Solubility Of Indomethacin Research Articles

Solubility improvement of indomethacin by novel biodegradable eutectic solvents based on protic ionic liquid monoethanolamine carboxylate/ethylene glycol

Currently, eutectic solvents and deep eutectic solvents (DESs) have gained considerable attention due to their wide range of academic and technological domains. Meanwhile, DESs based on ionic liquids (ILs) are a new generation of green solvents that have unique properties. The goal of this study was to investigate the sparingly soluble drug indomethacin (IMC) in three monoethanolamine carboxylate-based eutectic solvents with ethylene glycol (EG), including monoethanolamine propionate/ethylene glycol (MEAP/EG), monoethanolamine lactate/ethylene glycol (MEAL/EG), and monoethanolamine acetate/ethylene glycol (MEAA/EG). The shake flask method was employed in this investigation at an atmospheric pressure of 86.6 kPa and temperature range of T= (298.15–313.15) K. The outcomes demonstrated that the solubility of IMC was obtained approximately 600-fold more than its solubility in water. Numerous thermodynamic models, including the Jouyban-Acree model, the Van't Hoff-Jouyban-Acree model, the Modified Apelblat-Jouyban-Acree model, and the activity coefficient models Wilson and e-NRTL, accurately correlated the solubility data which their performance order is as follows: Modified Apelblat – Jouyban – Acree > Van't Hoff – Jouyban – Acree > Wilson > Modified Apelblat equation > e-NRTL > Jouyban-Acree model. Finally, Van't Hoff and Gibbs equations have been applied the apparent thermodynamic properties of dissolution in the investigated systems which the dissolution process is endothermic and enthalpy-driven in all of the co-solvents which have been utilized.

Solubility of naproxen and indomethacin in supercritical carbon dioxide/ethyl acetate mixtures

In this work, the solubilities of naproxen and indomethacin in supercritical carbon dioxide (scCO2) were investigated from both experimental and theoretical points of view. Experimentally, the solubilities of those active pharmaceutical ingredients (APIs) in scCO2 and scCO2/ethyl acetate were measured using a variable-volume high-pressure view cell at T=60℃ and pressures between 150 and 429 bar. Results showed two different trends for the solubility of naproxen in scCO2 and further PXRD analysis revealed a change in naproxen crystal structure for pressures above 250 bar. Moreover, the influence of ethyl acetate on the solubility of indomethacin in scCO2 was investigated. At constant pressure, solubility was observed to increase with increasing ethyl acetate concentration. PC-SAFT was used to describe the solubility of both APIs in scCO2 and of indomethacin in the scCO2/ethyl acetate mixture over the entire pressure range. The melting properties of different polymorphic forms were considered for the solubility calculations, and the model accurately described the investigated systems.

Computational Insights on Solvation and Hydrogen Bonding Studies of Indomethacin

Over a long time, non-steroidal anti-inflammatory drugs (NSAIDs) play a vital role in medical field. Indomethacin is a NSAID mainly used against inflammation and pain. But the poor solubility of indomethacin limits its therapeutic usage. Hydrotropy is a solubilization technique used to enhance the drug solubilization. Microscopic solvent effect is considered to be a part of hydrotropy in which hydrogen bond (H-bond) networks are formed with an isolated molecule with solvent molecules such as water. A comprehensive theoretical investigation was performed under density functional theory (DFT) to explore the isolated and monohydrated indomethacin complexes. The geometries were optimized on B3LYP method with 6-311G (2d,2p) basis set. The interaction energies of hydrated indomethacin complexes were computed by correcting the basis set superposition error. Natural bond orbital (NBO) study was performed in order to deepen the knowledge on O-H···O and C-H···O type H-bonds. A linear relationship between H-bond length and the stabilization energy (E(2))was observed in the solvated indomethacin complexes with a correlation coefficient of 0.8346. It identifies maximum E(2) (95.33 Kcal/mol) in INDO-12 complex. The molecular electrostatic potential mapping (MESP) for the optimized structures was also analyzed.

