Nonpolar Moieties Research Articles

Synthesis and properties of highly organosoluble and low dielectric constant polyimides containing non-polar bulky triphenyl methane moiety

Novel fluorinated aromatic polyimides were prepared by the conventional two-step imidization of 4.4′-(hexafluoroisopropylidene) diphthalic anhydride (6FDA) and diamines (TriPMPDA and TriPMMDA) bearing triphenyl methane moiety. Both of the flexible and tough polyimide films exhibited an intrinsic low dielectric constant (low-k) values of 2.56 and 2.33 at the frequency of 10kHz, respectively, due to the introduction of the bulky triphenyl methane side groups and the tortuous backbone structures. In addition, they showed light color, high thermal stability, moderate mechanical property, and more importantly, excellent solubility in common organic solvents (even completely dissolved in dichloromethane and chloroform). Thus, both of the functional polyimides possessed attractive potential applications in the field of high performance flexible polymer interlayer materials.

Towards a molecular level understanding of the sulfanilamide-soil organic matter-interaction

Sorption experiments of sulfanilamide (SAA) on well-characterized samples of soil size-fractions were combined with the modeling of SAA-soil-interaction via quantum chemical calculations. Freundlich unit capacities were determined in batch experiments and it was found that they increase with the soil organic matter (SOM) content according to the order fine silt > medium silt > clay > whole soil > coarse silt > sand. The calculated binding energies for mass-spectrometrically quantified sorption sites followed the order ionic species > peptides > carbohydrates > phenols and lignin monomers > lignin dimers > heterocyclic compounds > fatty acids > sterols > aromatic compounds > lipids, alkanes, and alkenes. SAA forms H-bonds through its polar centers with the polar SOM sorption sites. In contrast dispersion and π-π-interactions predominate the interaction of the SAA aromatic ring with the non-polar moieties of SOM. Moreover, the dipole moment, partial atomic charges, and molecular volume of the SOM sorption sites are the main physical properties controlling the SAA-SOM-interaction. Further, reasonable estimates of the Freundlich unit capacities from the calculated binding energies have been established. Consequently, we suggest using this approach in forthcoming studies to disclose the interactions of a wide range of organic pollutants with SOM.

Thermodynamic Study of the Solubility of Naproxen in Some 2-Propanol + Water Mixtures

The equilibrium solubilities of the anti-inflammatory drug naproxen (NPX) in 2-propanol + water mixtures were determined at several temperatures from 298.15 to 313.15 K. The Gibbs energy, enthalpy, and entropy of solution and of mixing were obtained from these solubility data. The solubility was maximal in φ1 = 0.90 and very low in pure water at all the temperatures studied. A non-linear plot of ∆solnH° vs. ∆solnG° with negative slope from pure water up to 0.20 in volume fraction of 2-propanol and positive beyond this composition up pure 2-propanol was obtained at the mean temperature, 305.55 K. Accordingly, the driving mechanism for NPX solubility in the water-rich mixtures was the entropy, probably due to water-structure loss around non-polar moieties of the drug and for the 2-propanol-rich mixtures it was the enthalpy, probably due to its better solvation of the drug.

Adsorption efficiency of a continuous trapping system and its use for the collection of root exudates from cucumber

Root exudates comprising soluble low-molecular-weight organic compounds (LMWOCs) play a crucial role in the rhizosphere processes. Therefore, accurate determination of the composition and quantity of these compounds is of importance. A continuous trapping system (CTS) with XAD-4 macroporous resin is widely used for collecting root exudates in hydroponics, and ion exchange resins are used in the separation of root exudates into neutral, acid and basic fractions. Here, we studied the adsorption equilibrium isotherms and dynamic adsorption properties of 27 standard LMWOCs on XAD-4 resin. The adsorption isotherms of most LMWOCs matched the Langmuir isotherm equations. Furthermore, we investigated the adsorption efficiency of the CTS for LMWOCs and the recovery ratios during fractionation by ion exchange resins. The adsorption capacities of the CTS for LMWOCs which are non-polar or having large non-polar moieties were higher. The recovery ratios of most LMWOCs were larger than 80% during fractionation. The overall recovery ratios of LMWOCs were ca. 10, 20, and 30% for sugars, organic acids, and amino acids, respectively. Using this collection method, we present the composition and quantity of root exudates of cucumber (Cumumis sativus L.) at four different growth stages. The major components of root exudates were similar to previous works, whereas the quantities were different. The various collection methods may be the main reason for these differences. Therefore, it is necessary to study the overall recovery ratios when the compositions of root exudates via different collection methods are compared.

