Indomethacin solubility in 1-Ethyl-3-Methylimidazolium Ethylsulfate and water mixtures at various temperatures

Hemayat Shekaari *, Mohammed Taghi Zafarani-Moattar, Masumeh Mokhtarpour, Saeid Faraji

Department of Physical Chemistry, University of Tabriz, Tabriz, Iran

*Correspondence: Tel.: +98-41-33393094. Fax: +98-41-33340191. E-mail address: hemayatt@yahoo.com.

Abstract

The mole fraction solubility of indomethacin was determined in binary mixtures of 1-Ethyl-3-Methylimidazolium Ethylsulfate [EMIM][ES] + water with seven different compositions of [EMIM][ES] at six different temperatures (293.15 K to 318.15 K). One of the ionic liquids (ILs) with very low toxicity is EMISE and the solubility in this solvent was increased with increasing the weight fraction of IL.

Keywords:  Indomethacin, Solubility, Methylimidazolium Ethylsulfate.

Introduction

Ionic liquids (ILs) are a great alternative to organic solvents in different processes [1, 2]. The growing interest in the use of ILs is well known in the pharmaceutical applications especially in the field of solubility of drugs, Recrystallization, as extractants of pharmaceutical compounds from aqueous solutions etc. The great interest of these solvents is their negligible vapor pressure, low melting point and good thermal stability making them liquid over large temperature ranges (typically 300 K) which include environment temperature. Furthermore, they are non-flammable and easy to recycle. These properties make them very attractive especially in the pharmaceutical industry [3]. On the other hand, low solubility of many drugs in water is one of the important issues in pharmacy which encouraged pharmacists look for ways to increase the solubility of drugs [4]. One of these methods is the use of ILs as co-solvent. Co-solvency is a simple, efficient, most

frequent and feasible solubilization method used in the pharmaceutical industry [5]. Some other physicochemical properties including permeability and dissolution rate of drugs can be also improved with utilizing this method [6]. This method is used to increase the solubility of many drugs including commonly used drugs such as indomethacin (IMC). IMC is a non-steroidal anti-inflammatory drug used as analgesic and antipyretic, among other indications [7]. Although IMC is used in therapeutics, the physicochemical information is not abundant about its solubility. Its solubility in water is very low [8, 9], but water-ILs mixtures have been used widely in pharmacy to increase the solubility of drugs [10, 11]. In addition, the choice of ionic liquid with very low toxicity is an important point in this regard. One of the ionic liquids with very low toxicity is 1-Ethyl-3-Methylimidazolium ethylsulfate [EMIM][ES]. This new IL is described based on the alkylation of the imidazole nucleus with dialkyl sulfates. This liquid exist as alkyl sulfate salts which are stable and show promise as alternative reaction media. The complete absence of halide ions from the synthesis is a major advantage of such a system [12].

In this work, [EMIM][ES] is used as co-solvent to increase the solubility of IMC. We measured the solubility of IMC in aqueous [EMIM][ES]  solutions at T = (293.15 to 318.15) K and the atmospheric pressure.

Experimental

1-Ethyl-3-methylimidazolium ethylsulfate was prepared according to: 0.42 mol of diethylsulfate was added dropwise to 0.42 mol of 1-methylimidazole in toluene and cooled in an ice bath under argon at a rate to maintain the reaction temperature below 313.15 K due to the reaction being highly exothermic. The reaction mixture was stirred at room temperature for (1 to 4) h depending on the amount of starting materials. The upper organic phase of the resulting mixture was decanted, and the lower IL phase was washed with ethyl acetate. After the last washing, the remaining ethyl acetate was removed by heating under reduced pressure. The IL obtained was dried by heating to (343.15 to 353.15) K and stirring under high vacuum for 48 h. The binary solvent mixtures (IL + water) were prepared by mixing the appropriate amounts (in grams) of solvents. The shake flask method has been employed in this work. Briefly, the sealed vials containing an excess amount of IMC powder in the solvent mixtures were mixed using a shaker (Behdad, Tehran, Iran) and placed in water bath thermostat for 3 days to reach equilibrium. The clear solutions were diluted with water and assayed by a double beam spectrophotometer (T80 UV-vis spectrometer PG instruments) at 321 nm. The concentrations of the diluted solutions were determined from the calibration curve with the correlation coefficient of 0.9999. Each experimental data point represented the average of at least three repetitive experiments.