Comparison study of physicochemical and biopharmaceutics properties of hydrophobic drugs ground by two dry milling processes

This study focuses on the dry milling of biopharmaceutical classification system (BCS) class II molecules. These molecules have a limited bioavailability because of their low aqueous solubility, poor water wettability and low dissolution rate. In order to improve these properties, indomethacin (IND) and niflumic acid (NIF) were milled using two different types of equipment: Pulverisette 0® and CryoMill®. Milled samples were characterized and compared to commercial molecules. IND shows a modified solid state, like surface crystallinity reduction and an increase in water vapor adsorption from to 2- up to 5-fold due to milling processes. The obtained solubility data resulted in an improvement in solubility up to 1.2-fold and an increase in initial dissolution kinetics: 2% of dissolved drug for original crystals against 25% for milled samples. For NIF no crystallinity reduction, no change of surface properties and no solubility improvement after milling were noticed. In addition, milled particles seemed more agglomerated resulting in no changes in dissolution rate compared to the original drug. IND solubility and dissolution enhancement can be attributed to the modification of surface area, drug crystallinity reduction, and water sorption increase due to specific behavior related to the drug crystal disorder induced by milling process.

Mechanism of Solubility Enhancement of Poorly Water-Soluble Drugs Triggered by Zeolitic Imidazolate Frameworks

Numerous efforts have been devoted to improving the solubility of poorly water-soluble drugs. Recently, it was reported that the use of metal-organic frameworks (MOFs), which are a new class of porous materials consisting of metal ions and organic ligands, is effective in improving the solubility of poorly water-soluble drugs. Our previous study demonstrated an improvement in the solubility of indomethacin (IDM) triggered by the zeolitic imidazolate framework-8 (ZIF-8). The present study aimed to elucidate the solubilization mechanism using the ZIF series, namely, ZIF-8, ZIF-67, and ZIF-L. It was confirmed that the solubility of ZIF-trapped IDM and ibuprofen (IBU) was enhanced compared to the raw drugs, regardless of the ZIF type. This study focused on 2-methylimidazole (2-MIM), which is commonly used as a ZIF organic ligand. Both IDM and IBU were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the solubility of the drugs. Inductively coupled plasma measurements also confirmed the presence of metal ions of ZIFs in the supernatant solution after the drug release tests, indicating the decomposition of ZIFs during drug release. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIF particles. We observed that the drugs loaded on the ZIFs were released simultaneously with the decomposition of some of the ZIFs. The 2-MIM molecules were also released concurrently. The presence of 2-MIM improved the solubility of poorly water-soluble drugs.

Amino acid hydrotropes to increase the solubility of indomethacin and carbamazepine in aqueous solution

A number of amino acids (AA) has been investigated as promising hydrotropes to improve the solubility of biopharmaceutics classification system (BCS) class II drugs carbamazepine (CBZ) and indomethacin (IND) via specific complexations in aqueous solution. The aim of this work is to understand the molecular basis of these hydrotropic interactions by investigating the two model drugs combined with 12 amino acids including phenylalanine, tryptophan, isoleucine, proline, valine, glycine, serine, threonine, arginine, lysine, histidine and aspartic acid in water at 25 °C, 30 °C and 45 °C. The amino acids were chosen based on their different side chains (neutral aromatic, aliphatic, polar charged or uncharged) to investigate their hydrotropic performance. A linear solubility curve was observed between indomethacin and mono-neutral hydrophobic amino acids (phenylalanine, tryptophan, isoleucine, proline and valine) well beyond 1:1 molar ratio indicating the interaction is predominantly non-ionic between the drug and the hydrotropes. Interestingly, the aqueous solubility of carbamazepine (a neutral compound) was enhanced by neutral, charged basic or acidic amino acids, confirming the presence of hydrophobic interactions that involve H-bonds, H/π and π/π stacking and the results were confirmed by UV-Vis spectroscopy. A combination of multiple neutral amino acids showed additive hydrotropic effect in indomethacin solubility with up to 7-folds increases. This study demonstrates for the first time the potential of amino acids as hydrotropes to improve aqueous solubility of poorly water-soluble drugs, which is important for pharmaceutical development.

