Common Cosolvent Research Articles

Thermodynamic study of choline chloride-based deep eutectic solvents with dimethyl sulfoxide and isopropanol

The thermodynamic properties of four binary mixtures of deep eutectic solvent (DES), i.e., ChCl/Gly (choline chloride + glycerol at a molar ratio of 1:2) and ChCl/EG (choline chloride + ethylene glycol at a molar ratio of 1:2) with two common co-solvents, i.e., dimethyl sulfoxide (DMSO) and isopropanol (IPA), were studied. Density and viscosity were determined at temperatures from 288.15 to 323.15 K, while measuring the enthalpy of mixing was performed at 308.15 and 318.15 K. The volumetric properties (i.e., excess molar volume and excess partial molar volume) and excess viscosities (i.e., viscosity deviation and logarithmic excess viscosity) were further calculated to investigate the effects of temperature, types of co-solvent and DES, and their contents on the non-ideal behavior of these systems, where the influence of treating the DES as a mixture of two components or a pseudo-component was discussed. The results of volumetric properties indicate that the combined influence of packing effects and H-bonding interactions between the DES and co-solvents led to the contraction of mixture volume, and the results of excess viscosities show H-bonding interactions play an important role in their variations. The results of enthalpy of mixing show that the mixing of DES with IPA is endothermic, while the mixing of DES with DMSO is exothermic. Furthermore, the nonrandom two-liquid (NRTL) model and Gibbs-Helmholtz equation were combined to represent the experimental results of the enthalpy of mixing, and the total average relative deviation (ARD) of all studied systems is 5.43%.

Implications of the Thermal Stability of FEC-Based Electrolytes for Li-Ion Batteries

Fluoroethylene-carbonate (FEC) is a common co-solvent for high-voltage cathodes and for silicon-based anodes in lithium-ion batteries. However, FEC has a limited thermal stability when used with LiPF6 as conductive salt, and its decomposition can trigger detrimental side reactions. Here, we will examine the reaction mechanism of FEC with LiPF6, confirming that vinylene-carbonate (VC) and HF are produced at elevated temperatures. By full-cell cycling at 45 °C in a T-cell setup with a micro-reference electrode (μ-RE), we can show by electrochemical impedance spectroscopy that these side reactions not only lead to an impedance increase of the anode and the cathode, but also trigger transition metal dissolution. By comparison of FEC and ethylene-carbonate (EC) as cyclic carbonate, we demonstrate that FEC has no advantage at high-voltage operation compared to EC, when employing cathode materials or cathode potentials for which no lattice oxygen is evolved. Finally, we use multi-layer pouch-cells to analyze the gassing of an EC- and FEC-based electrolyte upon extended charge/discharge cycling at 45 °C, showing that the latter leads to cell bulging upon extended charge/discharge cycling at 45 °C due to the oxidation of the VC formed by the thermal decomposition of FEC above ≈4.4 − 4.5 V vs. Li+/Li.

Small molecule co-solvents enhance activity of SARS-CoV-2 main protease through a dielectric effect.

Since the beginning of the pandemic, there has been a surge of interest to learn more about SARS-CoV-2 and its many drug-targetable proteins. The main protease (Mpro) is an excellent candidate for a drug target because of its vital role in coronavirus replication and because there exists no human homologue, minimizing off-target effects. We find that Mpro is active at very high concentrations of dimethyl sulfoxide (DMSO), a common co-solvent for inhibitor candidates. The enzyme has enhanced activity with DMSO, reaching a maximum at 33%: the effect is also observed with other solvent mixtures at a similar dielectric i.e., polyethene glycol. Molecular dynamics simulations suggest DMSO does not bind to a specific site, but rather does a global conformational change of the enzyme, particularly near the active site and at the C-terminus. This work attempts to better understand Mpro dimerization, substrate binding, and interaction with its chemical environment and ultimately provide important details for robust design of inhibitors against Mpro and future variants of its kind.

