Solubility of 3-methyl-4-nitrobenzoic acid in binary solvent mixtures of {(1,4-dioxane, N-methyl-2-pyrrolidone, N,N-dimethylformamide) + methanol} from T = (283.15 to 318.15) K: Experimental determination and thermodynamic modelling

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Highlights

  • Solubility of 3-methyl-4-nitrobenzoic acid in three binary mixed solvents was determined.

  • The determined solubility were correlated and calculated by six co-solvent models.

  • Standard dissolution enthalpies were computed.

Abstract

The solubility of 3-methyl-4-nitrobenzoic acid (MNBA) in binary (1,4-dioxane + methanol), (N-methyl-2-pyrrolidone (NMP) + methanol) and (N,N-dimethylformamide (DMF) + methanol) solvent mixtures were investigated by the isothermal dissolution equilibrium method under atmospheric pressure. The studies were performed at different mass fractions of 1,4-dioxane, DMF or NMP ranging from 0.1 to 0.9 at temperature T = (283.15 to 318.15) K. The solubility of MNBA in mixed solutions increased with increasing temperature and mass fraction of 1,4-dioxane, DMF or NMP for the three systems including (1,4-dioxane + methanol), (NMP + methanol) and (DMF + methanol). At the same mass fraction of 1,4-dioxane, DMF or NMP and temperature, the solubility of MNBA was greater in (DMF + methanol) than in the other mixed solvents. The obtained solubility data were correlated with Jouyban-Acree model, van’t Hoff-Jouyban-Acree model, modified Apelblat-Jouyban-Acree model, Ma model, Sun model and CNIBS/R-K model. The largest values of relative average deviations (RAD) and the root-mean-square deviations (RMSD) between the experimental and calculated solubility were 4.62 × 10−2 and 2.41 × 10−3, respectively. The calculated solubility with the six models agreed well with the experimental results. On the basis of the solubility obtained, the standard dissolution enthalpy of the dissolution process was calculated. Dissolution of MNBA in these mixed solvents was an endothermic process. The experimental solubility and the models in this study could be helpful in purifying the crude MNBA.

Introduction

3-Methyl-4-nitrobenzoic acid (abbreviated as MNBA; CAS Reg. No. 3113-71-1) is an important intermediate in the synthesis of telmisartan (via esterification, reduction, butyrylation, nitration, reduction and cyclization) which is used to treat essential hypertension. Telmisartan is a drug belonging to the group of antagonists of angiotensin II receptors. The active ingredient telmisartan counteracts the effect of angiotensin II, allowing the arteries to relax, thereby reducing blood pressure [1], [2]. As a precursor, pharmaceutical researchers have also synthesized anti-cancer substances and AIDS drugs with MNBA [3], [4]. The commercial value of MNBA has gradually raised people’s attention. However, during the preparation process of MNBA, it is accompanied by formation of a large amount of the side products 4-nitroisophthalic acid and 5-methyl-2-nitrobenzoic acid [4], [5], [6]. The yield of MNBA is no greater than 60% (mass fraction). The crude MNBA containing the side products restricts its further applications in many aspects. Due to the high boiling points of the main product and by products (MNBA, 629.2 K; 4-nitroisophthalic acid, 766.1 K; 5-methyl-2-nitrobenzoic acid, 637.0 K) [7], it is very difficult to obtain MNBA with high purity from the mixtures by distillation.

It is well known that solvent crystallization is usually used as an important separation and purification step in the production process. The solubility of solid in different solvents is an important physicochemical property for different areas such as crystallization, separation, liquid extraction, drug formulation, and can be recognized at all steps of drug discovery and development processes. The knowledge of thermodynamic parameters, particularly accurate solubility is needed for the design of crystallization process. Moreover, the solubility also plays a significant role during the separation process and determination of proper solvents via solvent crystallization. The purification of MNBA is recommended via a twofold recrystallization from methanol in the previous publication [5]. With the purpose of acquiring high purity MNBA, recently, the solubility of MNBA is determined in different pure solvents at various temperatures [8]. However, we cannot locate any research publication about solubility of MNBA in mixed solutions.

Solubility alteration of chemicals is needed in many industrial applications, and the solvent mixing is one of the most frequent and feasible methods used in the industry. Using different ratios of solvents, a wide range of solubility for a given compound can be attained. The next parameter which could be used in the chemical industry is the changing temperature of the system which makes a significant contribution in crystallization of a compound. So there is a strong need to determine the MNBA solubility in mixed solutions and build better models for describing these behaviours, especially in the cases of non-ideal systems. According to our previous studies [8], value of the solubility of MNBA is very high in N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) and 1,4-dioxane, and very low in methanol. In order to select an appropriate solvent system for MNBA purification, in the present study, we carry out the systematic studies on solubility of MNBA in binary mixed solvents. The objectives of this work are to (1) determine the solubility of MNBA (1,4-dioxane + methanol), (NMP + methanol) and (DMF + methanol) solvent mixtures with 1,4-dioxane. NMP or DMF contents from 0.10 to 0.90 (mass fraction) at different temperatures under atmospheric pressure; (2) correlate the solubility results with different models; (3) calculate the standard dissolution enthalpy for the solution process of MNBA in different binary solvents. The purification process of 4-nitrophthalimide is usually performed at below 320 K, so the temperature range from (283.15 to 318.15) K is selected.

Section snippets

Solubility models

In addition to the experimental efforts to measure solubility of solids in mixed solvents, several models have been proposed to correlate the solubility in mixed solvents. In this work, six models are employed to correlated the solubility of MNBA in binary solvent mixtures of (1,4-dioxane + methanol), (NMP + methanol) and DMF + methanol) at different temperatures, which correspond to Jouyban-Acree model [9], [10], a combination of Jouyban-Acree model with van’t Hoff equation [11], [12], a combination

Materials and apparatus

MNBA having a mass fraction of 0.981 was provided by Beijing Ouhe Chemical Technology Co., Ltd. It was recrystallized several times in methanol. The purified sample had a mass fraction purity of 0.994, which was confirmed by a high-performance liquid phase chromatograph (HPLC, Agilent-1260). The solvents of methanol, 1,4-dioxane, NMP and DMF with analytical grade were purchased from Sinopharm Chemical Reagent Co., Ltd., China. The mass fraction purities of these solvents were all greater than

Solubility results

Table 2, Table 3, Table 4 show the measured mole fraction solubility of MNBA in binary solvent mixtures of (1,4-dioxane + methanol), (NMP + methanol) and (DMF + methanol), respectively. In addition, the mole fraction solubility of MNBA in pure solvents [8] is also presented in Table 2, Table 3, Table 4. It can be seen from Table 2, Table 4 that, for a certain solvent mixture with given initial composition, the solubility of MNBA increases with increasing temperature and mass fraction of 1,4-dioxane,

Conclusions

The solubility of MNBA in three binary solvent mixtures of (1,4-dioxane + methanol), (NMP + methanol) and (DMF + methanol) with various composition was obtained experimentally at temperatures ranging from (283.15 to 318.15) K by using the isothermal dissolution equilibrium method under 101.0 kPa. For the three binary solvent mixtures, the solubility of MNBA increases with the increase in temperature. At the same temperature, the solubility of MNBA in (1,4-dioxane + methanol), (NMP + methanol) and (DMF + 

References (26)

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