磷酸可待因平衡溶解度及油水分配系数的测定

Determination of equilibrium solubility and apparent oil-water partition coefficient of codeine phosphate

目的:测定磷酸可待因在不同pH介质中的平衡溶解度以及油水分配系数,为药物的生物药剂学分类系统(BCS)分类提供试验依据。方法:采用摇瓶法-高效液相色谱法测定磷酸可待因在水、不同pH介质中的平衡溶解度和油水分配系数。采用Phenomenex C18色谱柱(150 mm×4.6 mm,5μm),流动相A为0.03 mol·L^(-1)醋酸钠溶液(用冰醋酸调pH至3.5),流动相B为甲醇,梯度洗脱,流速1.0 mL·min^(-1),柱温30℃,检测波长284 nm,进样量10μL。结果:37℃时磷酸可待因在水中的平衡溶解度为421 mg·mL^(-1),在pH 1.2～8.0的介质中,平衡溶解度基本稳定,无pH依赖性;25℃时磷酸可待因在正辛醇-水体系中的油水分配系数为0.051 7(lg P_(app)=-1.29);在pH 1.2～8.0的介质中,其油水分配系数随着pH升高而增大,具有pH依赖性。结论:磷酸可待因为高溶解性,渗透性较好的药物,本研究可以佐证其属于生物药剂学分类系统中的Ⅰ类药物。

Objective:To determine the equilibrium solubility of codeine phosphate in different pH media and the oil-water partition coefficient,and to provide a test basis for the biopharmaceutics classification system(BCS)classification of the drug.Methods:The equilibrium solubility and oil-water partition coefficient of codeine phosphate in water,different pH media were determined by high performance liquid chromatography combined with shake flask method.Good separations were obtained on a C18(150 mm×4.6 mm,5μm)column maintained at 30℃with linear gradient elution by a mixture of mobile phase A[0.03 mol·L-1 sodium acetate solution(adjusted pH to 3.5)]and mobile phase B(methanol)at a flow rate of 1.0 mL·min-1,the UV detection was284 nm,and the injection volume was 10μL.Results:At 37℃,the equilibrium solubility of codeine phosphate in water was 421 mg·m L-1;In the media of pH 1.2-8.0,the equilibrium solubility was basically constant with pHindependent;at 25℃,the oil-water partition coefficient of codeine phosphate in n-octanol-water system was 0.0517(lg Papp=-1.29);In the media of pH 1.2-8.0,the oil-water partition coefficient increases with the increase of pH,and shows pH dependence.Conclusion:Codeine phosphate is highly soluble and has good permeability.This study can support its belonging to the classⅠdrug in the biopharmaceutical classification system.