Effects of Solvents, Emulsions, Cosolvents, and Complexions on Ex Vivo Mouse Myometrial Contractility

A great need exists to develop tocolytic and uterotonic drugs that combat poor, labor-related maternal and fetal outcomes. A widely utilized method to assess novel compounds for their tocolytic and uterotonic efficacy is the isometric organ bath contractility assay. Unfortunately, water-insoluble compounds can be difficult to test using the physiological, buffer-based, organ bath assay. Common methods for overcoming solubility issues include solvent variation, cosolvency, surfactant or complexion use, and emulsification. However, these options for drug delivery or formulation can impact tissue function. Therefore, the goal of this study was to evaluate the ability of common solvents, surfactants, cosolvents, and emulsions to adequately solubilize compounds in the organ bath assay without affecting mouse myometrial contractility. We found that acetone, acetonitrile, and ethanol had the least effect, while dimethylacetamide, ethyl acetate, and isopropanol displayed the greatest inhibition of myometrial contractility based on area under the contractile curve analyses. The minimum concentration of surfactants, cosolvents, and human serum albumin required to solubilize nifedipine, a current tocolytic drug, resulted in extensive bubbling in the organ bath assay, precluding their use. Finally, we report that an oil-in-water base emulsion containing no drug has no statistical effect beyond the control (water), while the drug emulsion yielded the same potency and efficacy as the freely solubilized drug.

Effect of Co-Solvents on Physicochemical Properties and Stability of Areca Nut Extract Loaded Nanoemulsions

Areca nut extract provides a variety of pharmacological effects that are beneficial for skincare applications. A nanoemulsion of areca nut extract was developed to mask the intense color and to improve the water solubility of the extract. This work studied the impact of a co-solvent on the characteristics and stability of the nanoemulsion. Our former optimized nanoemulsion was modified by adding a common co-solvent, propylene glycol or polyethylene glycol 400 (PEG400), to the formula. Phase separation, particle characteristics, antioxidant activity, in vitro cytotoxicity, and stability of the modified nanoemulsion were evaluated. This work has shown the successful encapsulation of areca nut extract with a great improvement of stability, well-maintained antioxidant activity and low toxicity on normal human skin fibroblast.

Ultrafast Dynamics at the Lipid-Water Interface: DMSO Modulates H-Bond Lifetimes.

Dimethyl sulfoxide (DMSO) is a common cosolvent and cryopreservation agent used to freeze cells and tissues. DMSO alters the H-bond structure of water, but its interactions with biomolecules and, specifically, with biological interfaces remain poorly understood. Here we investigate the effects of DMSO on the H-bond dynamics at the lipid-water interface using a combination of ultrafast two-dimensional infrared (2D IR) spectroscopy and molecular dynamics simulations. Ester carbonyl absorption spectra show that DMSO dehydrates the interface, and simulations show that the area per lipid is decreased. Ultrafast 2D IR spectra measure the time scales of frequency fluctuations at the ester carbonyl positions located precisely between the hydrophobic and hydrophilic regions of the membrane. 2D IR measurements show that low DMSO concentrations (<10 mol %) induce ∼40% faster H-bond dynamics compared with pure water, whereas increased concentrations (>10-20 mol %) once again slow down the dynamics. This slow-fast-slow trend is described in terms of two different solvation regimes. Below 10 mol %, DMSO weakens the interfacial H bond, leading to faster "bulk-like" dynamics, whereas above 10 mol %, water molecules become "relatively immobilized" as the H-bond networks becoming disrupted by the H-bond donor/acceptor imbalance at the interface. These studies are an important step toward characterizing the environments around lipid membranes, which are essential to numerous biological processes.

Anaerobic degradation of 2-propanol: Laboratory and pilot-scale studies

The anaerobic degradation of 2-propanol, an important industrial solvent, was scaled-up from batch assays to a pilot expanded granular sludge bed (EGSB) reactor at 25°C. Batch studies indicated that 2-propanol followed Haldane kinetics, with a maximum rate at 10gCODL−1. Concentrations as high as 25gCODL−1 did not inhibit the degradation of ethanol, a common co-solvent. Similar specific methanogenic activities (SMA) were obtained for water-solvent and water-brewery sludges (88 and 77mlCH4g-VS−1d−1 at 5gCODL−1). Continuous degradation showed a lag-phase of three weeks with water-brewery sludge. Increases in 2-propanol load from 0.05 to 0.18kgCODkg-VS−1d−1 caused a shift from the consumption of soluble matter to methane production, indicating polyhydroxybutyrates (PHB) accumulation. Conversely, smooth increases of up to 0.29kgCODkg-VS−1d−1 allowed 2-propanol degradation without PHB accumulation. The slowdown rate of 2-propanol-oxidizer and acetate-utilizing methanogen bacteria below 20°C adversely impacted both removal and CH4 yield.

