Article Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX
pubs.acs.org/jced
Measurement and Correlation of the Solubility of Baicalin in Several Mixed Solvents Haoji Wang,† Ganbing Yao,‡ and Haojian Zhang*,† †
School of Materials and Chemical Engineering, Ningbo University of Technology, Ningbo, Zhejiang 315211, People’s Republic of China ‡ College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu 225002, People’s Republic of China
Downloaded via MACQUARIE UNIV on February 20, 2019 at 01:30:04 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: The baicalin was dissolved in four groups of mixed solvents consisting of organic solvents (methanol, ethanol, n-propanol, and isopropanol) and water in different proportions with the temperature 278.15−318.15 K. The solubility of baicalin at the steady state of the system was measured by static technique under 101.1 kPa. Under the condition of constant temperature, the proportion of organic solvent increased, and the solubility of baicalin increased accordingly; when the ratio of organic solvent was constant, the temperature increased and the mole fraction of baicalin also increased. In the case where the temperature and the ratio of the organic solvent were constant, the mixture of n-propanol and water had an advantage in dissolving baicalin. The solubility of baicalin was calculated by the Jouyban− Acree model, the van’t Hoff−Jouyban−Acree model, and the Apelblat− Jouyban−Acree model. The maximum value of RAD (average relative deviation) in all calculations was 1.63%. It is noteworthy that the solubility data presented in this work contribute to providing the necessary physical and chemical information for the pharmaceutical industry to improve production and purification processes.
■
INTRODUCTION Baicalin (CAS Registry No. 21967-41-9, chemical structure shown in Figure S1 of the Supporting Information (SI)) is well known as a traditional Chinese medicine with high drug activity, and its chemical nature is a flavonoid extracted from Scutellaria baicalensis Georgi. Baicalin is able to inhibit the growth of a variety of tumor cells by eliminating reactive oxygen species in normal cells, inhibiting the cell cycle, inducing apoptosis, and inhibiting the production of nuclear transcription factors.1,2 Moreover, baicalin is used to prevent and treat Zika virus infection, treat viral hepatitis effectively by inhibiting hepatitis B virus antigen, and interfere with the dengue virus replication cycle in Vero cells.3,4 With the continuous improvement of human material life, the weight of a considerable number of people has seriously exceeded the standard. Baicalin can alleviate some of the diseases caused by overweight, including nonalcoholic fatty liver disease, diabetes, and cardiovascular diseases, by stimulating the activity of carnitine palmitoyltransferase 1 in the liver.5 Even more incredible is that baicalin protects the memory nerve in the absence of ischemia by inhibiting the phosphorylation of calmodulin (CaM)-dependent protein kinase II (CaMKII) in the hippocampus.6 In addition, baicalin has also achieved remarkable success in the treatment of glaucoma.7 However, not only is baicalin widely used in the field of medicine but also it can be used to make antibacterial toothpaste.8 In the chemical and pharmaceutical industries, the main source of baicalin is extracted from Scutellaria baicalensis © XXXX American Chemical Society
Georgi, which leads to the mixing of some other similar flavonoids (baicalein, gonoside, wogonoside, etc.) and other natural products (terpenoids, alkaloids, quinonoids, etc.) in the product.9,10 In all processes for the production of drugs, the purification process is a very important process that directly determines whether the purity of the product can meet the standard. What’s more, the solubility data of the drug are also essential information in the process of purification process design. However, the solubility data of baicalin have hardly been found in the previously reported literature, and the research work provided herein provides effective solubility and thermodynamic data for its industrial production. In the process of drug development from research to mass production, the dissolution behavior of drugs has always played an important role. For example, the ratio of organic solvent and temperature has a significant effect on controlling the amount of drug dissolved in a binary mixed system. This property can be used to purify the original drug containing impurities, observe the crystal form of the drug after recrystallization in the solvent, and understand the physicochemical stability of the drug. Because of this, scientific and accurate determination of the equilibrium molar fraction of drugs in mixed solvents is an inevitable requirement of the pharmaceutical industry.11−13 Received: December 11, 2018 Accepted: February 5, 2019
A
DOI: 10.1021/acs.jced.8b01186 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data
Article
method,17−22 and the mole fraction of baicalin in the upper liquid phase was determined by HPLC (Agilent-1260) analysis under the steady state of the dissolution system. It was necessary to prepare a saturated solution of baicalin before obtaining each sample. First of all, a slight excess of baicalin solid powder and 60 mL of the previously prepared mixed solvent had been added to the laminated glass container. To fully dissolve the baicalin in the mixed solvent, the magnetic stirring device drove the rotor to rotate in the solution. The circulating fluid flowing through the interlayer was controlled by the thermostatic bath so that the dissolution process was carried without the effect of temperature change. The most important thing in the next steps was to know when the dissolution reached equilibrium. The rotor was stopped every 2 h. After a quiet period of time, the preheated syringe (2 mL) was used to draw 0.5 mL of the upper liquid, which was analyzed by the HPLC. If the results of three consecutive analyses were the same, then the dissolution process was considered to be saturated, and this time was the time required for the dissolution to reach equilibrium. Whether the sample was taken out in saturation was related to the accuracy of the experiment; two methods were used to verify this: One was to precipitate the solute from the supersaturated solution to reach equilibrium and the other was to add solute to the unsaturated solution to reach equilibrium. Through the verification of these two methods, the time required for the system to reach equilibrium was ∼12 h. When the components in the upper solution no longer changed, the magnetic stirrer stopped working to sink the dissolved solutes to the bottom of the vessel. The time for the upper liquid in the container to become clear was ∼1 h. A preheated pipet (2 mL) was employed to remove a small amount of the upper liquid into a preweighed volumetric flask. Methanol was used to fill the volumetric flask to the mark line. After shaking evenly, ∼1 μL of the sample was taken up to the HPLC for analysis. The equilibrium mole fraction of baicalin (xw,T) in mixed solvents is calculated by eq 1, and the initial percentage of each component in mixed solvent (w) is calculated by eqs 2 and 3.
Although mixed solvents are widely used as a technical means for purifying pharmaceuticals, the mechanism involves controlling the amount of solute dissolved in the solvent, and the solvent component preferentially dissolves the solute in a saturated solution, they still attract more and more scientific researchers.14,15 Although many thermodynamic researchers have spent much effort summarizing some semiempirical thermodynamic models to estimate the mole percent of drug in saturated solution, accurate and reliable solubility experimental data for pharmaceutical researchers is still the basis for calculating solubility by using these models.16 Because baicalin is highly difficult to dissolve in water, some organic solvents such as methanol and ethanol are added as cosolvents to water to increase its solubility.
■
EXPERIMENTAL SECTION Materials and Apparatus. The manufacturer of baicalin (mass fraction: 0.989) was Rhawn Reagent, China. The baicalin was purified by recrystallization from methanol, and the process was repeated three times. The purity of the recrystallized drug was 0.996, and the mass fraction of the drug was obtained by characterization using high-performance liquid chromatography (HPLC, Agilent 1260). The source of the organic solvents was Sinopharm Chemical Reagent, China, and their purity levels were of analytical reagent grade (mass fraction ≥0.994). The purity data of the reagents were obtained by gas chromatography (Smart (GC-2018)). The water was distilled water obtained by two distillations (conductivity
