蒿甲醚在不同介质中的平衡溶解度及表观油水分配系数的测定

Determination of equilibrium solubility of artemether in various media and its apparent partition coefficients in octanol-aqueous systems

目的测定蒿甲醚在正辛醇-水/缓冲体系中的表观油水分配系数(lgP)及其在常用的注射用油、乳化剂及助乳化剂等不同介质中的平衡溶解度。方法使用摇瓶法测定蒿甲醚在正辛醇-水中的lgP;采用高效液相色谱法(HPLC)测定蒿甲醚在各种介质中的浓度。结果在37℃下,蒿甲醚在水及pH 5.0、6.8、7.4、8.0的磷酸盐缓冲液中的lgP分别为2.2、1.6、1.5、2.6、2.2。在37℃时,蒿甲醚在注射用油中链甘油三酯(MCT)、橄榄油、大豆油、蓖麻油及肉豆蔻酸异丙酯(IPM)中的平衡溶解度分别为306.9、246.6、222.8、265.0、273.3mg/mL。在乳化剂(6mg/mL胶束溶液)泊洛沙姆188(F68)、壬基酚聚氧乙烯醚(OP乳化剂)、聚山梨酯80、大豆卵磷脂、聚氧乙烯氢化蓖麻油(RH40)中的平衡溶解度分别为0.1、1.4、0.5、0.6、0.6mg/mL。在无水乙醇、1,2-丙二醇、丙三醇、异丙醇、正丁醇中的平衡溶解度分别为177.3、37.0、3.4、204.1、303.1mg/mL。结论蒿甲醚表观油水分配系数随水相pH不同而不同;蒿甲醚在注射用油MCT、OP乳化剂、助乳化剂正丁醇中的溶解度较大。

Objective To determine the apparent partition coefficients （lgP） ofartemether in octanol-water/buffer systems as well as its equilibrium solubility in various media, such as oil for injection, surfactants, and co-surfactants. Methods Waving bottle method was adopted to determine the lgP of artemether in octanol-water/buffer. High performance liquid chromatography （HPLC） was used to determine the concentration of artemether in different media. Results lgP values of artemether in octanol-water or buffer solutions （pH 5.0, 6.8, 7.4, and 8.0） were 2.2, 1.6, 1.5, 2.6, and 2.2, respectively. The equilibrium solubility of artemether in injection oil media-chain triglycerides （MCT）, olive oil, soybean oil, castor oil, and isopropyl myristate （IPM） at 37 ＊C was 306.9, 246.6, 222.8, 265.0, and 273.3 mg/mL, respectively. The equilibrium solubility of artemether in surfactant （6 mg/mL micellar solution）, such as Poloxamer 188 （F68）, OP emulsifier （OP）, polysorbate 80, soybean lecithin, and cremophor-RH40 （RH40） was 0.1, 1.4, 0.5, 0.6, and 0.6 mg/mL, respectively. The equilibrium solubility of artermether in cosurfactants ethanol, propylene glycol, glycerin, isopropyt alcohol, and n-butanol was 177.3, 37.0, 3.4, 204.1, and 303.1 mg/mL, respectively. Conclusion The lgP of artemether is different in buffer with difference ofpH values. Artemether has a higher solubility in MCT, surfactant OP, and cosurfactant n-butanol.