Perspectives on the integration of a supercritical fluid extraction plant to a sugarcane biorefinery: thermo-economical evaluation of CO2 recycle systems

Abstract In the present study, the software Aspen Plus® was used to analyse two different systems for CO2 recycle in a SFE process for extraction of more polar compounds using ethanol as co-solvent, the most common co-solvent used due to its environment-friendly nature. The extraction process of β-ecdysone from Brazilian ginseng roots was considered as example in the computational simulations. The first CO2 recycle system, named Recycle A, considered the compression of the CO2 separated in the second flash to the recycle pressure assumed at the first flash tank, its cooling to 25 °C and recirculation, while the second recycle system, named Recycle B, considered the cooling and pumping of the CO2 separated in the second flash, its heating to 25 °C and recirculation. The best techno-economic condition to operate the recycling step would be using Recycle A at 40 bar and 30 °C considering a stand-alone SFE process; and using Recycle B at 40 bar and 40 °C, considering this process in close proximity of a hypothetical sugarcane biorefinery. Therefore, these results suggest that the selection where would be located the SFE plant should be taken into account during the first steps of the process design.

Systematic investigations of peak deformations due to co-solvent adsorption in preparative supercritical fluid chromatography

Strangely shaped overloaded bands were recently reported using a standard supercritical fluid chromatographic system comprising a diol column as the stationary phase and carbon dioxide with methanol as the mobile phase. Some of these overloaded elution profiles appeared strongly deformed and even had “anti-Langmuirian” shapes although their solute compounds had “Langmuirian” adsorption. To obtain a more complete understanding of the generality of these effects, the investigation was expanded to cover also other common co-solvents, such as ethanol, 2-propanol, and acetonitrile, as well as various stationary phase materials, such as silica, and 2-ethylpyridine. From this expanded study it could be confirmed that the effects of deformed overloaded solute band shapes, due to co-solvent adsorption, is general phenomena in supercritical fluid chromatographic. It could also be concluded that these effects as well as previously observed “solvent effects” or “plug effects” are entirely due to competition between the solute and solvent molecules for the adsorption sites on the stationary phase surface. Finally, guidelines were given for how to evaluate the risk of deformations occurring for a given solvent–column combination, based simply on testing retention times of solutes and co-solvent.

Hydrothermal Synthesis of SnO&lt;sub&gt;2&lt;/sub&gt; Structures with Various Morphologies in the Presence of Different Alcoholic Co-Solvents

The addition of certain co-solvents to the hydrothermal synthesis starting solution can greatly alter morphology and enhance different morphology dependent properties of the synthesized material. While ethanol is the most common co-solvent used for the synthesis of various SnO2 nano/microstructures by hydro/solvothermal process, it is not clear how the use of some other alcoholic co-solvents (for example, methanol or isopropanol) affect morphology and properties of SnO2, especially if synthesis is done under similar conditions as in the case of ethanol co-solvent. In the present study, we investigated how the use of various alcoholic co-solvents (methanol, ethanol, 2-propanol, ethylene glycol and glycerol) affects crystal structure, morphology and specific surface area of the hydrothermally synthesized SnO2. Additionally, sensitivity towards 100 ppm ethanol of the synthesized materials was tested. The formation of nanoparticles, rod-cluster structures and spherical SnO2 structures were observed depending on the alcoholic co-solvent used. The highest sensitivity (~22 at 250 °C) showed the material that was synthesized in the presence of ethanol co-solvent.

Influence of cosolvent retention on film formation and surface mechanical properties of water based acrylic coatings by atomic force microscopy

Abstract The influence of several common cosolvents on the level of film formation and surface mechanical properties of water-based acrylic coatings is investigated by atomic force microscopy (AFM) and AFM based nano-indentation technique. The amount of residual cosolvents in the coatings is determined and it is found that the aforementioned properties of coatings with the exact same polymer composition can be significantly different depending on the amount of residual cosolvents, which is related to the evaporation rate of the solvent as well as the interaction between the solvent, water and the polymer. Butyl glycol, for example, has good interaction with the acrylic polymer and water but due to its fast evaporation, does not improve film formation. Texanol, on the other hand, presents in the film at a large amount but it reduces the surface stiffness of the film and can have a detrimental effect on the surface mechanical properties of the coating.

Surface Tension Components Based Selection of Cosolvents for Efficient Liquid Phase Exfoliation of 2D Materials.

