Solubility measurement and modelling of ethyl 5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophenecarboxylate in four groups mixed solvents

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Highlights

  • Solubility of ACET in four groups mixed solvents were determined.

  • Solubility data were correlated and calculated by three cosolvency models.

  • The standard dissolution enthalpy for the dissolution processes were calculated.

Abstract

The solubility of ethyl 5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophenecarboxylate (ACET) in binary (acetone + methanol), (acetone + ethanol), (acetone + 1-butanol) and (acetone + isopropanol) solvent mixtures was investigated by the isothermal dissolution equilibrium method under 101.3 kPa. This study was carried out at different mass fractions of acetone ranging from 0.1 to 0.9 at T = (273.15–318.15) K. For the nine groups with each solvent mixture studied, the solubility of ACET in the mixed solutions increased with increasing temperature and mass fraction acetone. At the same temperature and mass fraction of acetone, the solubility of ACET was greater in (acetone + methanol) than in the other three solvent mixtures. The experimental solubility values were correlated by three co-solvency models (Jouyban-Acree model, van’t Hoff-Jouyban-Acree model and Apelblat- Jouyban-Acree model). The relative average deviations (RAD) and the root-mean-square deviations (RMSD) were all less than 1.49 × 10−2 and 8.99 × 10−4, respectively. The Apelblat-Jouyban-Acree model provided best representation of the experimental solubility. Furthermore, the standard molar enthalpy of the ACET during the dissolving process (ΔsolHo) was also derived in this work, and the results showed that the dissolution process is endothermic. The experimental solubility and the models used in this work would be helpful in purifying of ACET from its crude mixtures.

Introduction

Ethyl 5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophenecarboxylate (CAS Reg. No. 58168-20-0; abbreviated to ACET) is an important organic intermediate in the synthesis of anti-osteoporosis drugs such as tetraethyl ranelate and strontium ranelate [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. In the present works, some methods have been put forward to prepare ACET [14], [15], [16], [17], [18]. Reaction of 1,3-acetonedicarboxylic acid diethyl ester with malononitrile in ethanol is a common way to produce ACET in industry at present [4], [10], [14], [18]. During the production process of ACET, however, some by-products (unknown at present) are also generated. The obtained product is a mixture of ACET, unknown by-product and unreacted raw materials. The crude product restricts its further use in many fields. In order to extend the application of ACET, it is vital to isolate and purify the crude product to obtain high purity product. Solvent crystallization is a valuable method to purify ACET with low cost [14], [15], [16], [17], [18], [19]. A basic step in purification and improve productivity of a drug or any chemical substance is to determine its solubility behaviour, which can give a demonstrative description of its physicochemical properties and thermodynamic functions. Thus the knowledge of the solubility of ACET in different solvents is of clear importance for the purity and quality of the final product.

As we know, solubility plays a significant role in optimizing the crystallization procedure and improving the purity and yield of the solid compound. The solubility has a direct effect on the purity and quality of the final product. The basis of ACTE purification via solvent crystallization is the solubility of ACET in different solvents. However, to the best of the authors’ present knowledge, many studies focus only on the production process of ACET, although a few researchers try to construct purification methods to acquire product with high purity. In order to enrich knowledge of the solubility and provide the comprehensive basic data for engineering application, recently, Han and co-workers reports the solubility of ACET in nine pure organic solvents [20]. But, up to now, we don’t find any researches about the solubility of ACET in mixed solutions. We also know that solvent mixing with temperature alteration is a usual method to vary the solubility of compounds in crystallization investigations. The generated data will be helpful in understanding solute-solvent interactions and in process optimization. There is a strong need to determine the solubility of ACET in mixed solutions and build better models for predicting these behaviours, particularly in the cases of non-ideal systems. According to the Ref. [20], the solubility of ACET is greater in acetone, and lower in the four solvents of methanol, ethanol, 1-butanol and isopropanol. The mixed solvents can change the solubility of ACET.

In order to select a suitable solvent system used for ACET purification, it is necessary to know the solubility of ACET in binary solvent mixtures. Therefore, in the present paper, we report the results of our systematic studies on solubility of ACET in the binary solvents. The objectives of this work are to (1) determine the solubility of ACET in binary solvent mixtures of (acetone + methanol), (acetone + ethanol), (acetone + 1-butanol) and (acetone + isopropanol) from T = (273.15 to 318.15) K under atmosphere pressure; (2) correlate the experimental solubility results with different models; and (3) calculate the dissolution enthalpy for the dissolution process of ACET in solvent mixtures. In general, the purification process of ACET is performed at below 320 K, so the temperature range from (273.15 to 318.15) K is selected.

Section snippets

Solubility models

In addition to the experimental efforts to measure the solubility of a solid in mixed solvents, a number of models have been put forward to correlate the solid solubility in mixed solvents. In this work, three models widely used solid-liquid phase equilibrium are employed to correlate the solubility of ACET in binary solvent mixtures of (acetone + methanol), (acetone + ethanol), (acetone + 1-butanol) and (acetone + isopropanol) at various temperatures. These are the Jouyban–Acree model [21], [22], [23]

Materials

In this study, ACET was purchased from Shanghai Xuxin Chemical Technology Co., Ltd with initial mass fraction 0.98. It was recrystallized several times in aqueous solutions of methanol (volume ration of methanol to water is 95:5). Finally, its’ mass fraction purity was 0.997, which was verified by a high-performance liquid phase chromatograph (HPLC; Agilent Technologies, USA). The solvents of methanol, ethanol, isopropanol, 1-butanol and acetone were obtained from Merck, whose mass fraction

Solubility results

Values of the measured solubility in mole fraction (x) of ACET in (acetone + methanol), (acetone + ethanol), (acetone + 1-butanol) and (acetone + isopropanol) over the temperature range from 273.15 K to 318.15 K and different solvent compositions are presented in Table 2, and plotted in Fig. 2, Fig. 3, Fig. 4, Fig. 5. It is noted that the mole fraction solubility of ACET in pure solvents (methanol, ethanol, acetone, 1-butanol and isopropanol) at T = (273.15, 278.15, 283.15, 288.15, 293.15, 298.15, 303.15,

Conclusions

The solubility of ACET in four binary solvent mixtures of (acetone + methanol), (acetone + ethanol), (acetone + 1-butanol) and (acetone + isopropanol) at various composition was obtained experimentally at temperatures ranging from (273.15 to 318.15) K by using the isothermal dissolution equilibrium method under 101.3 kPa. For the four binary solvent mixtures, the solubility of ACET increases with the increase in temperature, however the increments with temperature varied for different mixed solvents. At

Acknowledgment

This work was supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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