Co-solvence phenomenon and thermodynamic properties of edaravone in pure and mixed solvents

doi:10.1016/j.jct.2019.06.018

The Journal of Chemical Thermodynamics

Volume 138, November 2019, Pages 304-312

https://doi.org/10.1016/j.jct.2019.06.018 Get rights and content

Highlights

•
Research the solubility of edaravone in pure and mixed solvents.
•
Extended Hildebrand Solubility Approach was applied to explain co-solvence phenomenon.
•
The solubility data were correlated by some thermodynamic models.
•
Some apparent thermodynamic properties were evaluated.

Abstract

The dissolution behavior of drugs in cosolvent mixtures is very important, especially in systems with co-solvence phenomenon. The solubility of edaravone in pure and mixed solvents was determined experimentally by using the isothermal dissolution equilibrium method within the temperature range from (273.15 to 313.15) K under atmosphere pressure (101.3 kPa). The maximum solubility was (4.72 × 10⁻² in mole fraction) obtained at 313.15 K in n-propanol, and the minimum data was found at 273.15 K in acetonitrile. However, in mixed solvents, the solubility of edaravone increased with the increasing temperature, while increased with increasing co-solvent mass fraction (w) to a maximum value at w = 0.6 and then decreased, and Extended Hildebrand Solubility Approach was applied to explain this phenomenon. In addition, the solubility data obtained were correlated with the modified Apelblat equation, λh equation, Jouyban-Acree model and CNIBS/R-K model. The results indicated that the modified apelblat equation and Jouyban-Acree model are more suitable to correlate solubility data of edaravone in studied pure and mixed solvents, respectively. The apparent dissolution standard enthalpy ( $Δ H_{sol}^{o}$ ), apparent molar standard Gibbs energy ( $Δ G_{sol}^{o}$ ) and $Δ S_{sol}^{o}$ of edaravone in pure and mixed solvents were also evaluated.

Graphical abstract

Introduction

Edaravone, (CAS. NO. 89-25-8, chemical name, 3-methyl-1-phenyl-2-pyrazolin-5-one) developed by Mitsubishi Chemical Corporation of Japan, June 2001 in Japan Listing. Edaravone is a free radical scavenger with powerful free radical scavenging and anti-peroxidation [1], [2], [3]. Since it was put on the market, international medical workers have made a lot of research on its mechanism of action. It has only been used in clinical practice in China in recent years. Edaravone can inhibit the oxidative damage of brain cells, vascular endothelial cells and nerve cells, and is easily absorbed through the blood-brain barrier. Edaravone can prevent the progress of brain edema and cerebral infarction and alleviate the accompanying neurological symptoms and inhibit delayed neuronal death [4], [5], [6], [7]. The main characteristics of this product are obvious pharmacological effects, less adverse reactions, controllable pharmacokinetics and pharmacodynamics, fewer contraindications, suitable for different populations, and is currently the most recommended brain protective agent in the world [8], [9]. At present, the main synthetic route of edaravone is reflux reaction using ethanol as solvent, phenylhydrazine and ethyl acetoacetate at 348.15 K. When the reaction is over, the solid solute is precipitated by lowering the temperature of the solution. However, the solid compounds obtained by cooling must be refined in order to meet the application in the field of medicine [10], [11], [12], [13] (Fig 1).

Fortunately, like many other pharmaceutical manufacturing processes, solution crystallization is the final step to obtain edaravone with high purity. According to the above literature, researchers usually use ethanol to recrystallize crude products [10], [11], [12], [13], and the purity of the product completely meets the requirements of the medical field. Moreover, through previous experiments, we found that the dissolution process of the target compound existed co-solvence phenomenon in the mixed system of (ethyl acetate + ethanol). While the solubility behavior of drugs in cosolvent mixtures is very important because cosolvent blends are frequently used in purification methods, preformulation studies, and pharmaceutical dosage forms design, among other applications.

So it is important to know the solubility data for industry. Based on the work of previous researchers, the solubility data of edaravone in ethanol, methanol, isopropanol, n-propanol, ethyl acetate, toluene, acetonitrile, acetone, (ethyl acetate + methanol) and (ethyl acetate + ethanol) were studied and correlated with some thermodynamic models. Moreover, Extended Hildebrand Solubility Approach was applied to explain co-solvence phenomenon. Furthermore, the thermodynamic properties of the target compound in different solvents were studied.

Section snippets

Materials

Edaravone with a mass fraction of 0.995 was purchased from Shanghai MacClean Biochemical Technology Co., Ltd, and the purity was confirmed by a high-performance liquid chromatography (HPLC). The solvents, including methanol, ethanol, isopropanol, n-propanol, ethyl acetate, toluene, acetone and acetonitrile with analytical grade were provided by Sinopharm Chemical Reagent Co., Ltd., China. The mass fraction purities of these solvents were all higher than 0.994, which were provided by supplier.

DSC curves of edaravone

The results of DSC curves for raw material and excess solid solute in solvent were shown in Fig. 2. From Fig. 2-A (the results of raw material and excess solid solute in pure solvents), it can be found that Onset temperature and peak temperature were 400.15 K and 403.15 K, respectively. Here, we use the Onset temperature as the melting point of edaravone, which is closely to the values reported in Refs. [16], [17]. Moreover, in Fig. 2-B, the DSC curves of raw material and excess solid solute in

Conclusion

The solubility of edaravone in pure and mixed solvents was determined experimentally by using the isothermal dissolution equilibrium method within the temperature range from (273.15 to 313.15) K under atmosphere pressure (101.3 kPa). The solubility data of edaravone in different pure solvents decreases according to the following order: n-propanol > ethanol > ethyl acetate > isopropanol > ethanol > methanol > acetone > toluene > acetonitrile. However, in mixed solvents, the solubility of

Acknowledgements

The project was supported by the National Natural Science Foundation, China (21506138, 21375092, 21575097and 21606199), Science and Technology Plan Project of Taizhou (1803gy01 and 1803gy03).

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Co-solvence phenomenon and thermodynamic properties of edaravone in pure and mixed solvents

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials

DSC curves of edaravone

Conclusion

Acknowledgements

Brain Res.

Neuroscience

Neuropharmacology

Am. J. Obstet. Gynecol.

Neurosci. Lett.

Ultrason. Sonochem.

J. Chem. Thermodyn.

Thermochim. Acta

J. Chem. Thermodyn.

Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury

CNS Drug Rev.

Research and development of the free radical scavenger edaravone as a neuroprotectant

Yakugaku Zasshi

Edaravone reduces brain oedema and attenuates cell death after intracerebral haemorrhage in mice

Brain Injury