摘要
目的:考察乌拉地尔不同溶剂重结晶产物溶解性差异及在大鼠不同肠段的肠吸收特性。方法:采用溶出仪测定乌拉地尔不同溶剂重结晶产物的溶解曲线及溶解性的差异;采用大鼠外翻肠囊法,研究乌拉地尔同一结晶产物在大鼠不同肠段的吸收情况,以及不同溶剂重结晶产物在大鼠同一肠段的吸收情况,并分别计算累积吸收量(Q_(120))、转运速率(V_t)和表观渗透系数(P_(app))。分析不同溶剂重结晶产物的溶解性与大鼠肠吸收特性的关系。结果:乌拉地尔的氯仿、二氯甲烷、丙酮、乙酸乙酯、正丁醇重结晶产物溶解度较大,溶出速率较快,异丙醇、乙醇-水(1∶1)其次,甲醇重结晶产物溶解度最小。大鼠肠囊实验结果表明,氯仿、二氯甲烷和正丁醇重结晶产物肠吸收量较多,吸收速率较快,丙酮、乙酸乙酯和异丙醇其次,乙醇-水(1∶1)、甲醇重结晶产物肠吸收量较少。结论:乌拉地尔正丁醇重结晶产物的溶解度和溶出速率较好,肠吸收速率较快,是相对最适合工业生产的溶剂。本研究为多晶型药物优势晶型的选择,特别是乌拉地尔固体制剂优势晶型的选择提供了新的研究思路。
Objective：To examine the different solubility of urapidil crystals re-crystallized in different solvents and to investigate the intestinal absorption characteristics of the crystals at different intestine segments. Methods： The dissolution curves and solubility of urapidil crystals that re-crystallized in different solvents were determined by dissolution apparatus. Rat everted intestine sacs were used to determine the absorption characteristics of the crystals in rats. The absorption amount （ Q12o ）, absorption rate （ Vt ） and apparent permeability coefficients （ Papp ） of the same crystals in different intestinal segments and different crystals in the same intestinal segments were calculated. The relationship between the solubility and intestinal absorption characteristics were analyzed. Results： The solubility of the products re-crystallized in chloroform, dichloromethane, acetone, ethyl acetate and n-butyl alcohol were better and the dissolution rates were higher. The solubility and dissolution rates of the products re-crystallized in isopropyl alcohol and alcohol-water （ 1 ： 1 ） were ranked in the second group and the products re-crystallized in methanol were in the last. The experimental results of the rat intestinal sac showed that, the crystals re-crystallized in chloroform, dichloromethane and n-butyl alcohol had more intestinal absorption amount and higher intestinal absorption rate, the crystals re-crystallized in acetone, ethyl acetate and isopropyl alcohol were ranked in the second group, the crystals re-crystallized in ethanol-water （ 1 ： 1 ） and methanol had least intestinal absorption. Conclusion： Urapidil crystals re-crystallized in n-butyl alcohol have better solubility, higher dissolution rate and higher intestinal absorption rate. n-butyl alcohol is the most suitable solvent for urapidil industrial production. This study provides a new strategy for the selection of the dominant crystal of poly crystalline drugs, especially for urapidil solid preparation.
出处
《药物分析杂志》
CAS
CSCD
北大核心
2017年第9期1654-1659,共6页
Chinese Journal of Pharmaceutical Analysis
基金
国家十二五"重大新药创制"专项(No.2015ZX09303001)
陕西省社会发展科技攻关项目(No.2016SF-058)
关键词
尿嘧啶衍生物
乌拉地尔
重结晶
溶解性
外翻肠囊
肠吸收
uracil derivatives
urapidil
recrystallization
solubility
intestinal eversion
intestinal absorptions