Ball milling and hot-melt extrusion of indomethacin–l-arginine–vinylpyrrolidone-vinyl acetate copolymer: Solid-state properties and dissolution performance

Commonly applied approaches to enhance the dissolution properties of low water-soluble crystalline active pharmaceutical ingredients (APIs) include their amorphization by incorporation into a polymeric matrix and the formation of amorphous solid dispersions, or blending APIs with low-molecular-weight excipients and the formation of a co-amorphous system. This study focused on the preparation and characterization of binary (consisting of indomethacin (IND) and polymer – copovidone (PVP VA 64), as a carrier, or amino acid – L-arginine (ARG), as a co-former) and ternary (comprising the same API, polymer, and amino acid) formulations. Formulations were produced by ball milling (BM) and/or hot-melt extrusion (HME), and extensive physicochemical characterization was performed. Specifically, the physicochemical and solid-state properties of a model IND–ARG system incorporated into a polymeric matrix of PVP VA 64 by HME and BM as well as by combined BM/HME method together with the impact of the preparation strategy on the dissolution profiles and long-term physical stability were investigated. Ball-milled binary and ternary formulations were found to be amorphous. The residual crystals corresponding to IND–ARG salt were identified in the ternary formulations produced via HME. Despite the presence of a crystalline phase, dissolution tests showed that ternary systems prepared by HME exhibited improved IND solubility when compared to pure crystalline IND and their corresponding physical mixture. None of the binary and ternary formulations that were initially fully amorphous did undergo recrystallization during the entire period of preservation (minimum of 12 months) in dry conditions at 25 °C.

Ocular Drug Delivery System-based on Solid Nanoparticles

The use of eye drops is a well-established practice in the treatment of ophthalmic diseases, although the bioavailability of traditional eye drops, which are either solutions or suspensions, is insufficient, as the corneal barrier and dilution by lacrimation prevent the transcorneal penetration of drugs. Additionally, frequent instillation may cause undesirable systemic side effects and local corneal toxicity. To overcome these problems, micro- and nanoparticles, hydrogels, and viscous solutions have been tested, and solid nanoparticles are also expected to be applied. This review examines the usefulness of ophthalmic formulations based on solid nanoparticles, by using the specific example of indomethacin (IMC). Ophthalmic formulations based on solid IMC nanoparticles (IMC-NP dispersions) have been prepared using various additives (benzalkonium chloride, mannitol, methylcellulose, and cyclodextrin) and a rotation/revolution pulverizer (NP-100), to produce particles of 50-220 nm in size. The solubility of IMC in IMC-NP dispersions was 4.18-fold higher than that in the suspensions containing IMC microparticles (IMC-MP suspensions), and IMC-NP dispersions were better tolerated than commercially available NSAIDs eye drops, such as IMC, pranoprofen, diclofenac, bromfenac, and nepafenac eyedrops, in human corneal epithelial cells. Moreover, the corneal penetration in IMC-NP dispersions was higher than that in commercially available IMC and IMC-MP suspensions, and three energy-dependent endocytosis pathways (clathrin-dependent endocytosis, caveolae-dependent endocytosis, and macropinocytosis) were related to the high ophthalmic bioavailability of IMC-NP dispersions. This information can be used to support future studies aimed at designing novel ophthalmic formulations.

The Use of Glycerol as an Enabling Excipient for Microwave-Induced In Situ Drug Amorphization

Microwave-induced in situ amorphization is a promising approach to circumvent stability and manufacturing issues associated with amorphous solid dispersions (ASD). Using in situ amorphization, the crystalline state of the drug is converted into its amorphous form inside the dosage form, e.g. a compact, upon exposure to microwave radiation. The study aimed to investigate the feasibility of using glycerol as an enabling excipient in compacts prepared from mixtures of indomethacin and Soluplus®. Additionally, the possibility to form a supersaturated ASD upon exposure to microwave radiation due to elevated temperatures was investigated. It was found that glycerol i) acts as a dielectric heating source absorbing the microwaves, ii) plasticizes the polymer Soluplus® and iii) increases the solubility of the drug indomethacin in the polymer Soluplus®. Additionally, it was found that fully amorphous ASDs could be achieved with drug loadings below -, and slightly above the saturation solubility of indomethacin in the Soluplus®/glycerol mixtures, after exposure to 20 min of microwave radiation. Hence, glycerol was a feasible excipient for the microwave-induced in situ amorphization and allowed the preparation of a, at room temperature, supersaturated ASD, due to the elevated temperatures obtained during exposure to microwave radiation.

