Solubility determination and thermodynamic modelling of 2,4-dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one in twelve organic solvents from T = (278.15 to 313.15) K and mixing properties of solutions

https://doi.org/10.1016/j.jct.2016.08.007Get rights and content

Highlights

  • Solubility of 2,4-dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one in twelve solvents were determined.

  • The solubility were correlated with four thermodynamic models.

  • Mixing properties of the solutions were computed.

Abstract

The solubility of 2,4-dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one in twelve organic solvents including methanol, ethanol, n-propanol, isopropanol, ethylbenzene, toluene, n-butanol, acetonitrile, ethyl acetate, 1,4-dioxane, cyclohexane and isopentanol were determined experimentally by using the isothermal saturation method over a temperature range from (278.15 to 313.15) K under 101.3 kPa. For the temperature range studied, the solubility of 2,4-dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one in the solvents increased with a rise of temperature. The mole fraction solubility obeyed the following order from high to low in different solvents: isopentanol > 1,4-dioxane > n-butanol > n-propanol > ethyl acetate > methanol > ethanol > isopropanol > ethylbenzene > toluene > acetonitrile > cyclohexane. The obtained solubility data of 2,4-dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one in the studied solvents 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 1.35 × 10−4 and 0.32%, respectively. The RAD values obtained with the modified Apelblat equation were smaller than those with the other three models for a given solvent. So the four thermodynamic models were all acceptable for the systems of 2,4-dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one in these solvents. Furthermore, the mixing Gibbs energy, mixing enthalpy, mixing entropy, activity coefficient (γ1) and reduced excess enthalpy (H1E,) at infinitesimal concentration were calculated. The obtained solubility and thermodynamic studies would be very helpful for optimizing the purification process of 2,4-dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one.

Introduction

2,4-Dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one (CAS Reg. No. 86-92-0; also named 1-(p-tolyl)-3-methyl-5-pyrazolone (abbreviated as PTMP); structure shown in Fig. 1) is an important intermediate of pharmaceutical. As a type of brain-protecting agent, it can inhibit oxidative damage to brain cells and nerve cells [1]. It also offers immense therapeutic value due to their broad biological spectrum which includes antimicrobial, antibacterial, anti-inflammatory, antitumor, antidepressant and neuro-protective activity [2], [3], [4], [5]. What’s more, it can be used as a raw material to produce dyestuff [6]. Some methods have been put forward to synthesize the PTMP [1], [2], [7], [8], [9], [10], [11], [12]. At present, the main preparation method of PTMP is using phenylhydrazine hydrochloride and ethyl acetoacetate as raw material. During the reaction process, some unknown by-products are also produced [7], [8], [9], [10], [11], [12]. With the development of pharmaceutical industry, the requirements for product purity are becoming greater. The crude PTMP restricts its further applications in many aspects.

As is known, solvent crystallization is an effective method in solid purification. The solubility of solid in different solvents is an important 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 is needed for the design of crystallization process. In previous publications, the purification of PTMP is recommended via a twofold recrystallization from ethyl acetate [1], or recrystallization from ethanol [7]. The solubility data are necessary in designing the crystallization process and conducting further thermodynamic research. These data are very important in the purification process of PTMP via the solvent crystallization method. Nevertheless, to the best of the authors’ present knowledge, no solubility data of PTMP are reported in the previous works. In order to acquire high purity PTMP, the knowledge of PTMP solubility in different solvents at various temperatures and the thermodynamic properties of solution is a necessary procedure.

In general, the purification process of PTMP is performed in organic solvents at below 320 K. In order to find a suitable solvent to purify PTMP, the purposes of the work are to (1) determine the solubility of PTMP in methanol, ethanol, n-propanol, isopropanol, ethylbenzene, toluene, n-butanol, acetonitrile, ethyl acetate, 1,4-dioxane, cyclohexane and isopentanol at temperatures ranging from (278.15 to 313.15) K by using the isothermal saturation method; (2) correlate the solubility data with different thermodynamic models; and (3) calculate the mixing properties for the solution process of PTMP in different solvents.

Section snippets

Solid-liquid phase equilibrium models

In order to find an appropriate model to describe the solubility behaviour of PTMP in the studied solvents, in this work, four models are employed to correlate the solubility data, which correspond to the modified Apelblat equation [13], [14], λh equation [15], Wilson model [16] and NRTL model [17].

Materials and apparatus

PTMP having a mass fraction of 0.985 was provided by Beijing HWRK Chemical Co., Ltd. It was crystallized three times in ethyl acetate. The purified sample had a mass fraction purity of 0.997, which was determined by high-performance liquid phase chromatograph (HPLC, Agilent-1260). The solvents, including methanol, ethanol, n-propanol, isopropanol, ethylbenzene, toluene, n-butanol, acetonitrile, ethyl acetate, 1,4-dioxane, cyclohexane and isopentanol were of analytical grade and all provided by

Melting properties of PTMP

The DSC scan of PTMP is shown in Fig. 3. From the DSC scan results, the melting temperature Tm and melting enthalpy ΔfusH of PTMP are 406.65 K and 26.52 kJ·mol−1, respectively. The melting temperature Tm determined in this work is lower than the values determined by Hiroyoshi [7] and Baraeva [8], and higher than that determined by Yu [9], but in the range presented in Ref. [21]. This case may be due to the difference in equipment, purity of samples and/or measured conditions.

According to the

Conclusions

In this work, the equilibrium solubility was acquired experimentally for PTMP in twelve pure organic solvents within the temperature range from (278.15 to 313.15) K under 101.3 kPa. The solubility of PTMP in the selected pure solvents increased with increase in temperature. At a certain temperature, the mole fraction solubility ranked as isopentanol > 1,4-dioxane > n-butanol > n-propanol > ethyl acetate > methanol > ethanol > isopropanol > ethylbenzene > toluene > acetonitrile > cyclohexane. The experimental

Acknowledgment

This work is financial supported by the Natural Science Foundation of the Anhui Province (Project numbers: 1408085MB40 and KJ2016A888). The authors would also like to express their gratitude for the National Natural Science Foundation of China (Project number: 21406192) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

References (28)

  • P. Gupta et al.

    Synthesis and biological significance of pyrazolones: A Review

    Int. J. Pharm. Sci. Res.

    (2015)
  • A.E.A. Hassan et al.

    Synthesis and antimicrobial evaluation of novel pyrazolones and pyrazolone nucleosides

    Nucleosides Nucleotides Nucleic Acids

    (2012)
  • F. Ernst, Monoazo-dyestuffs insoluble in water, US Patent 2,220,598. Nov. 5,...
  • N. Hiroyoshi, W. Toshiaki, Y. Satoshi, M. Yasuhiro, I. Katsuhiko, S. Hiroko, Prophylactic and therapeutic agent for...
  • Cited by (0)

    View full text