Solubility measurement and thermodynamic functions of dehydroepiandrosterone acetate in different solvents at evaluated temperatures

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Highlights

Abstract

The solubility was measured for dehydroepiandrosterone acetate in cyclohexane, acetone, ethyl acetate, acetonitrile, methanol, 1-butanol, ethanol and isopropanol by high-performance liquid chromatography analysis under the pressure of 101.3 kPa. The temperature of the determination varied from (273.15 K to 318.15) K. The dehydroepiandrosterone acetate solubility increased with the increase in temperature, and obeyed the following order from high to low: ethyl acetate > acetone > 1-butanol > acetonitrile > (cyclohexane, isopropanol) > ethanol > methanol. They were correlated with four models, viz. the modified Apelblat equation, λh equation, Wilson model and NRTL model. The largest average standard deviation is 5.93 × 10−4, and the largest relative average deviation is 1.18% for each set of solubility values. The calculated solubility was in good agreement with the experimental values for the four models. Moreover, the thermodynamic properties of the solution process, including the apparent standard dissolution enthalpy and excess enthalpy were calculated. The experimental solubility, thermodynamic models and thermodynamic properties are very important in the purification process of dehydroepiandrosterone acetate.

Introduction

Dehydroepiandrosterone acetate (CAS No: 853-23-6, abbreviated as DHEA acetate) is a white or nearly white crystalline powder with molar mass and molecular formula of 330.47 g·mol−1 and C21H30O3, respectively. Its chemical structure is shown in figure 1. DHEA acetate is an important pharmaceutical intermediate and has achieved industrial importance for the synthesis of various hormones, for example, testosterone, methyl testosterone, estradiol, estriol [1], [2], [3]. In recent years, much attention has been attracted on exploiting the new applications of DHEA acetate [4], [5], [6]. Some methods for DHEA acetate preparation have been put forward in the literature [7], [8], [9], [10]. Generally, it can be synthesized by using 5,16-pregnane diene-3 beta-20-keto-3-acetic ester [7] or acetate pregnancy dehydropregnenolone [8] as the raw materials. However during the preparation process of DHEA acetate, the reaction product usually contains some unknown by-product and a few unreacted materials [7], [8], [9], [10]. The impurities seriously affect the subsequent reaction. So it should be purified before use to obtain high purity product.

The solvent crystallization process is a critical step that determines the quality of the product of DHEA acetate with sufficient purity for the next reaction. Solubility is an essential physicochemical property that plays an important role in the solvent crystallization process. So it is significant to know the solubility of DHEA acetate as a function of temperature in selected solvents required for the preparation and purification of the product. A few crystallization methods have been employed to purify DHEA acetate from its mixture [7], [8], [9], [10]; nevertheless, to the best of authors’ present knowledge, no study has been made for determining and correlating the solubility of DHEA acetate in the open publications. The most basic information on solving the solvent selection problem for the purification process of a solid is solubility data. In order to obtain high purity DHEA acetate, it is necessary to know the solubility of DHEA acetate in different solvents at various temperatures and the thermodynamic properties of the solution process.

The objects of this work are to (1) determine the solubility of DHEA acetate in different solvents (cyclohexane, acetone, ethyl acetate, acetonitrile, methanol, 1-butanol, ethanol and isopropanol) over the temperature range from (273.15 to 318.15) K under pressure of 101.3 kPa; (2) correlate the solubility obtained with the modified Apelblat equation [11], [12], Buchowski–Ksiazaczak λh equation [13], [14], Wilson equation [15] and NRTL model [16]; and (3) compute the thermodynamic properties for the solution process of DHEA acetate in the selected solvents.

Section snippets

Materials and apparatus

A white crystalline powder of DHEA acetate was supplied by Shanghai Lingfeng Chemical Reagent Co., Ltd, China. It was recrystallized twice in pure acetone. The final mass fraction of DHEA acetate was higher than 0.995, which was measured by a Shimadzu-6A high-performance liquid phase chromatograph (HPLC). The solvents of analytical grade, including cyclohexane, acetone, ethyl acetate, acetonitrile, methanol, 1-butanol, ethanol and isopropanol were all supplied by Sinopharm Chemical Reagent Co.,

Property of pure component

The thermal analysis of DHEA acetate is shown in figure 3. It can be seen from the DSC results that the fusion point Tm and fusion enthalpy ΔfusH of DHEA acetate are T = 442.78 K and 29.29 kJ·mol−1, respectively. The determined value of Tm in this work is lower than that given in references [21], [22], [23], [24], however it is within the range of that reported in [25] and [26].

Based on the melting temperature and fusion enthalpy ΔfusH of DHEA acetate measured in this work, the fusion entropy ΔfusS

Conclusions

The solubility of DHEA acetate in a total of eight solvents was determined from (273.15 to 318.15) K by the high-performance liquid chromatography analysis and simple solubility apparatus under 101.3 kPa. For all solvents, solubility is a function of temperature and increases with increasing temperature. The highest solubility occurs in ethyl acetate and the lowest in methanol. DHEA acetate solubility fits the following order from high to low: ethyl acetate > acetone > 1-butanol > acetonitrile > 

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (Project number: 21406192) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors would like to express their gratitude for the Practice Innovation Project of Jiangsu Province for Post Graduate Students (Project number: SJZZ15_0180).

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