"Hydration Shells" of CH2 Groups of ω-Amino Acids as Studied by Deuteron NMR Relaxation.

Hydration phenomena play a very important role in various processes, in particular in biological systems. Water molecules in aqueous solutions of organic compounds can be distributed among the following substructures: (i) hydration shells of hydrophilic functional groups of molecules, (ii) water in the environment of nonpolar moieties, and (iii) bulk water. Up to now, the values of hydration parameters suggested for the description of various solutions of organic compounds were not thoroughly analyzed in the aspect of the consideration of the total molecular composition. The temperature and concentration dependences of relaxation rates of water deuterons were studied in a wide range of concentration and temperature in aqueous (D2O) solutions of a set of ω-amino acids. Assuming the coordination number of the CH2 group equal to 7, which was determined from quantum-chemical calculations, it was found that the rotational correlation times of water molecules near the methylene group is 1.5-2 times greater than one for pure water. The average rotational mobility of water molecules in the hydration shells of hydrophilic groups of ω-amino acids is a bit slower than that in pure solvent at temperatures higher that 60 °C, but at lower temperatures, it is 0.8-1.0 of values of correlation times for bulk water. The technique suggested provides the basis for the characterization of different hydrophobic and hydrophilic species in the convenient terms of the rotational correlation times for the nearest water molecules.

Oxyethylene chain length affects the physicochemical properties of sugar-based anionic surfactants with phosphates groups

In this study we prepared a series of novel sugar based anionic-polyoxyethylene stearyl ether surfactants through reactions of propylene glycol dextrin with oxirane-containing polyoxyethylene stearyl ethers and phosphorus oxychloride. These surfactants, which contain polyoxyethylene chains and sodium phosphonate groups as hydrophilic moieties, exhibited surface activities superior to those of traditional surfactants containing only one nonpolar or hydrophobic moiety and one polar head unit. The critical micelle concentration (cmc), surface excess concentration at the surface (Γcmc) and standard free energy of micellization per mole (ΔGm°) of these surfactants decreased upon increasing the length of their polyoxyethylene chain. In addition, we used UV–vis spectroscopy to study the interactions of dyes with these sugar based anionic surfactants in solution, the results shows that the interaction of the dye and surfactant molecules and the type of dye–surfactant aggregate formed will depend upon chemical structure of dye and surfactant.

Investigation of bovine serum albumin-surfactant aggregation and its physicochemical characteristics

Abstract The mechanism of the formation of aggregates between a protein, bovine serum albumin (BSA), and alkyltrimethylammonium bromides of varied hydrocarbon chain lengths, namely, cetyltrimethylammonium bromide (CTAB), tetradecyltrimethylammonium bromide (TTAB), and dodecyltrimethylammonium bromide (DTAB) in an aqueous solution and the physicochemical characteristics of the aggregates were systematically investigated by surface tensiometry, fluorimetry, UV–vis spectrometry, dynamic light scattering, zeta potential, and differential scanning calorimetry (DSC). The surface tension and fluorimetry data indicate a steady decrease in the critical micelle concentrations of the surfactants with an increase in the amount of BSA in the mixture. The evolution of an additional nonpolar segment in the backbone of BSA was indicated by the fluorescence of pyrene and the intrinsic fluorescence of BSA as well. The decrease in the aggregation number, increase in the area per molecule of the surfactant at the interface with a concomitant increase in the hydrodynamic radius of the aggregate were attributed to the formation of BSA–surfactant mixed aggregate and the induction of the unfolding of BSA by the surfactants. The DSC study and nature of the denaturation curves of BSA indicate that the stability of the BSA–surfactant complex follows the order: CTAB > TTAB > DTAB. The neutralization of the negatively charged surface of BSA by the positively charged surfactants is evident from the zeta potential measurements. Both the head group and nonpolar moiety of the surfactants affected the surface charge of the aggregates and the studied surfactants denature and unfold BSA; the extent of denaturation is predominately decided by the hydrocarbon chain length of the former. The in situ unfolding of the protein and the subsequent formation of the aggregates are proposed. The characteristic parameters of the aggregates were determined.

