (Form II) crystals because it could form stronger hydrogen bonds due to its ketone functional group, hence inhibited the growth of the mefenamic acid (Form II) crystal facets.

Solubility data and solubility parameters of barnidipine in different pure solvents

Introduction: Solubility studies and obtaining physicochemical data on drugs in pure solvents belonging to different chemical classes are key to developing new drug formulations. In this work, Hansen partial solubility parameters (HSP) were calculated to assess the miscibility and intermolecular interactions of barnidipine in seventeen pure solvents. The comparison of the results obtained with the theoretical values ​​calculated according to the structure of barnidipine, were valuable to analyse the influence of the solute-solute, solute-solvent relationships of the additive contribution groups, on the chemical and physical properties of this molecule with the solvents of different polarity tested, to provide relevant information highly useful in the pharmaceutical industry. Method: Equilibrium barnidipine solubilities in mono-solvents was determined using the classical shake-flask method, followed by UV-spectrophotometric analysis at 298.15 K. The partial solubility parameters were calculated by applying theoretical group contribution methods, proposed by Hoftyzer-Van Krevelen and Fedors. The KAT-LSER model was used to investigate the effect of solvent based on the concept of linear solvation energy relationships. The mole fraction was obtained from the densities of the solutions. Solid-phase analyses were made by calorimetry differential scanning. Results: The modification introduced in the extended Hansen method, that is, the use of lnX2 as the dependent variable, provided excellent results. The highest solubility values have been found in polar solvents. It is observed that solvent-solvent and solute-solvent intermolecular interactions through hydrogen bonds and van der Waals forces, significantly influence drug solubility. Conclusions: The affinity between barnidipine and each one of the selected solvent was evaluated by using HSP. Results showed that HSP could be well used to analyse drug solubility in particular solvents. Barnidipine is easier to dissolve in solvents with shorter carbon chains and higher polarity.

Prediction of cosolvent effect on solvation free energies and analysis of intermolecular forces of tizanidine hydrochloride in ethyl acetate + methanol / ethanol mixtures

The solubility of small molecule drug in solvents can be dramatically affected by addition of a suitable cosolvent, which makes the screening of the best-suited cosolvent an important task for the purification and preparation. The present work aims to improve the fundamental understanding of tizanidine hydrochloride (TIZ HC) solvation by cosolvent. Solubility experimental data from TIZ HCl in mixtures of ethyl acetate + alcohols were obtained at different temperatures with the method of isothermal equilibrium. In the system of ethyl acetate + methanol, the solubility data increased firstly and then decreased with an increase in ethyl acetate content, however, the strictly monotonic decreasing of solubility in ethyl acetate + ethanol mixtures was observed. The solubility correlation fitting was performed with the Jouyban-Acree model and CNIBS/R-K model. The solvent effect analysis indicates that the hydrogen bond acidity, the polarity / polarizability and the cohesive forces of the solvent have a greater influence on the solubility, which was further validated by the local quantitative molecular surface analysis results of electrostatic potential (ESP). The dissolution process of TIZ HCl in systems with different solvent compositions was analyzed in the form of preferential solvation parameters, it was found that methanol is the preferred solvent in the solvation shell of TIZ HCl in methanol-rich and ethyl acetate-rich mixtures but the ethanol is preferred in intermediate compositions and ethyl acetate-rich mixtures. Moreover, the types of intermolecular solute–solvent interactions were discussed on the basis of the structural characteristics of TIZ HCl. The solvation free energy is a key parameter describing solvent effects, which is extremely important for understanding solution chemistry. For this part, with the aid of density functional theory (DFT) and molecular dynamics (MD) simulations, it was found that the cosolvent effect is consistent with the prediction trend of solvation free energy of TIZ HCl in each systems. The effect of the cavity formed by the solvent molecules and dipole moment of solute was calculated accordingly by the solvation model based on density (SMD) for explaining the former behavior.

