Article Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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Solubility Determination and Modeling for Artesunate in Binary Solvent Mixtures of Methanol, Ethanol, Isopropanol, and Propylene Glycol + Water Renjie Xu,* Ting Han, Li Shen, Jianguo Zhao, and Xiang’an Lu Guangling College, Yangzhou University, YangZhou, Jiangsu 225000, People’s Republic of China
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S Supporting Information *
ABSTRACT: Artesunate is dissolved in an aqueous solution of several organic solvents (methanol, ethanol, isopropanol, and PG), and the mole fraction of artesunate is determined by the static method. When the system reaches equilibrium, the range of system temperature is 278.15−318.15 K and the pressure environment is 101.1 kPa. When the temperature is constant, the equilibrium mole fraction of artesunate is proportional to the mass percentage of organic solvents, and the relationship between artesunate solubility and temperature is the same as before under certain conditions of the organic solvent component. When the external conditions are the same, artesunate is more likely to dissolve in the ethanol + water mixture than in several other systems. Besides, three classical mixed solvent thermodynamic equationsJouyban−Acree model, van’t Hoff−Jouyban−Acree model, and Apelblat−Jouyban−Acree modelare applied to calculate the equilibrium mole fraction of artesunate. The maximum value of average relative deviations (ARD) obtained during the calculation is 0.83%. The experimentally measured data on artesunate has different general meanings for the expansion of application and production in the pharmaceutical field and provides theoretical data for its industrial production.
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INTRODUCTION Artesunate (CAS Registry No. 88495-63-0, chemical structure shown in Figure S1 of the Supporting Information) is wellknown as a derivative of artemisinin, which has better stability and a better curative effect. For a long time, artesunate has been considered by the World Health Organization to be a very effective antimalarial drug and more effective in combination with drugs such as quinolone.1,2 Moreover, artesunate also plays a pivotal role in the treatment of human melanoma; it is usually used as an adjunct to the chemotherapy process and has achieved encouraging results.3 Besides, artesunate has a good performance in the antitumor field including breast cancer, cervical cancer, and other cancers.4,5 And, more importantly, artesunate can maintain a high concentration in the brain for a long time, which is able to have a good effect on the treatment of complex neurological diseases such as stroke and other central nervous system diseases.6 In addition, artesunate can regulate the body’s immune function and relieve the symptoms of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.7 Even more incredible is that artesunate has a protective effect on lung injury caused by lipopolysaccharide.8 In the chemical and pharmaceutical industries, the synthesis of artesunate is mainly based on dihydroartemisinin, which leads to the mixing of some unreacted dihydroartemisinin in the product.9,10 In order to obtain higher purity artesunate, removal of impurities from artesunate is a very critical step in the process of obtaining it. Thus, obtaining the saturated mole fraction of artesunate in binary solvent mixtures is an © XXXX American Chemical Society
early step in the design and study of the separation process. Furthermore, although the use of artesunate is so extensive, there is almost no literature on the solubility data and physicochemical properties of artesunate, which has caused great trouble in industrial production. From the perspective of industrial applications, exploring the relationship between the equilibrium molar fraction of the drugs in the mixed systems, the temperature and the composition of the organic solvent, which has an irreplaceable effect on the impurity removal of the drug substance, the crystal form transformation before and after dissolution and the dissolution stability of the drug. Therefore, systematic determination of the mole fraction of drugs in a hybrid system consisting of organic solvent and water is of practical significance.11−13 Mixed solvents have been used as a means of increasing the solubility of difficult substances for a long time; recently, the preferential dissolution effect of various solvent components on the solute in saturated solution has been attracting more and more attention.14,15 For some research pharmacologists, although some classical cosolvent models can be used to predict the mole fraction of drugs, it is also based on experimentally measured solubility data.16 Because artesunate is poorly water-soluble, some organic solvents are added to the system to increase its solubility. Thus, there are two main goals of this work: (1) Received: October 29, 2018 Accepted: January 15, 2019
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DOI: 10.1021/acs.jced.8b00988 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data
Article
supernatant solution of the equilibrium solution was taken and analyzed by HPLC (Agilent 1260). In order to obtain a saturated solution of artesunate in four mixed solvents. it was necessary to add a relatively large amount of artesunate powder to the jacketed beaker and mix it with the previously prepared mixed solvents. A magnetic rotor controlled by a micro magnetic stirrer was added to the mixed system, and continuous stirring was performed to ensure that the solution and the drug can be thoroughly mixed at a certain temperature. The thermostatic bath was able to control the temperature of the circulating fluid and thus maintained the mixed solution under a suitable temperature condition. Measuring how long it takes for the solid−liquid system to reach equilibrium state was a key step in the experiment. Thus, approximately 0.5 mL of the supernatant was removed from the mixed solution by a preheated syringe (2 mL) equipped with a pore syringe filter (PTFE 0.2 μm); the time interval was 2 h; afterward, the sample was diluted by a volumetric flask according to a certain ratio and then analyzed by HPLC (Agilent-1260). When the composition of the supernatant was in a stable state, the mixed solution was considered to reach a solid−liquid equilibrium state. Two experimental methods were used to verify that the sampling was performed under equilibrium conditions of the saturated solution: the solute was precipitated from the supersaturated solution to reach equilibrium and the solute was added to the unsaturated solution to reach equilibrium. The consistent result obtained by the two verification methods was that the system reaches equilibrium after continuous stirring for about 12 h. Then, the stirring device was turned off, the bath was kept in working condition, and the solid−liquid mixtures were left quietly for about 1 h to ensure that the dissolved solutes completely settled to the bottom of the vessel. A 2 mL portion of equilibrated clear solution was added to a preweighed volumetric flask quickly with a preheated syringe. Subsequently, methanol was added to the volumetric flask to the tick and shaken evenly; then, 1 μL of the diluted sample was taken and injected into the HPLC for analysis. The solubility of artesunate (xw,T) is able to be calculated by eq 1, and the mass percentage of each component (w) is calculated by eqs 2 and 3
obtain the saturated mole fraction of artesunate by the experimental method; (2) verify the experimental results with three classical thermodynamic equations.
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EXPERIMENTAL SECTION Materials and Apparatus. Artesunate (purity: 98.9% in mass fraction) was purchased from Aladdin Reagent Co., Ltd., China. Methanol was used to recrystallize the drug, repeated three times. After the completion of the three recrystallization processes, the purity of the drug reached 99.9% (analyzed by high-performance liquid chromatography, Agilent 1260) in mass fraction, which was in line with the purity requirement for determining solubility. The manufacturer of four solvents (purity: ≥99.4% in mass fraction, analyzed by gas chromatography Smart (GC-2018)) was Sinopharm Chemical Reagent Co., Ltd., China. The water was twice-distilled water (conductivity