Relationships between human intestinal absorption and polar interactions drug/phospholipids estimated by IAM–HPLC.

Phospholipid affinity indexes (logkWIAM) for 15 structurally non-related basic, acidic, ampholytic, and neutral drugs were measured by HPLC on two different phospholipid stationary phases (immobilized artificial membrane – IAM). According to a method we previously proposed, polar and electrostatic forces involved in drug/membrane interactions were quantified both as ΔlogkWIAM and as Δ′logkWIAM. These values are the differences between the experimental logkWIAM and the values expected for a neutral compound having the lipophilicity value equal to either that of the neutral form of the analyte (logPN) or that of the mixture of charged and neutral forms of the analyte at jejunum pH 6.5 (logD6.5), respectively. Jejunum absorption values, logPeff, measured by the Loc-I-Gut technique, did not relate with logkWIAM values. A moderate linear relationship was observed with logPN values for all the analytes and a weak parabolic relationship was observed with logD6.5 values, but only after the exclusion of two analytes. In contrast, a highly significant linear inverse relationship was observed with ΔlogkWIAM values. Therefore, differently from the results of our recent studies on blood–brain barrier passage, the intestinal absorption data for not only bases and zwitterions but also for acids relate significantly with ΔlogkWIAM and not with Δ′logkWIAM values.The results suggest that membrane passage at jejunum level can be described according to the “flip-flop” model; indeed, the lipophilicity of the neutral forms (logPN) appears related to the passage through the non-polar inner moieties of phospholipids whereas ΔlogkWIAM parameter appears related to the “trapping” forces at their polar surfaces.The method, easy to perform and at medium throughput, could be of use for preliminary screening of new drugs based on oral absorption potential.

Sorption mechanism and predictive models for removal of cationic organic contaminants by cation exchange resins.

Understanding the sorption mechanism of organic contaminants on cation exchange resins (CXRs) will enable application of these resins for the removal of cationic organic compounds from contaminated water. In this study, sorption of a diverse set of 12 organic cations and 8 neutral aromatic solutes on two polystyrene CXRs, MN500 and Amberlite 200, was examined. MN500 showed higher sorbed concentrations due to its microporous structure. The sorbed concentrations followed the same trend of aromatic cations > aliphatic cations > neutral solutes for both resins. Generally, solute-solvent interactions, nonpolar moiety of the solutes, and resin matrix can affect selectivity of the cations. Sorbed concentrations of the neutral compounds were significantly less than those of the cations, indicating a combined effect of electrostatic and nonelectrostatic interactions. By conducting multiple linear regression between Gibbs free energy of sorption and Abraham descriptors for all 20 compounds, polarity/polarizability (S), H-bond acidity (A), induced dipole (E), and electrostatic (J(+)) interactions were found to be involved in the sorption of the cations by the resins. After converting the aqueous sorption isotherms to sorption from the ideal gas-phase by water-wet resins, a more significant effect of J(+) was observed. Predictive models were then developed based on the linear regressions and validated by accurately estimating the sorption of different test set compounds with a root-mean-square error range of 0.91-1.1 and 0.76-0.85 for MN500 and Amberlite 200, respectively. The models also accurately predicted sorption behavior of aniline and imidazole between pH 3 and 10.

Understanding and Modeling Removal of Anionic Organic Contaminants (AOCs) by Anion Exchange Resins