Thermodynamic analysis of nifedipine sublimation, dissolution and solvation

The saturated vapour pressure of the cardiovascular drug nifedipine is measured within the temperature range (390.15–404.15) K by the inert gas-carrier method. The thermodynamic functions of sublimation of the compounds are calculated at a reference temperature. The standard molar enthalpy of nifedipine sublimation is found to be equal to 144.8 kJ∙mol−1. The drug solubility in solvents modeling various media of the human body is determined in the temperature range (293.15–313.15) K. In the ascending order of solubility values of the studied compound, the solvents can be arranged as follows: buffer pH 7.4, buffer pH 2.0, n-hexane, 1-octanol. The solute–solvent intermolecular interactions are discussed based on the thermodynamic functions of solubility, solvation and transfer.

Molecular mechanism of liquid–liquid phase separation in preparation process of crystalline materials

Molecular mechanism of liquid–liquid phase separation (LLPS) before nucleation in the preparation of crystalline materials is not well understood. In this work, the evolutions of solute–solvent intermolecular interactions and molecular self-assembly before and after LLPS were investigated by using citicoline sodium as model compound. Raman spectroscopy and molecular dynamics simulation (MD) were applied to reveal different interactions. It was found that the solute–solvent intermolecular interactions were firstly enhanced and then weakened before and after LLPS, indicating that LLPS was caused by the enhanced solute–solvent intermolecular interactions. Solute molecules will self-assemble to form clusters in binary mixed solvents, according to the 2D 1H–1H NOESY measurements and small angle X-ray scattering (SAXS). The clusters will further self-assemble to form a dense liquid phase with the process proceeding. Based on these results, the molecular mechanism of LLPS was proposed and discussed.

Study of solute-solvent intermolecular interactions and preferential solvation for mevastatin dissolution in pure and mixed binary solvents

The solute-solvent and solvent-solvent interactions between mevastatin and different solvents were studied. In pure solvent, the largest solubility was found in 2-butanone (2.592×10−2) and minimum in cyclohexane (5.068×10−5) at 318.15 K. The non-specific and hydrogen bonding interactions including the dipolarity/polarizability (π*), Hildebrand solubility parameter (δH), hydrogen bond acidity (α) and hydrogen bond basicity (β) were analyzed. In mixture of (ethyl acetate + ethanol), the maximum solubility (2.144×10−2) is observed in 80%: 20% w/w of ethyl acetate: ethanol. Almost the same interaction energy and equilibrium mixing energy between solute and solvent promote the occurrence of co-solvency phenomenon. Moreover, according to the preferential solvation results, it is conjecturable that in intermediate composition mixtures and ethyl acetate-rich mixtures, mevastatin molecules are acting mainly as Lewis acid and Lewis base, respectively. Meanwhile, two thermodynamic models including modified Apelblat equation and Jouyban-Acree model are suitable to evaluate the dissolution profile, and the maximum value of relative average deviation is no >5%. The apparent thermodynamic properties of dissolution process in all investigated solvents are calculated which suggest that dissolution process is an endothermic process.

Solubility determination and correlation for spirotetramat in different solvent systems at T = 278.15–318.15 K

The solubility of spirotetramatin four binary solvents (methanol + water, ethanol + water, isopropanol + water, acetone + water) were studied by laser monitoring observation technique. The solubility data of spirotetramat in binary mixed solvents were subsequently fitted by the modified Apelblat model, λh model, Van't Hoff model, Jouyban-Acree model and NRTL model. The results showed that Apelblat model and Van't Hoff model were more suitable for fitting the solubility data. Furthermore, the effects of the solute–solvent intermolecular interactions on the solubility were analyzed using the KAT-LSER model. The results showed that the dipolar/polarizability of the solvent had the greatest influence on the solubility of spirotetramat.

Application of the Solute-Solvent Intermolecular Interactions as Indicator of Caffeine Solubility in Aqueous Binary Aprotic and Proton Acceptor Solvents: Measurements and Quantum Chemistry Computations.

