磷酸可待因平衡溶解度及油水分配系数的测定

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，5 μm），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10 μL。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, 5 μm) 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 was 284 nm, and the injection volume was 10 μL.Results:At 37℃, the equilibrium solubility of codeine phosphate in water was 421 mg·mL^-1;In the media of pH 1.2-8.0, the equilibrium solubility was basically constant with pH-independent;at 25℃, the oil-water partition coefficient of codeine phosphate in n-octanol-water system was 0.0517 (lg P_app=-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.

[1] 韩颜,陈泊颖,苏娜,等.盐酸氨溴索平衡溶解度和表观油水分配系数的测定[J].药物评价研究,2016,39(4):615 HAN Y,CHEN BY,SU N,et al.Determination of equilibrium solubility and apparent oil/water partition coefficient of ambroxol hydrochloride[J].Drug Eval Res,2016,39(4):615
[2] 薛璟,贾晓斌,谭晓斌,等.雷公藤甲素表观油水分配系数的测定及其对吸收预测的研究[J].中国药学杂志,2009,44(20):1560 XUE J,JIA XB,TAN XB,et al.Determination of apparent oil/water partition coefficient and absorption prediction of triptolide[J].Chin Pharm J,2009,44(20):1560
[3] 刘岩,孙英华,王尚,等.HPLC法测定恩替卡韦的平衡溶解度和表观油水分配系数[J].中国药剂学杂志,2014,12(6):201 LIU Y,SUN YH,WANG S,et al.Determination of equilibrium solubility and apparent oil-water partition coefficient of entecavir by HPLC[J].Chin J Pharm,2014,12(6):201
[4] CDER/FDA.Guidance for Industry:Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on A Biopharmaceutics Classification System[EB/OL].[2018-12-05].http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
[5] GB/T 21853-2008化学品分配系数(正辛醇-水)摇瓶法试验[S].2008 GB/T 21853-2008 Chemicals Partition Coefficient(n-octanol-water) Shake Flask Method[S].2008
[6] 卢玉梅,陈楚乔,杨凤娉,等.盐酸雷洛昔芬平衡溶解度与表观油水分配系数的测定[J].广东药科大学学报,2014,30(3):269 LU YM,CHEN CQ,YANG FP,et al.Determination of equilibrium solubility of raloxifene hydrochloride and apparent oil-water partition coefficient[J].J Guangdong Pharm Univ,2014,30(3):269
[7] 蒋公建,周建瑜,骆世军,等.妥曲珠利在不同介质中的溶解度及其表观油水分配系数的测定[J].四川农业大学学报,2017,35(1):106 JIANG GJ,ZHOU JY,LUO SJ,et al.Determination of solubility in different media and apparent octanol-water partition coefficient of toltrazuril[J].J Sichuan Agric Univ,2017,35(1):106
[8] 孙进.口服药物吸收与转运//现代药物制剂技术丛书[M].北京:人民卫生出版社,2006:345 SUN J.Oral Drug Absorption and Transportation/Modern Drug Preparation Technology Series[M].Beijing:People's Medical Publishing House,2006:345
[9] 杨秀丽,孙进,何仲贵.格列吡嗪油水分配系数和平衡溶解度的测定[J].中国药剂学杂志,2009,7(3):121 YANG XL,SUN J,HE ZG.Determination of oil-water partition coefficient and equilibrium solubility of glipizide[J].Chin J Pharm,2009,7(3):121
[10] 何琳,龙晓英,丁沐淦,等.水飞蓟素平衡溶解度及表观油水分配系数的测定[J].广东药学院学报,2011,27(5):445 HE L,LONG XY,DING MG,et al.Determination of equilibrium solubility and apparent oil/water partition coefficient of silymarin[J].Acad J Guangdong Coll Pharm,2011,27(5):445
[11] ZUR M,HANSON AS,DAHAN A.The complexity of intestinal permeability:assigning the correct BCS classification through careful data interpretation[J].Eur J Pharm Sci,2014,61:11
[12] DAHAN A,WOLK O,ZUR M,et al.Biowaiver monographs for immediate-release solid oral dosage forms:codeine phosphate[J].J Pharm Sci,2014,103(6):1592