磷酸可待因平衡溶解度及油水分配系数的测定
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摘要
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,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 was284 nm,and the injection volume was 10 μL.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 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 class Ⅰ drug in the biopharmaceutical classification system.
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 was284 nm,and the injection volume was 10 μL.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 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 class Ⅰ drug in the biopharmaceutical classification system.
引文
[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):615HAN 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
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[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):201LIU 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].2008GB/T 21853-2008 Chemicals Partition Coefficient(n-octanolwater)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):269LU 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):106JIANG 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,2006:345SUN 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):121YANG 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):445HE 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
[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):1560XUE 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):201LIU 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].2008GB/T 21853-2008 Chemicals Partition Coefficient(n-octanolwater)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):269LU 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):106JIANG 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,2006:345SUN 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):121YANG 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):445HE 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
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