The solubility of caffeine in aqueous binary mixtures was measured in five aprotic proton acceptor solvents (APAS) including dimethyl sulfoxide, dimethylformamide, 1,4-dioxane, acetonitrile, and acetone. The whole range of concentrations was studied in four temperatures between 25 °C and 40 °C. All systems exhibit a strong cosolvency effect resulting in non-monotonous solubility trends with changes of the mixture composition and showing the highest solubility at unimolar proportions of organic solvent and water. The observed solubility trends were interpreted based on the values of caffeine affinities toward homo- and hetero-molecular pairs formation, determined on an advanced quantum chemistry level including electron correlation and correction for vibrational zero-point energy. It was found that caffeine can act as a donor in pairs formation with all considered aprotic solvents using the hydrogen atom attached to the carbon in the imidazole ring. The computed values of Gibbs free energies of intermolecular pairs formation were further utilized for exploring the possibility of using them as potential solubility prognostics. A semi-quantitative relationship (R2 = 0.78) between caffeine affinities and the measured solubility values was found, which was used for screening for new greener solvents. Based on the values of the environmental index (EI), four morpholine analogs were considered and corresponding caffeine affinities were computed. It was found that the same solute–solvent structural motif stabilizes hetero-molecular pairs suggesting their potential applicability as greener replacers of traditional aprotic proton acceptor solvents. This hypothesis was confirmed by additional caffeine solubility measurements in 4-formylmorpholine. This solvent happened to be even more efficient compared to DMSO and the obtained solubility profile follows the cosolvency pattern observed for other aprotic proton acceptor solvents.

The co-solvency and thermodynamic properties of camptothecin in mixtures of (ethyl acetate + methanol/ethanol)

The solubility profile, molecular interactions and apparent dissolution thermodynamic properties of camptothecin in mixtures of (ethyl acetate + methanol) and (ethyl acetate + ethanol) was studied at the temperature range from T = (273.15 to 318.15) K under 101.3 kPa. In two mixtures, the solubility profile increased firstly and then decreased with the increasing mass fraction of ethyl acetate. In mixture of (ethyl acetate + methanol) at 318.15 K, it reached a maximum (9.176 × 10-5) in mole fraction when the mass fraction of ethyl acetate (w) = 0.80, and 7.554 × 10-5 in mixture of (ethyl acetate + ethanol) at w = 0.60. The Jouyban-Acree model and CNIBS/R-K model were applied to evaluate the solubility profile. The relative average deviation (RAD) data of Jouyban-Acree model in mixture of (ethyl acetate + methanol) was 3.81%, and 5.50% in mixture of (ethyl acetate + ethanol). However, it was no more than 3.59% for CNIBS/R-K model. The CNIBS/R-K model was more consistent than Jouyban-Acree model. In addition, the KAT-LSER model was used to analyse the effect of the solute–solvent intermolecular interactions on solubility profile. Furthermore, apparent dissolution thermodynamic analysis of camptothecin in mixtures of (ethyl acetate + methanol) and (ethyl acetate + ethanol) at the mean harmonic temperature was also performed. The results indicated that the dissolution process was endothermic and entropy-increasing, and the enthalpy is the main contributor to standard free energy of solution process.

Measurement and correlation of the solubility of 3-methoxybenzoic acid in fourteen mono-solvents at temperatures from 278.15 K to 323.15 K

A gravimetric method was used to determine the equilibrium solubility of 3-methoxybenzoic acid (3MBA) in 14 kinds of organic mono-solvents (methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, formic acid, acetic acid, ethyl formate, methyl acetate, ethyl acetate, iso-propyl acetate, butyl acetate) from 278.15 K to 323.15 K at 0.1 MPa. In all the solvent systems studied, the solubility increases monotonously with the increasing of temperature. In addition, the effect of solvent properties on solid–liquid equilibrium of 3MBA was investigated. The results show that dissolving process of 3MBA in solvent is a complex process, which is affected by the action of solvent properties; Correlation analysis found that the solvent properties containing hydrogen bond donation (α), hydrogen bond acceptance (β), polarity index (ET30), Hildebrand solubility parameter (δH), cohesive energy density and surface tension process great influence on the dissolving behavior of 3MBA. And then, topological index (H) which can reflect the molecular structure information of the solvents was calculated. It was found that the solubility of 3MBA decreased with the increasing of H values in alcohol and ester solvents, and increased with the increasing of H values in carboxylic acid solvents. Besides, the solubility of 3MBA were related to the modified Apelblat model, λh model, van’t Hoff model and NRTL model, and the modified Apelblat model gave the best correlation results, with the ARD% of 0.68%. In addition, COSMO-RS model was used to calculate the σ-profiles and solvation free energy of selected solute–solvent systems, σ-profiles analysis was qualitatively described the intermolecular interaction, it was found that the solubility of 3MBA in the selected solvents was correlated with the solute–solvent intermolecular interactions; Solvation free energy was calculated in the “Molar” framework and found that the solubility of 3MBA in alcohols, esters and carboxylic acids decreased with the decreasing of the absolute value of the solvation free energy.