Results and Discussion

IMC aqueous solubility as mole fraction, x₁, in (IMC (1) + water (2) + IL (3)) systems was determined in binary mixtures at six temperatures and they are reported in Table 1. Also, they are calculated by using of Eq. (1):

(1)

where M_i and w_i are the molecular mass and mass fraction of i component in the saturated solution, respectively [13]. The comparison between solubility of IMC, mole fraction x₁, versus w₃ in aqueous IL solutions with different weight fractions at 293.15 and 318.15 K has been shown in Fig. 1. It can be seen from this figure that the solubility of IMC was increased not only by increasing the mass fraction of IL (w₃) but also at higher temperatures. In 1,4-dioxane + water co-solvent with 1,4-dioxane weight fraction of 0.2 and 298.15 K, the value of  4.60×10^-6 (mole fraction) has been reported by Ruidiaz et al. [14]. The value of 3.42×10^-5 was obtained at the same temperature in [EMIM][ES] aqueous solution. Also, mole fraction for solubility of IMC in IL co-solvent system indicate an improvement in the solubility of this drug by using this IL. Peña et al [15] reported the solubility of IMC in ethanol + water solvent mixtures at 293.15 K with weight fraction of 0.2 ethanol (3.42×10^-5)  and in Propylene glycol + water (5.06×10^-6) which much lower than its solubility found in IL.

Fig. 1. The relationship between solubility of IMC, mole fraction x₁, versus w₃ in aqueous [EMIM][ES] solutions at T = 293.15 (♦), 298.15(▲), 303.15 (●), 308.15 (■), 313.15 (◊), 318.15 (∆).

Table 1. The experimental solubility of IMC in the aqueous [EMIM][ES] solutions at different temperatures.

Conclusions

We have experimentally determined indomethacin solubility in aqueous solutions of 1-ethyl-3-methylimidazolium ethyl sulfate at various temperatures and ambient pressure. Results show that the solubility of this drug increased more than 30,000 times rather than water at 318.15 K and this ionic liquid is a wonderful solvent for indomethacin in pharmaceutical science.

Acknowledgment

The authors wish to thank financial support from the graduate council of the University of Tabriz.

References

[1] Zaitsau D.H., Kabo G.J., Strechan A.A., Paulechka Y.U.,  Tschersich A., Verevkin S.P., Heintz A., Experimental vapor pressures of 1-alkyl-3-methylimidazolium bis (trifluoromethylsulfonyl) imides and a correlation scheme for estimation of vaporization enthalpies of ionic liquids, J. Phys. Chem. A, 2006; 110:7303-7306.

[2] Rebelo L., Lopes J., EsperanĮ JMSS, Filipe E., Phys J.. Chem. B, 2008;53: 6040-6043.

[3] Seddon K.R., Ionic liquids for clean technology, J. Chem. Technol. Biotechnol. 1997;68: 351-356.

[4] Marrucho I., Branco L., Rebelo L., Ionic liquids in pharmaceutical applications, ‎Annu. Rev. Chem. Biomol. Eng. 2014; 5 :527-546.

[5] Vahdati S., Shayanfar A., Hanaee J., Martínez F., Acree Jr,  Jouyban A., Solubility of carvedilol in ethanol+ propylene glycol mixtures at various temperatures, Ind. Eng. Chem. Res.2013;52:16630-16636.

[6] Abbott A.P., Capper G., Davies D.L., Munro H.L., Rasheed R.K., Tambyrajah V., Preparation of novel, moisture-stable, Lewis-acidic ionic liquids containing quaternary ammonium salts with functional side chainsElectronic supplementary information (ESI) available: plot of conductivity vs. temperature for the ionic liquid formed from zinc chloride and choline chloride (2∶ 1).Chem. Comm.  2001;2010-2011.

[7] Troy D.B., Hauber M., Remington: The science and practice of pharmacy. 21st, Baltimore: Lippincott Williams & Wilkins, 2005.

[8] Rubino J.T., Cosolvents and cosolvency, Encyclopedia of pharmaceutical technology, 1988; 3: 375-398.

[9] Yalkowsky S.H., Solubility and solubilization in aqueous media, American Chemical Society1999.

[10] Mehrdad A., Miri A.H., Influence of 1-butyl-3-methyl imidazolium bromide, ionic liquid as co-solvent on aqueous solubility of acetaminophen, J. Mol. Liq. 2016;221: 1162-1167.

[11] Mehrdad A., Miri A.H., Aqueous solubility of acetaminophen in the presence of 1-hexyl-3-methyl imidazolium bromide, ionic liquid as co-solvent, Fluid Phase Equilib. 2016;425: 51-56.

[12] Holbrey J.D., Reichert M.D., Swatloski R.P., Broker G.A., Pitner W.R., Seddon K.R., Rogers R.D., Efficient, halide free synthesis of new, low cost ionic liquids: 1, 3-dialkylimidazolium salts containing methyl-and ethyl-sulfate anions, Green Chem. 2002; 4: 407-413.

[13] Forte A., Melo C.I., Bogel-Łukasik R., Bogel-Łukasik E., A favourable solubility of isoniazid, an antitubercular antibiotic drug, in alternative solvents,  Fluid Phase Equilib. 2012;318: 89-95.

[14] Ruidiaz M.A., Delgado D.R., Martínez F., Marcus Y., Solubility and preferential solvation of indomethacin in 1, 4-dioxane+ water solvent mixtures, Fluid Ph. Equilibria, 2010;299:259-265.

[15] Peña M.A., Delgado D.R., Martínez F., Preferential solvation of indomethacin in some aqueous co-solvent mixtures, Chem. Eng. Comm. 2016;203: 619-627.