Ionic organic contaminants (OCs) are a growing concern for water treatment and the environment and are removed inefficiently by many existing technologies. This study examined removal of anionic OCs by anion exchange resins (AXRs) as a promising alternative. Results indicate that two polystyrene AXRs (IRA910 and IRA96) have higher sorption capacities and selectivity than a polyacrylate resin (A860). For the polystyrene resins, selectivity follows: phenolates ≥ aromatic dicarboxylates > aromatic monocarboxylates > benzenesulfonate > aliphatic carboxylates. This trend can be explained based on hydration energy, the number of exchange groups, and aromaticity and hydrophobicity of the nonpolar moiety (NPM) of the anions. For A860, selectivity only varies within a narrow range (0.13-1.64). Despite the importance of the NPM of the anions, neutral solutes were sorbed much less, indicating synergistic combinations of electrostatic and nonelectrostatic interactions in the overall sorption. By conducting multiple linear regression between Abraham's descriptors and nature log of selectivity, induced dipole-related interactions and electrostatic interactions were found to be the most important interaction forces for sorption of the anions, while solute H-bond basicity has a negative effect. A predictive model was then developed for carboxylates and phenolates based on the poly parameter linear free energy relationships established for a diverse range of 16 anions and 5 neutral solutes, and was validated by accurate prediction of sorption of five test solutes within a wide range of equilibrium concentrations and that of benzoate at different pH.

Polymeric Wax Inhibitors and Pour Point Depressants for Waxy Crude Oils: A Critical Review

Paraffin precipitation during pipeline transport of waxy crude oils gives rise to several challenges, including wax deposition, flow reduction, and gel formation, which adversely impacts pipeline performance. Small dosages of polymeric wax inhibitors or pour point depressants comprise an effective preventative measure. In this article, the structural character, functionality, and mechanisms of the polymeric additives targeting paraffin wax are reviewed, and factors influencing product efficacy are summarized. Most polymeric additives contain a nonpolar moiety as well as a polar moiety, with the exception of crystalline-amorphous copolymers. Via nucleation, adsorption, co-crystallization and solubilization interactions, polymeric additives alter the morphology and interface of precipitated wax crystals, inhibiting wax deposition, improving flow, and impeding gel formation. The presence of asphaltenes significantly impacts wax crystal morphology and interfaces, thus influencing the mechanism of polymeric additives. Most polymeric additives fall into the categories of crystalline-amorphous copolymers, ethylene-vinyl acetate copolymers, comb polymers and nanohybrids. Factors influencing polymeric efficacy include molecular structure, fluid composition, and pipeline transport conditions.

A study of the antibacterial activity of l-Phenylalanine and l-Tyrosine esters in relation to their CMCs and their interactions with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC as model membrane

Cationic amino acid-based surfactants are known to interact with the lipid bilayer of cell membranes resulting in depolarization, lysis and cell death through a disruption of the membrane topology. A range of cationic surfactant analogues derived from l-Phenylalanine (C1–C20) and l-Tyrosine (C8–C14) esters have been synthesized and screened for their antibacterial activity. The esters were more active against gram positive than gram negative bacteria. The activity increased with increasing chain length, exhibiting a cut-off effect at C12 for gram positive and C8/C10 for gram negative bacteria. The cut-off effect for gram negative bacteria was observed at a lower alkyl chain length. The CMC was correlated with the MIC, inferring that micellar activity contribute to the cut-off effect in antibacterial activity. The interaction of the cationic surfactants with the phospholipid vesicles (1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) in the presence of 1-anilino-8-naphthalene sulfonate (ANS) and 1,6-diphenyl-1,3,5-hexatriene (DPH) as fluorescence probes showed that an increase in ionic interaction causes an increase in antibacterial activity. Increase in hydrophobic interaction increases the antibacterial activity only to a certain chain length, attributing to the cut-off effect. Therefore, both electrostatic and hydrophobic interactions, involving the polar and nonpolar moieties are of paramount importance for the bactericidal properties.

Discovery of a Novel Class of Potent HCV NS4B Inhibitors: SAR Studies on Piperazinone Derivatives

HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p-fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and 1a potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.

Solubility of daidzein in propylene glycol plus water cosolvent mixtures

The solubility of daidzein in propylene glycol+water cosolvent mixtures was determined by UV spectrophotometry, and predicted using the Jouyban–Acree model and the mathematical model based on the algebraic rule of mixing. The thermodynamic functions, such as Gibbs energy, enthalpy, and entropy of solution and of mixing and so on, were obtained from these solubility data by using the van’t Hoff and Gibbs equations. The results show that the daidzein solubility increases as propylene glycol proportion increases in the mixtures and the solution temperature increases. The Jouyban–Acree model can be used to predict the solubility of daidzein in propylene glycol+water cosolvent mixtures at different temperatures. The driving mechanism for daidzein solubility in water-rich mixtures is the entropy, probably due to water-structure loss around the drug non-polar moieties by effect of propylene glycol, whereas the driving mechanism is the enthalpy above 0.20 mass fraction of propylene glycol, probably due to daidzein solvation increase by the cosolvent molecules. Non linear enthalpy–entropy compensation with negative slope from water up to 0.20 mass fraction of propylene glycol and positive slope beyond this composition up to pure propylene glycol is found.