Possibilities of the microemulsion use as indomethacin solubilizer and its effect on in vitro and ex vivo drug permeation from dermal gels in comparison with transcutol®

Objective Transcutol® is a perfect solubilizer and an effective permeation enhancer of many active substances commonly used in cosmetics. Microemulsions due to the content of surfactant and co-surfactant could be also considered as chemical permeation enhancers that may support transdermal delivery of poorly water- soluble drugs. The purpose of this study was to investigate the effect of Transcutol® and potential microemulsions on diffusion of poorly soluble indomethacin through an artificial membrane and excised rat skin. Methods After drug solubilization in different enhancers, drug was dispersed in sodium alginate or carbopol gel used as dermal basis. For characterization of the microemulsions, the basic physico-chemical properties were determined. In vitro as well as ex vivo drug release was determined by vertical Franz cells. Results Enhancing effect of the examined microemulsions was observed only in carbopol gel. There was an increase in cumulative drug amount released through synthetic membrane by 37.7–39.8% from the microemulsion formulation and 90.6% from Transcutol® formulation within 6 h compared to the control samples. The differences between the permeation curves with or without the content of the enhancers were statistically significant (p < .05). Pearson correlation coefficients indicate a very high degree of dependence (r > 0.9) between in vitro and ex vivo drug release from all dermal vehicles used. Conclusion It can be stated that Transcutol® is the best solubilizer and also penetration enhancer from the examined, and therefore it seems to be effective excipient/solubilizer in topical IND formulation.

Solubility of Pharmaceutical Ingredients in Natural Edible Oils.

Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.

Effect of supersaturation on absorption of indomethacin and tadalafil in a single pass intestinal perfusion rat model, in the absence and presence of a precipitation inhibitor

The effect of the degree of supersaturation (DS) on absorption of the model drugs indomethacin and tadalafil was elucidated in a single-pass intestinal perfusion (SPIP) model in rats. In addition, the performance of the precipitation inhibitor (PI) hydroxypropylmethylcellulose (HPMC) was evaluated when added at a concentration of 0.1% (w/v) to fasted state simulated intestinal fluid (FaSSIF and FaSSIFHPMC) used as perfusion medium.A supersaturated state was created by a solvent shift method where indomethacin or tadalafil dissolved in dimethyl sulfoxide (DMSO) were administered to a segment of the small intestine, which subsequently was perfused with FaSSIF or FaSSIFHPMC. The perfusate was collected for 60 min, and for one group of rats dosed with 30 mg tadalafil, for 120 min. Blood samples were drawn every 15 min. The solubility of indomethacin and tadalafil in the perfusate was determined. The DS of each drug in the perfusate was calculated by dividing the concentration in the perfusate at selected time points with the solubility. The DS was above one for all timepoints for both drugs, thus showing supersaturation during the time of perfusion. For indomethacin, no improvement of the DS was seen when perfusing with FaSSIFHPMC, compared to FaSSIF. For tadalafil, a higher DS was achieved when perfusing with FaSSIFHPMC compared to FaSSIF. Perfusing the drugs with FaSSIFHPMC resulted in a significantly lower area under the curve (AUC0-60 min) for plasma concentrations of indomethacin, and no increase in the AUC0-60 min of plasma concentrations of tadalafil compared to perfusion with FaSSIF.The importance of simultaneously estimating the intraluminal DS and absorption of a drug was demonstrated by the SPIP model in the present study. Further, the study highlights the discrepancy between optimal in vitro supersaturation, intraluminal supersaturation and in vivo performance of two poorly soluble drugs, and further emphasizes the importance of optimization of in vitro methods in order to predict in vivo supersaturation and precipitation of drugs.

Polymorphic Control and Scale-up Strategy for Crystallization from a Ternary Antisolvent System by Supersaturation Control

Antisolvent crystallization of indomethacin (IMC) was investigated in this work by using an acetone–methanol (66.5–33.5 wt %) mixture as solvent and water as antisolvent. Selecting the binary mixture as the solvent led to an increased yield of the batch process, as the solubility of IMC is higher in the mixed solvents. Adding methanol to the solvent system mitigated the nucleation of the acetone solvate, which is dominating in the acetone–water system. Process analytical technologies were implemented to ensure that the desired polymorph was present throughout the process. Supersaturation control (SSC) was applied as a closed-loop feedback control strategy, to achieve a rapid direct design of the crystallization process using the principles of quality by control. The antisolvent flow-rate profiles, obtained by the SSC, were implemented in open loop and used for scaling up the process by 1 order of magnitude. The results show how feedback control of crystallization from a ternary solvent mixture increases productivity and simultaneously ensures suppression of nucleation to obtain the desired particle size distribution and polymorph. The direct design approach can be applied in the design and development of crystallization processes to yield the chosen solid phase of IMC when scaling from small to large scale.