A proper design of direct liquid phase exfoliation (LPE) for 2D materials as graphene, MoS2 , WS2 , h-BN, Bi2 Se3 , MoSe2 , SnS2 , and TaS2 with common cosolvents is carried out based on considering the polar and dispersive components of surface tensions of various cosolvents and 2D materials. It has been found that the exfoliation efficiency is enhanced by matching the ratio of surface tension components of cosolvents to that of the targeted 2D materials, based on which common cosolvents composed of IPA/water, THF/water, and acetone/water can be designed for sufficient LPE process. In this context, the library of low-toxic and low-cost solvents with low boiling points for LPE is infinitely enlarged when extending to common cosolvents. Polymer-based composites reinforced with a series of different 2D materials are compared with each other. It is demonstrated that the incorporation of cosolvents-exfoliated 2D materials can substantially improve the mechanical and thermal properties of polymer matrices. Typically, with the addition of 0.5 wt% of such 2D material as MoS2 nanosheets, the tensile strength and Young's modulus increased up to 74.85% and 136.97%, respectively. The different enhancement effect of 2D materials is corresponded to the intrinsic properties and LPE capacity of 2D materials.

Effects of THF as cosolvent in the preparation of polydimethylsiloxane/polyethersulfone membrane for gas separation

Polydimethylsiloxane/polyethersulfone (PDMS/PES) asymmetric membranes are widely applied in gas separation. However, the effects of common cosolvent on these membranes remain unknown. In order to study the changes in membrane morphology and gas separation properties, asymmetric PDMS/PES membranes were prepared. The studied parameters were types of cosolvents, tetrahydrofuran (THF) concentration, evaporation time, and PDMS concentration. Membrane morphology was examined using scanning electron microscopy and gas separation was conducted using pure CO2, N2, CH4, and Hat 25°C. The addition of cosolvent into the polymer solution decreased the dope viscosity and delayed liquid–liquid demixing during phase inversion. Macrovoids formation was observed in substructure layer after adding THF and these macrovoids elongated with the reduction in THF content. There were microvoids formed on top of macrovoids and microvoids layer became thicker due to the increasing evaporation time of solvents before coagulation in nonsolvent. The PDMS coating on the PES membrane formed a dense skin layer and exhibited higher selectivity compared to the uncoated membrane. Membrane contained THF cosolvent with 60 s evaporation time and 3 wt% coated PDMS is the optimum membrane among other membranes in this work. The CO2/N2 selectivity was enhanced by 73.3% with CO2 permeance of 44.86 GPU. POLYM. ENG. SCI., 54:2177–2186, 2014. © 2013 Society of Plastics Engineers

The Effects that Cosolvent Takes on Ink Used in Water-Borne Pen Performance and Quality

In order to discuss the effects that cosolvent takes on ink used in water-borne pen performance and quality, select and use ethanol, methanol, isopropanol, Ethylene glycol monobutyl ether, ethanediol and propanediol six common water-soluble cosolvent, using them to prepare the samples of ink used in Water-borne pen, testing the surface tension, viscosity, drying rate and adhesionforce. Select three kinds of cosolvent to carry the formula experiment. The results of the study show that: the ink prepared with different kinds csolvent have different performance. The ink prepared by isopropyl alcohol has good quality performance.

Solubility of Pioglitazone Hydrochloride in Binary and Ternary Mixtures of Water, Propylene Glycol, and Polyethylene Glycols 200, 400, and 600 at 298.2 K