Protein Folding and Binding Characterized by Mass Spectrometry

This presentation will illustrate how the combination of solution phase labeling with mass spectrometry (MS) can elucidate mechanistic aspects of protein behavior. We will focus on two ongoing projects in our laboratory. (A) The initial (submillisecond) stages of protein folding represent a formidable experimental challenge. We have begun to address this issue by using submillisecond mixing with laser-induced oxidative labeling. Apomyoglobin (aMb) serves as a model system for these measurements. Exposure of the protein to a brief pulse of hydroxyl radical (•OH) at different time points during folding introduces covalent modifications at solvent accessible side chains. The extent of labeling is monitored using MS-based peptide mapping, providing spatially-resolved measurements of changes in solvent accessibility. The technique introduced here is capable of providing in-depth structural information on time scales that have thus far been dominated by low resolution spectroscopic probes. (B) The bacterial protease ClpP is a multi-subunit complex with a central degradation chamber that can be accessed via axial pores. In free ClpP these pores are obstructed. Acyldepsipeptides (ADEPs) are antibacterial compounds that bind ClpP and cause the pores to open up. The ensuing uncontrolled degradation of intracellular proteins is responsible for the antibiotic activity of ADEPs. We use hydrogen/deuterium exchange MS to obtain insights into the ClpP behavior with and without ADEP1. Our data point to a mechanism where the pore opening mechanism is mediated primarily by changes in the packing of N-terminal nonpolar side chains. We propose that a “hydrophobic plug” causes pore blockage in ligand-free ClpP. ADEP1 binding provides new hydrophobic anchor points that nonpolar N-terminal residues can interact with. In this way ADEP1 triggers the transition to an open conformation, where nonpolar moieties are clustered around the rim of the pore.

A Simple Atomic-Level Hydrophobicity Scale Reveals Protein Interfacial Structure

Many amino acid residue hydrophobicity scales have been created in an effort to better understand and rapidly characterize water–protein interactions based only on protein structure and sequence. There is surprisingly low consistency in the ranking of residue hydrophobicity between scales, and their ability to provide insightful characterization varies substantially across subject proteins. All current scales characterize hydrophobicity based on entire amino acid residue units. We introduce a simple binary but atomic-level hydrophobicity scale that allows for the classification of polar and non-polar moieties within single residues, including backbone atoms. This simple scale is first shown to capture the anticipated hydrophobic character for those whole residues that align in classification among most scales. Examination of a set of protein binding interfaces establishes good agreement between residue-based and atomic-level descriptions of hydrophobicity for five residues, while the remaining residues produce discrepancies. We then show that the atomistic scale properly classifies the hydrophobicity of functionally important regions where residue-based scales fail. To illustrate the utility of the new approach, we show that the atomic-level scale rationalizes the hydration of two hydrophobic pockets and the presence of a void in a third pocket within a single protein and that it appropriately classifies all of the functionally important hydrophilic sites within two otherwise hydrophobic pores. We suggest that an atomic level of detail is, in general, necessary for the reliable depiction of hydrophobicity for all protein surfaces. The present formulation can be implemented simply in a manner no more complex than current residue-based approaches.

