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