Glitazones (GZs) or thiazolidinediones are oral hypoglycemic agents used in the treatment of type II diabetes. They are acting as insulin sensitizers by regulating the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. The first report of their glucose-lowering effects was published in 1980s, and troglitazone was launched as an oral hypoglycemic agent in 1997, and two others, i.e., pioglitazone (PGZ) and rosiglitazone, were approved by the FDA in 1999 (1,2). Troglitazone was withdrawn because of its hepato-toxicity; the incidence of liver toxicity of PGZ and rosiglitazone are minor; however, investigations for finding more active glitazones with less side effects are still ongoing (2). PGZ is the most popular drug, and its prescription is increased by the rate of 14% during 2005–2007 (3). In addition to its antidiabetic activity, it demonstrates other activities including reduction of reactive oxygen species from adipose tissue (4) and improving cognition and regional cerebral blood flow in patients with mild Alzheimer (5). PGZ hydrochloride (PGZ-HCl) is used in pharmaceutical formulations to achieve a more soluble form of the drug; however, the aqueous solubility of PGZ-HCl is still low, and a number of investigations were reported dealing with solubilization of PGZ or PGZ-HCl (6–10). Common cosolvents in pharmacy are ethanol, propylene glycol (PG), glycerin, polyethylene glycol 400 (PEG 400), and N-methyl-2-pyrrolidone (NMP; 11). Polyethylene glycols (PEGs) are linear or branched polyethers with the approximate molecular weight of 200–36,000. PEG 200 to PEG 800 are in liquid form, whereas PEG 1000 and higher molar masses are solids. Liquid PEGs are commonly used as cosolvents for solubilization of drugs in preclinical and clinical studies (12). Because of strong H-bonding between PEGs and water, they are freely soluble in water and in many organic solvents. PEGs have variety of applications in the pharmaceutical, chemical, cosmetic, and food industries (13). Their low toxicity and high water solubility enable their use for purification of biological materials. Among them, PEG 400 is the most commonly used cosolvent in the pharmaceutical industries for preparation of cosmetics, ointments, suppositories, ophthalmic solutions, and sustained-released oral pharmaceutical formulations (14). Propylene glycol is a stable and low toxic pharmaceutical cosolvent which is used in many commercially available oral and parenteral formulations of poorly soluble drugs (15,16). The well-known parenteral formulations containing PG are diazepam, fenoldopam mesylate, melphalan HCl, oxytetracycline, paricalcitol, pentobarbital Na, phenytoin Na, chlordiazepoxide HCl, lorazepam, and phenobarbital. PG is also used in many oral formulations of drugs including amprenavir, clofazimine, cyclosporine A, digoxin, lopinavir, ritonavir, sirolimus, loratadin, and itraconazole (15). Our intent was to measure the solubilities of PGZ-HCl in a series of aqueous and non-aqueous solvent systems containing ethanol, PG, NMP, and PEGs at 298.2 K which extends the available database of drugs solubilities in mixed solvents (17), fitting the data to the Jouyban-Acree model that relates the solubilities in solvent mixtures to the fractions of the solvent components and constants computed by a regression analysis (18). In previous reports, the solubility of PGZ-HCl in aqueous solutions of ethanol, PG, and NMP (8), in binary mixtures of PEG 600 with water and ethanol, ternary mixtures of PEG 600-ethanol-water (9), and also in binary mixtures of PEG 400 with ethanol, PG, NMP, and water (10) were discussed. In this work, the solubility of PGZ-HCl in binary and ternary mixtures of water, PG, and PEGs 200, 400, and 600 at 298.2 K are reported. The generated data are predicted using numerical methods, and the accuracies of different methods are discussed.

Effect of propylene glycol on ibuprofen absorption into human skin in vivo

The objective was to assess the impact of propylene glycol (PG), a common cosolvent in topical formulations, on the penetration of ibuprofen into human skin in vivo. Drug uptake into the stratum corneum (SC), following application of saturated formulations containing from 0 to 100% v/v PG, was assessed by tape-stripping. Dermatopharmacokinetic parameters, characterizing drug amount in and diffusivity through the SC, were derived. The solubility behavior of ibuprofen in PG-water mixtures was carefully evaluated, as were a number of other physical properties. Ibuprofen delivery depended on the level of PG in the vehicle, despite all formulations containing the drug at equal thermodynamic activity. PG appeared to alter the solubility of ibuprofen in the SC (presumably via its own uptake into the membrane), the effect becoming more important as the volume fraction of cosolvent in the formulation increased. In summary, tape-stripping experiments, with careful interpretation, can reveal details of a drug's bioavailability in the skin following topical application and may be used to probe the mechanism(s) by which certain excipients influence local drug delivery.

Solubility parameter of drugs for predicting the solubility profile type within a wide polarity range in solvent mixtures

The solubility enhancement produced by two binary mixtures with a common cosolvent (ethanol–water and ethyl acetate–ethanol) was studied against the solubility parameter of the mixtures ( δ 1) to characterize different types of solubility profiles. Benzocaine, salicylic acid and acetanilide show a single peak in the least polar mixture (ethanol–ethyl acetate) at δ 1 = 22.59, 21.70 and 20.91 MPa 1/2, respectively. Phenacetin displays two solubility maxima, at δ 1 = 25.71 (ethanol–water) and at δ 1 = 23.30 (ethyl acetate–ethanol). Acetanilide shows an inflexion point in ethanol–water instead of a peak, and the sign of the slope does not vary when changing the cosolvent. The solubility profiles were compared to those obtained in dioxane–water, having a solubility parameter range similar to that covered with the common cosolvent system. All the drugs reach a maximum at about 90% dioxane ( δ 1 = 23 MPa 1/2). A modification of the extended Hildebrand method is applicable for curves with a single maximum whereas a model including the Hildebrand solubility parameter δ 1 and the acidic partial solubility parameter δ 1a is required to calculate more complex solubility profiles (with inflexion point or two maxima). A single equation was able to fit the solubility curves of all drugs in the common cosolvent system. The polarity of the drug is related to the shape of the solubility profile against the solubility parameter δ 1 of the solvent mixtures. The drugs with solubility parameters below 24 MPa 1/2 display a single peak in ethanol–ethyl acetate. The drugs with δ 2 values above 25 MPa 1/2 show two maxima, one in each solvent mixture (ethanol–water and ethanol–ethyl acetate). The position of the maximum in ethanol–ethyl acetate shifts to larger polarity values (higher δ 1 values) as the solubility parameter of the drug δ 2 increases.