Activation of ClpP Protease by ADEP Antibiotics: Insights from Hydrogen Exchange Mass Spectrometry

The bacterial protease ClpP consists of 14 subunits that assemble into two stacked heptameric rings. The central degradation chamber can be accessed via axial pores. In free ClpP, these pores are obstructed by the N-terminal regions of the seven subunits at either end of the barrel. Acyldepsipeptides (ADEPs) are antibacterial compounds that bind in hydrophobic clefts surrounding the pore region, causing the pores to open up. The ensuing uncontrolled degradation of intracellular proteins is responsible for the antibiotic activity of ADEPs. Recently published X-ray structures yielded conflicting models regarding the conformation adopted by the N-terminal regions in the open state. Here, we use hydrogen/deuterium exchange (HDX) mass spectrometry to obtain complementary insights into the ClpP behavior with and without ADEP1. Ligand binding causes rigidification of the equatorial belt, accompanied by destabilization in the vicinity of the binding clefts. The N-terminal regions undergo rapid deuteration with only minor changes after ADEP1 binding, revealing a lack of stable H-bonding. Our data point to a mechanism where the pore opening mechanism is mediated primarily by changes in the packing of N-terminal nonpolar side chains. We propose that a “hydrophobic plug” causes pore blockage in ligand-free ClpP. ADEP1 binding provides new hydrophobic anchor points that nonpolar N-terminal residues can interact with. In this way, ADEP1 triggers the transition to an open conformation, where nonpolar moieties are clustered around the rim of the pore. This proposed mechanism helps reconcile the conflicting models that had been put forward earlier.

APS8, a Polymeric Alkylpyridinium Salt Blocks α7 nAChR and Induces Apoptosis in Non-Small Cell Lung Carcinoma

Naturally occurring 3-alkylpyridinium polymers (poly-APS) from the marine sponge Reniera sarai, consisting of monomers containing polar pyridinium and nonpolar alkyl chain moieties, have been demonstrated to exert a wide range of biological activities, including a selective cytotoxicity against non-small cell lung cancer (NSCLC) cells. APS8, an analog of poly-APS with defined alkyl chain length and molecular size, non-competitively inhibits α7 nicotinic acetylcholine receptors (nAChRs) at nanomolar concentrations that are too low to be acetylcholinesterase (AChE) inhibitory or generally cytotoxic. In the present study we show that APS8 inhibits NSCLC tumor cell growth and activates apoptotic pathways. APS8 was not toxic for normal lung fibroblasts. Furthermore, in NSCLC cells, APS8 reduced the adverse anti-apoptotic, proliferative effects of nicotine. Our results suggest that APS8 or similar compounds might be considered as lead compounds to develop antitumor therapeutic agents for at least certain types of lung cancer.

Interaction Energies of Ionic Liquids with Metallic Nanoparticles: Solvation and Stabilization Effects

The interaction energies and solvation structure of ruthenium nanoparticles (RuNPs) in ionic liquids are studied here by titration calorimetry and by molecular simulation. The size of metallic nanoparticles synthesized in situ in ionic liquids can be controlled, and the resulting suspensions are stable without additional surface-active molecules. However, little is known about the energetics and mechanisms of solvation of nanoparticles in these complex, structured solvents. Ionic liquids were added into a suspension of RuNPs in [C1C4Im][NTf2], and the heat effect was recorded. The background heat of mixing of the two ionic liquids was measured separately. The interaction energy of [C1CnIm][NTf2] (n = 6, 8, 10) with RuNPs is larger than that of [C1C4Im][NTf2] indicating that longer alkyl side chains enhance the interactions with RuNPs. [C1C2Im][NTf2] also has stronger interactions with the nanoparticles, but this cation does not possess a significant nonpolar moiety. Ionic liquids with lesser propensity to...

Solution Thermodynamics of Piroxicam in some Ethanol + Water Mixtures and Correlation with the Jouyban–Acree Model

The solubility of piroxicam (PIR) in several ethanol + water mixtures was determined at five temperatures from 293.15 to 313.15 K. The thermodynamic functions; Gibbs energy, enthalpy, and entropy of solution and of mixing were obtained from these solubility data and the drug properties of fusion by using the van’t Hoff and Gibbs equations. The greatest solubility value was obtained in pure ethanol. A non-linear enthalpy–entropy relationship was observed from a plot of enthalpy versus Gibbs energy of solution. Accordingly, the driving mechanism for PIR solubility in water-rich mixtures is the entropy, probably due to water-structure loss around the drug’s non-polar moieties by ethanol, whereas, in ethanol-rich mixtures the driving mechanism is the enthalpy, probably due to better PIR solvation by the co-solvent molecules. The solubilities and the derived thermodynamic properties in mixed solvents were correlated using the Jouyban–Acree model.