Prediction of the hydrophobicity of platinum(IV) complexes based on molecular surface properties

A quantitative structure–property relationship (QSPR) study was performed for predicting the hydrophobicity of Pt(IV) complexes. Two four-parameter equations, one based solely on structural descriptors derived from electrostatic potentials (ESPs) on molecular surface, and the other integrated ESP descriptors with molecular surface area (AS), were firstly constructed. Mechanistic interpretations of the structural descriptors introduced were elucidated in terms of solute-solvent intermolecular interactions. Subsequently, several up-to-date modeling techniques, including support vector machine (SVM), least-squares support vector machine (LSSVM), random forest (RF) and Gaussian process (GP), were utilized to build the nonlinear models. Systematical validations including leave-one-out cross-validation, the validation for test set, as well as a more rigorous Monte Carlo cross-validation were performed to verify the reliability of the constructed models. The predictive performances of the four different nonlinear modeling methods follow the order of LSSVM≈GP > RF > SVM. The pure-ESP-based models are generally inferior to the AS-integrated ones. Comparisons with previous results were made.

Gatifloxacin–Ionic Surfactant Interactions: Volumetric, Acoustic, Voltammetric, and Spectroscopic Studies

AbstractSurfactant systems have been frequently used as pseudomodels for investigating interactions of drugs with biological membranes because of their structural similarities with the latter. This helps to understand complicated yet very important biological processes like diffusion of bioactive moieties through biomembranes. The current study deals with voltammetric and spectroscopic studies to evaluate the interaction of a potential antibacterial drug, gatifloxacin (GTF), with a cationic surfactant, dodecyltrimethylammonium bromide (DTAB), and an anionic surfactant, sodium dodecyl sulfate (SDS), under physiological conditions (phosphate buffer, pH 7.4). For more detailed insight into the GTF–ionic surfactant interactions, density and acoustic data were also recorded and used to calculate several important parameters, namely, apparent molar volume (ɸV), isentropic compressibility (Ks), and apparent molar isentropic compressibility (ɸK) at T = 298.15, 303.15, 308.15, and 313.15 K. Values for partial molar volume (, partial molar expansivity , specific acoustic impedance (Z), relative association (RA), intermolecular free length (Lf), and sound velocity number (U) were also obtained. The interpretation of the concentration dependence of the above‐mentioned quantities using a cosphere overlap model led to a better apprehension of solute–solute and solute–solvent intermolecular interactions present in the investigated system, whereas cyclic voltammetry and ultra violet (UV)–visible spectroscopic studies assisted in predicting the location of adsorbed GTF molecules within the DTAB and SDS micelles.

Preferential solvation of pomalidomide, an anticancer compound, in some binary mixed solvents at 298.15 K

Abstract Preferential solvation of pomalidomide (PMD) was explored in dimethyl sulfoxide (DMSO)-dimethylformamide (DMF), DMSO-tetrahydrofuran (THF), DMSO-methanol (MeOH), DMSO-isopropanol, DMSO-water, water-DMF, water-THF, water-MeOH, and water–isopropanol binary mixed solvents at 298.15 K. Bosch-Rose model was utilized to determine the electronic transition energies (ET) and other preferential solvation parameters, describing solute-solute and solute-solvent interactions. We found that λmax situation shifted with dielectric constant of the pure solvents meaningfully. According to the obtained results, ET enhanced and λmax shifted to the lower wavelengths as the percentage of DMSO decreased in the binary mixtures, remarking the important role of DMSO for stabilizing the excited state (π⁎) of PMD chromophore via efficient intermolecular solute-solvent interactions. In addition, the aqueous binary systems showed an optimum point for the ET values as the percentage of water changed in the solutions. The local mole fraction of the solvents in the cybotactic region was also estimated to describe the specific and non-specific interactions in the systems.