Drug-Polymer Solubility Determination: A New Thermodynamic Model Free from Lattice Theory Assumptions.

Traditional methods for estimating drug-polymer solubility either require fast dissolution in the polymeric matrix, rapid re-crystallization kinetics from supersaturated states or derive from regular solution theories. In this work, we present a new method for determining drug solubility, purely based on thermodynamic considerations, that uses only experimental data from DSC for calculations. The new thermodynamic model presented combines DSC analysis and application of Hess's law to determine free energies of conversion of binary mixtures to amorphous solid dispersions, free energies of mixing as well as solubility as a function of temperature. The model drug indomethacin and polymers HPMCAS LF, PVP K29/32 and Eudragit EPO were used in these studies. Free energies were calculated as a function of temperature, for different drug-polymer compositions and the results show that HPMCAS LF solid dispersion with high drug content are less thermodynamically favorable compared to other polymer systems. Solubility of indomethacin in HPMCAS LF, PVP K29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C. The thermodynamic model presented has great advantages over traditional methods. It does not require estimation of any interaction parameters, it is almost assumption-free and uses only thermal data for calculations.

Effect of Tetrabutylammonium Bromide-Based Deep Eutectic Solvents on the Aqueous Solubility of Indomethacin at Various Temperatures: Measurement, Modeling, and Prediction with Three-Dimensional Hansen Solubility Parameters.

Deep eutectic solvents (DESs) have recently been getting a great deal of attention in many fields of science and technology. The objective of this study was to peruse the solubility of indomethacin (IMC) as sparingly soluble drug in some tetrabutylammonium bromide (TBAB)-based DESs (TBAB/ethylene glycol and TBAB/glycerol). The shake flask method has been employed in this study at temperature ranges T = (298.15-313.15)K and atmospheric pressure (pP = 86.6kPa). The results showed that the solubility of IMC in TBAB/ethylene glycol systemwas obtained approximately 17,000-fold more than its solubility in water. The solubility data were accurately correlated by the famous local composition activity coefficient models including e-NRTL and UNIQUAC. It was also our aim to evaluate Hansen solubility parameters in IMC solubility prediction. These parameters can help to predict thesolvent performance during the manufacturing processes and will be useful in guessing solvent behavior in many other fields of effort. The experimental and the Hansen solubility parameters results are very well matched. In addition, the apparent thermodynamic properties of dissolution and mixing were studied in these solutions based on Van't Hoff and Gibbs equations.

Exploring the use of spray congealing to produce solid dispersions with enhanced indomethacin bioavailability: In vitro characterization and in vivo study

The current study proposes an original oral delivery system for the bioavailability enhancement of indomethacin (IND), a BCS class II drug, with the aim to overcome the common limitations of amorphous solid dispersion. In fact, the potential risk of drug re-crystallization is a serious concern for the stability of amorphous systems and represents, despite the great bioavailability, one of the primary causes of their limited clinical applications. IND-loaded microparticles (MPs) were prepared by spray congealing using oral-approved excipients (Gelucire 50/13 and the recently marketed Gelucire 48/16). MPs were characterized regarding particle size, morphology, drug content and IND solid state; moreover, they were tested in vitro for IND solubility and dissolution rate. Solid state characterization indicated that IND was present into the MPs in the amorphous form. The best formulation showed a considerable enhancement in drug dissolution rate and 31-fold higher drug solubility than pure γ-IND. The oral administration of MPs showed 2.5-times increased bioavailability in vivo compared to either pure γ-IND or its physical mixture with unloaded MPs. Notably, the formulation was stable after 18 months with no changes in IND solid state and dissolution performance. This study offers a valid approach to enhance IND oral bioavailability by conversion into the amorphous form by spray congealed MPs, which have great potential for industrial application due to their characteristics of high encapsulation efficiency, no-toxicity, low-cost, prolonged stability and the use of a simple and easily scaled-up manufacturing technology.

