Solubility determination and thermodynamic modelling for 2-amino-4-chlorobenzoic acid in eleven organic solvents from T = (278.15 to 313.15) K and mixing properties of solutions

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Highlights

  • Solubility of 2-amino-4-chlorobenzoic acid in eleven solvents were determined.

  • Four thermodynamic models were employed to correlate the solubility data.

  • The mixing properties of solutions were calculated.

Abstract

The solubility of 2-amino-4-chlorobenzoic acid in eleven organic solvents including N-methyl-2-pyrrolidone, ethanol, n-propanol, isopropanol, ethyl benzene, toluene, n-butanol, acetonitrile, ethyl acetate, 1,4-dioxane and acetone were determined experimentally using the isothermal saturation method over a temperature range from (278.15 to 313.15) K under 101.2 kPa. Within the temperature range studied, the mole fraction solubility of 2-amino-4-chlorobenzoic acid in the solvents increased with a rise of temperature. On the whole, they obeyed the following order from high to low in the selected solvents: N-methyl-2-pyrrolidone > acetone > 1, 4-dioxane > ethyl acetate > ethanol > isopropanol > n-propanol > n-butanol > acetonitrile > toluene > ethyl benzene. The solubility values obtained for 2-amino-4-chlorobenzoic acid were correlated with the modified Apelblat equation, λh equation, Wilson model and NRTL model. The largest values of root-mean-square deviation (RMSD) and relative average deviation (RAD) were 8.25 × 10−4 and 3.35%, respectively. The modified Apelblat equation correlated the experimental solubility best on the basis of the result of AIC analysis. Furthermore, the mixing Gibbs energy, mixing enthalpy, mixing entropy, activity coefficient (γ1) and reduced excess enthalpy (H1E,) at infinitesimal concentration were determined. Solubility and thermodynamic studies are very important for optimizing the purification process of 2-amino-4-chlorobenzoic acid.

Introduction

2-Amino-4-chlorobenzoic acid (CAS No. 89-77-0, also named as 4-chloroanthranilic acid) is an important intermediate of pharmaceutical and organic synthesis. Its downstream products have wide applications in many aspects. The 4-chlorosalicylic acid which shows a strong antifungal activity is prepared by treating 2-amino-4-chlorobenzoic acid with nitrous acid [1], [2]. 1-[[2-(Dimethylamino)ethyl]amino]-4-[N-[2-(dimethylamino)ethyl]carbamoyl]-7-hydroxy-9-oxo-9,10-dihydroacridine, which shows a usefully wide spectrum of cytotoxic activity toward tumour cell lines, is also produced by 2-amino-4-chlorobenzoic acid [3]. In addition, it can be used as raw material to produce a novel Tb3+ complex [4], Eu(2-amino-4-chlorobenzoic acid)31,10-phenanthroline [5] and 6-chlorothianaphthene [6]. Due to its good properties, 2-amino-4-chlorobenzoic acid has been received great attention. Nowadays, some methods have been proposed to synthesize 2-amino-4-chlorobenzoic acid [7], [8], [9], [10], [11], [12]. However, during the preparation process of 2-methyl-5-chloroaniline, the reaction product generally contains some unknown by-product, which must be removed from the crude product to obtain high purity product. A basic step in purification and improve productivity of a drug or any chemical substance is to determine its solubility, which can provide a demonstrative description of its physicochemical properties and thermodynamic functions.

It is well-known that solvent crystallization is commonly employed as an essential separation and purification step in the production procedure. The solid solubility in different solvents is a significant physicochemical property which plays an important role for understanding the (solid + liquid) equilibrium (SLE) or phase equilibrium in the development of a crystallization process. More particularly, the knowledge of accurate solubility data is required for the design of crystallization process. In the previous publications, the purification of 2-amino-4-chlorobenzoic acid is recommended via a twofold recrystallization from dilute alcohol [12]. Knowledge of the solubility is very important in the purification process of 2-amino-4-chlorobenzoic acid via the solvent crystallization method. However, to the best of the authors’ present knowledge, no solubility is reported in previous works. In order to acquire high purity 2-amino-4-chlorobenzoic acid, knowledge of 2-amino-4-chlorobenzoic acid solubility in different solvents at various temperatures and the thermodynamic properties of solution is required.

From many species of organic solvents, we chose eleven commonly used organic solvents (N-methyl-2-pyrrolidone, ethanol, n-propanol, isopropanol, ethyl benzene, toluene, n-butanol, acetonitrile, ethyl acetate, 1,4-dioxane and acetone) in industrial purification process. The purposes of this work are to (1) determine the solubility of 2-amino-4-chlorobenzoic acid in the selected solvents by using the isothermal saturation method; (2) correlate the solubility with different thermodynamic models; and (3) calculate the mixing properties for the solution procedure of 2-amino-4-chlorobenzoic acid in different solvents. For the reason that the temperature of solvent-assisted crystallization of 2-amino-4-chlorobenzoic acid les close to the temperature range from 273 K to 320 K, the temperature range from (278.15 to 313.15) K was selected.

Section snippets

Solid-liquid phase equilibrium models

In order to discover the suitable models to describe the solubility behaviour of 2-amino-4-chlorobenzoic acid in the studied solvents, in this work, four models are used to correlate the solubility results, which correspond to the modified Apelblat equation [13], [14], λh equation [15], Wilson model [16] and NRTL model [17].

Materials and apparatus

2-Amino-4-chlorobenzoic acid having a mass fraction of 0.983 was provided by Beijing HWRK Chemical Co., Ltd. It was recrystallized three times in ethanol. The purified sample had a purity of 0.997 in mass fraction, which was confirmed by a high-performance liquid phase chromatograph (HPLC, Agilent-1260). All the solvents (N-methyl-2-pyrrolidone, ethanol, n-propanol, isopropanol, ethyl benzene, toluene, n-butanol, acetonitrile, ethyl acetate, 1,4-dioxane and acetone) purchased from Sinopharm

Melting properties of 2-amino-4-chlorobenzoic acid

Fig. 2 contains the DSC curve of 2-amino-4-chlorobenzoic acid. From the DSC analysis results, the melting temperature Tm and melting enthalpy ΔfusH of 2-amino-4-chlorobenzoic acid are 507.5 K and 28.76 kJ mol−1, respectively. The melting temperature Tm determined in this work is lower than the value reported in Ref. [22], and higher than that reported in Ref. [24], but in the range presented in Ref. [23]. This case may be due to the difference in equipment, samples and/or measured conditions.

Based

Conclusions

The equilibrium solubility was determined experimentally for 2-amino-4-chlorobenzoic acid in a total of eleven pure organic solvents within the temperature range from (278.15 to 313.15) K under 101.2 kPa. The mole fraction solubility of 2-amino-4-chlorobenzoic acid in the selected pure solvents increases with the increase in temperature. At a certain temperature, they ranked as N-methyl-2-pyrrolidone, ethanol, n-propanol, isopropanol, ethyl benzene, toluene, n-butanol, acetonitrile, ethyl

Acknowledgments

This work was supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors would like to express their gratitude for the Innovation Project of Jiangsu Province for Post Graduate Students (Project number: KYLX16_1396).

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