Improvement of solubility and analysis thermodynamic properties of β tegafur in pure and mixed organic solvents

The purpose is to study the dissolution behaviour for β form of racemic tegafur with therapeutic purpose in different solvent, and select suitable co-solvent to improve dissolving capacity. Before and after experiment, tegafur existed in the form of β in all studied solvents. The solubility values were obtained by using the isothermal equilibrium method and correlated with the modified Apelblat equation and Jouyban-Acree model. In pure solvent, the largest data at 313.15 K was found in acetone (3.875 × 10−2 in mole fraction), and followed by ethyl acetate (1.748 × 10−2), methanol (1.255 × 10−2), ethanol (0.767 × 10−2), n-propanol (0.618 × 10−2) and isopropanol (0.545 × 10−2). In systems of (acetone + ethanol), the solubility increased monotonically with the increase of temperature and acetone mass fraction. While in mixture of (ethyl acetate + ethanol), it increased at first and then decreased with the increasing mass fraction of ethyl acetate. Moreover, the effect of the solute-solvent intermolecular interactions on the solubility in pure and mixed solvents was discussed. In the following, the analysis of apparent thermodynamic analysis indicates that the dissolution is an endothermic, spontaneous and entropy driven process. More importantly, the effect of co-solvent on the dissolution process of β tegafur is important to its recrystallization and purification.

The dissolution behaviour and thermodynamic properties calculation of praziquantel in pure and mixed organic solvents

The purpose is to study the dissolution behaviour for praziquantel in different solvent. The dissolution capacity within the temperature range from 273.15 K to 313.15 K was researched by using the isothermal equilibrium method and evaluated with the modified Apelblat equation, λh equation and Jouyban-Acree model. In pure solvents, the largest values were found in N-methyl pyrrolidone (NMP, 8.106 × 10−2 in mole fraction) at 313.15 K, and followed by cyclohexanone (5.964 × 10−2), toluene (3.842 × 10−2), acetonitrile (3.519 × 10−2), acetone (3.001 × 10−2), ethyl acetate (2.896 × 10−2), n-octanol (2.715 × 10−2), isopropanol (1.882 × 10−2) and n-hexane (4.379 × 10−2). While in mixtures of (NMP + isopropanol), the solubility capacity increased monotonically with the increase of temperature and NMP mass fraction. KAT-LSER method was applied to analyse the effect of solute–solvent intermolecular interactions on the solubility in pure solvents. More importantly, the selection of appropriate solvents for praziquantel dissolution is important to its application. Moreover, the effect of the solute–solvent intermolecular interactions on the solubility in pure and mixed solvents was discussed as well. In the following, the analysis of apparent thermodynamic analysis indicates that the dissolution is an endothermic, spontaneous and entropy driven process.

Solid-liquid equilibrium and thermodynamic properties of dipyridamole form II in pure solvents and mixture of (N-methyl pyrrolidone + isopropanol)

The solid–liquid equilibria of a poorly soluble drug namely dipyridamole were assayed to determine solubility in pure and binary mixtures between 273.15 K and 313.15 K under atmospheric pressure. The solubility profiles of dipyridamole in pure and mixed solvents were evaluated by some thermodynamic models. The maximum solubility in mole fraction was obtained in pure N-methyl pyrrolidone (NMP) in all tested solvents. In mixtures of (NMP + isopropanol), the values increased monotonically with the increasing temperature and mass fraction of NMP. The Kamlet, Abboud and Taft Linear Solvation Energy Relationship (KAT-LSER) model was applied to analyze the effect of the solute–solvent intermolecular interactions on the solubility. The results of dissolution thermodynamic properties indicate that the dissolution behavior were endothermic and entropy-driven in all tested solvents. The experimental solubility data and mathematically correlated equations of dipyridamole estimated in this work may be useful for studies on the crystallization process of the final step of dipyridamole synthesis, for the purification dipyridamole of pharmaceutical applications.

Analysis of solubility parameters of fenbendazole in pure and mixed solvents and evaluation of thermodynamic model

In this work, the purpose is to improve the solubility of fenbendazole by co-solvent, and study the effects of solubility parameters of solvents and solute on the solubility of objective compound. The solubility of fenbendazole in pure and mixed solvents was experimentally determined and correlated by some thermodynamic models. As expected, the mole fraction solubility increased with increasing temperature, and at 298.15 K, it was ranked in the following order: 1,4-dioxane > ethyl acetate > acetone > 1-butanol > n-propanol > ethanol > methanol > isopropanol > acetonitrile. Moreover, Hansen solubility parameter was applied to analyze the effect of solute-solvent intermolecular interactions on the solubility in pure solvents. Meanwhile, in order to estimate maximum solubility in the co-solvent in appropriate ratios, the solubility parameter of the mixtures was evaluated as well. In addition, based on the experimental solubility data, the correlation results of fenbendazole in pure and mixed solvents were described mathematically by using statistical analysis.