Molecular structure and impact of amorphization strategies on intrinsic dissolution of spray dried indomethacin

Amorphous systems prepared with different strategies, such as solid dispersion with colloidal particles or soluble polymers and inclusion complex, have been used for improving solubility and dissolution of poorly water soluble drugs. The purpose of this study was to obtain a deeper understanding of the impact of three different amorphous systems prepared by spray drying with silica, polyvinylpyrrolidone (PVP) or 2-hydroxypropyl-β-cyclodextrin (HPβCD) using indomethacin (IND) as a model drug. IND was spray dried with silica, PVP or HPβCD at different mass ratios, and the obtained powders were characterized with respect to colloidal silica particle redispersion, morphology, thermal properties, solid state properties and physical stability. The solubility and intrinsic dissolution rate of IND in the different powders were assessed. It was found that all the three amorphization strategies resulted in amorphous IND product. PVP showed the best stabilizing effect on amorphous IND for at least four months while silica was the worst for no more than 18 days. The solubility of IND decreased with the decrease of HPβCD or PVP ratio in the amorphous products. Samples with HPβCD showed the highest improvement in the dissolution rate at low drug loading, i.e. 15% while samples with PVP resulted in the highest improvement of dissolution rate at high drug loading, i.e. 70%. We conclude that amorphization with PVP was the best strategy for amorphous IND stabilization among all the amorphous products investigated in this project and improved IND dissolution mostly at high drug loadings. HPβCD improved IND dissolution mostly at low drug loadings. Effect of solid dispersion with silica nanoparticles on the dissolution behavior was always the least significant among the three investigated amorphization strategies.

Solubilization of Biologically Active Heterocyclic Compounds by Biocompatible Microemulsions

Microemulsions based on biocompatible components with high water content are applied to increase the solubility of medicinal drugs of the heterocyclic series indomethacin and 1-[5-(4-chlorophenyl)-3-phenylpyrrole-2-yl]benzimidazole-2(3H)-one (PBI). The solubilizing capacity is characterized quantitatively via spectrophotometry. It is shown that four-component microemulsion water/oleic acid/Tween 80/ethanol increases the limits of indomethacin solubility by more than two orders of magnitude, and that of PBI by more than three orders relative to water.

Effect of Solid Dispersions with Polyethylene Glycol 1500 on the Solubility of Indomethacin

Solid dispersions (SDs) of indomethacin with polyethylene glycol 1500 (PEG-1500) were studied to determine their effect on indomethacin solubility. Production of SDs increased the solubility and dissolution rate of indomethacin in H2O. The solubility and dissolution rate of indomethacin from SDs increased by 1.8 – 2.2 and 3.1 – 4.4 times, respectively. Indomethacin became less crystalline and then amorphous during preparation of the SDs. Dissolution of the SDs solubilized indomethacin and formed colloidal solutions.

Effect of 1-ethyl-3-methylimidazolium ethyl sulfate ionic liquid on the solubility of indomethacin in aqueous solutions at various temperatures

Due to very low solubility of indomethacin (IMC) in water, the solubility of IMC was measured in full ranges concentrations w3=(0.0, 0.2, 0.4, 0.6, 0.8, 0.9, and 1.0) of 1-ethyl-3-methylimidazolium ethyl sulfate [EMIM][ES] ionic liquid (IL) in aqueous solutions at several temperatures T=(293.15K to 318.15K). The results indicate that the solubility of IMC is increased by increasing the concentration of [EMIM][ES] and temperature. The solubility of IMC in [EMIM][ES] was raised 30,000 times greater than water. The solubilities were correlated by e-NRTL, Wilson, and UNIQUAC activity coefficient models. The obtained ARD% values show that the e-NRTL model has good agreement with the experimental solubility data. In addition, the thermodynamic functions, Gibbs free energy, enthalpy, and entropy for dissolution and mixing process were estimated by use of van't Hoff equation. The results of the thermodynamic functions confirming the strong interactions between IMC and the IL and indicates that enthalpy is main contribution for the solubility in the aqueous [EMIM][ES] solutions.