Osmolyte effects on helix formation in peptides and the stability of coiled-coils.

The ability of several naturally occurring substances known as osmolytes to induce helix formation in an alanine-based peptide have been investigated. As predicted by the osmophobic effect hypothesis, the osmolytes studies here do induce helix formation. Trimethylamine-N-oxide (TMAO) is the best structure-inducing osmolytes investigated here, but it is not as effective in promoting helix formation as the common cosolvent trifluoroethanol (TFE). We also provide a semiquantitative study of the ability of TMAO to induce helix formation and urea, which acts as a helix (and protein) denaturant. We find that on a molar basis, these agents are exactly counteractive as structure inducing and unfolding agents. Finally, we extend the investigations to the effects of urea and TMAO on the stability of a dimeric coiled-coil peptide and find identical results. Together these results support the tenets of the osmophobic hypothesis and highlight the importance of the polypeptide backbone in protein folding and stability.

Screening of cosolvents for a supercritical fluid: A fully predictive approach

AbstractSolubility of solids was modeled in modified supercritical carbon dioxide as a predictive method. The Peng‐Robinson equation of state was used to characterize the ternary systems using the one‐fluid van der Waals rules. Ternary mixture parameters k12, k23, and k13 were obtained from the binary mixtures using Wong‐Sandler mixing rules or the linear combination of Vidal‐Michelsen mixing rules together with UNIFAC as required as a fully predictive tool for the liquid activity coefficients. When this method was applied to predict the solubility of β‐naphthol in CO2 modified with 6% and 10% toluene, values for the predicted solubility were very similar to the measured ones, with deviations of 9.6 and 26.3%, respectively. However, when the method was applied to the data of Simon et al. who examined six common cosolvents, the results were not as good in absolute terms, but the solvents were sorted in about the same order as found experimentally. The method provides quite an approximate guide to judge the most effective cosolvent from several candidates using a fully predictive methodology.

Thermodynamic Origin of the Solubility Profile of Drugs Showing one or two Maxima Against the Polarity of Aqueous and Nonaqueous Mixtures: Niflumic Acid and Caffeine

The purpose of this work was to investigate the origin of the different solubility profiles of drugs against the polarity of solvent mixtures with a common cosolvent. Niflumic acid and caffeine where chosen as model drugs. The solubilities were measured at five or six temperatures in aqueous (ethanol–water) and nonaqueous (ethyl acetate–ethanol) mixtures. The enthalpies of solution were obtained at the harmonic mean of the experimental temperature. Solid phase changes were analyzed using differential scanning calorimetry and thermomicroscopy. A single solubility maximum was obtained for niflumic acid against the solubility parameter of both mixtures that is not related to solid phase changes. In contrast, caffeine displays two maxima and anhydrous–hydrate transition occurs at the solubility peak in the amphiprotic mixture. The apparent enthalpies of solution of both drugs show endothermic maxima against solvent composition that are related to hydrophobic hydration. A general explanation for the cosolvent action in aqueous mixtures is proposed. The dominant mechanism shifts from entropy to enthalpy at a certain cosolvent ratio dependent on the hydrophobicity and the solubility parameter of the drug. Niflumic acid and caffeine show enthalpy–entropy compensation in ethanol–water, and this relationship is demonstrated for the first time in nonaqueous mixtures. The results support that enthalpy–entropy compensation is a general effect for the solubility of drugs in solvent mixtures. The shape of the solubility curves is correlated with the compensation plots. The solubility peaks separate different enthalpy–entropy relationships that also differentiate the solubility behavior of the hydrate and the anhydrous forms of caffeine. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 874–883, 2002