Dissolution behavior and thermodynamic properties of lapatinib ditosylate in pure and mixed organic solvents from T = (283.15–323.15) K

The purpose of this work is to study the dissolution behavior of lapatinib ditosylate (LB-DT) in different solvents and determine the suitable solvent and composition to improve dissolving capacity. In selected pure organic solvents, LB-DT exists in the form of anhydrous. The largest solubility data was found in acetone and lowest in toluene at the determined temperature, and it decreases as the following order: acetone > tetrahydrofuran (THF) > acetonitrile > n-propanol > isopropanol > 1-butanol > ethyl acetate > toluene. While in mixture of THF aqueous, it exist the form of monohydrate, and the solubility increases at first and then decreases with the increasing mass fraction of THF. The composition dependence of the solubility has a maximum around w = 0.6 at all investigated temperatures. The (KAT-LSER) model was applied to analyze the effect of the solute-solvent intermolecular interactions on the solubility in pure organic solvents. A series of models based on solubility parameter and the solid-liquid equilibrium equation were employed to provide insight to data. In the following, the analysis of apparent thermodynamic properties indicates that the dissolution process is apparently not only endothermic but also entropy-driving.

Design of arginine-based therapeutic deep eutectic solvents as drug solubilization vehicles for active pharmaceutical ingredients.

The solvation of lidocaine in three newly designed deep eutectic solvents is studied using combined experimental and theoretical methods that include density functional theory and molecular dynamics methods. The intermolecular forces between lidocaine and the hydrogen bond acceptors and hydrogen bond donors of the deep eutectic solvents were analysed regarding the type and the strength of inter- and intra-molecular bonding. The structure, composition and properties of the lidocaine solvation shells are analysed together with the possible lidocaine-clustering around the studied deep eutectic solvents and their constituent molecules. Furthermore, the changes in the solvent structures upon lidocaine solubilization are also studied. Natural product-based eutectic solvents showed considerably high solvation of lidocaine in all three deep eutectics based on the strong solute-solvent intermolecular interactions accompanied by a slight volume expansion and minor solvent structural changes. These non-toxic and almost null-volatile therapeutic deep eutectic solvents can be considered as suitable solubilization media for developing pharmaceutical applications and they can be considered as effective drug delivery vehicles for active pharmaceutical ingredients.

Solubility parameter of lenalidomide for predicting the type of solubility profile and application of thermodynamic model

The dissolving capacity of lenalidomide in pure and mixed solvents is limited. The purpose of this work is to enhance the solubility and study the solubility parameter of pure and mixtures (δ1) to characterize different types of solubility profiles. The solubility of lenalidomide in acetonitrile (MeCN), methanol (MT), ethanol (EA), ethyl acetate (EAC) and isopropanol (IPA) was experimentally determined at T = 293.15–333.15 K. Its solubility in binary mixtures of EA and EAC was also investigated. The polarity of lenalidomide is related to the tendency of the solubility data against the solubility parameter δ1 of pure and binary solvent mixtures. Consequently, the method of linear solvation energy relationships introduced by Kamlet, Abboud and Taft (KAT-LSER) was applied to analyze the effect of the solute-solvent intermolecular interactions on the solubility in pure solvents. In order to estimate maximum solubility in a specific co-solvent ratio, we also attempt to calculate the Hansen solubility parameter (HSP) of lenalidomide and to compare it with HSP of solvent mixture. Based on the experimental solubility data, two thermodynamic models including modified Apelblat equation and Jouyban-Acree model were then assessed. Meanwhile, a modification of the extended Hildebrand solubility approach (EHSA) including the Hildebrand solubility parameter (δ1) and the acidic and basic partial solubility parameters (δ1a and δ1b) of the solvent mixtures was used to simulate lenalidomide solubility in pure and binary mixture compositions.