分子烙印及相关技术分离分析那格列奈和氨基安替比林
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摘要
分子烙印以其良好的专一性和卓越的分子识别能力可用于高效液相色谱(HPLC)、毛细管电色谱(CEC)和薄层色谱(TLC)的固定相，固相萃取(SPE)等许多方面。那格列奈为新型抗糖尿病新药，关于其质量的分析测定极其重要。全文共分四章，分别介绍了分子烙印技术的发展概况、分子烙印技术在药物分析中应用以及那格列奈的液相色谱分析。
第一章：介绍了分子烙印技术的基本知识和发展状况以及在药物分析中的应用。
第二章：以甲基丙烯酸为功能单体，乙二醇二甲基丙烯酸酯为交联剂，合成了一种氨基安替比林分子烙印聚合物。将所得聚合物用作高效液相色谱的固定相，研究了对结构类似物氨基安替比林和氨基比林的拆分能力。分析结果表明，在以甲醇：异丙醇=2：8的条件下两种结构类似物可以得到基线分离，实验还发现在以100％异丙醇为流动相时只有氨基比林被洗脱出来，而模板分子氨基安替比林完全被保留在色谱柱上。
第三章：建立了一种抗糖尿病新药那格列奈的高效液相色谱(HPLC)手性拆分的新方法。D，L-那格列奈在sumichiral OA-3300色谱柱上实现了分离。试验证明那格列奈的最佳拆分条件为0.0025 mol/L NH_4AC甲醇溶液，紫外检测波长为210nm。在此条件下，那格列奈在12min内实现了基线分离，D-那格列奈的检测限为80pg，L-那格列奈的检测限为120pg。
第四章：建立了反相高效液相色谱法测定国家二类新药那格列奈溶出度的方法。色谱条件为：色谱柱，JASCO-ODS柱；流动相，乙腈—甲醇—磷酸二氢铵(0.1mol／L)=5：2：4(以磷酸调节pH至3.0)；检测波长为210 nm；30 min内平均溶出度为99.9％。通过与进口药片对比结果显示，那格列奈的溶出度与进口片的溶出度差别不大，且不同批号之间无明显差异，稳定性较好。
Molecular imprinting polymer (MIP) has draw increasing attention in recent years. Because of its higher molecular recognition ability and stability than that of biological molecules. MIP has been used in a wide rang of applications, such as chiral separartion, solid phase extraction, sensor, immuno-analysis and has become an effective strategy to prepare stationary phase of HPLC having a specific molecular recognition. In this thesis, four chapters are consisted, the technological and development of MIP, the application of MIP in Pharmaceuticals, the chiral separation of Nateglinide and the determination of degree of stripping of Nateglinide by reverse phase high performance liquid chromatography.
Chapter one: it is an introduction of the basic knowledge of molecular imprinting and its application in pharmaceutical analysis.
Chapter two: A synthetic polymer selector for aminoantipyrine is prepared by molecular imprinting technology. Methacrylic acid and ethylene glycol dimethacrylate are copolymerised in the presence of the template aminoantipyrine. The template is extracted from the polymer leaving specific recognition sites, complementary to the template. The polymer is utilized as a stationary phase in HPLC. The mixture of the two close analogues, aminoantipyrine and aminopyrine, can be baseline separated when the mobile solution is composed of methanol: isopropanol = 2: 8. When the concentration of isopropanol is 100%, only aminopyrine is eluted and the aminoantipyrine is completely reserved by the column.
Chapter three: A high-performance liquid chromatographic method was developed for separation of a new anti-diabetic agent, N-(trans-4-isopropylcyclohexylcarbonyl)--D-phenyl- alanine, and its L-enantiomer. The separtion was performed on a Sumichiral OA-3300 column. Optimized mobile phase was 0.025 mol/L ammoniumacetate in methanol solution. UV detection was at 210nm. Baseline chiral separation was obtained within 12 minutes. The detection limits are 80 pg for D-enantiomer and 120 pg for the L-enantiomer. RSD of the method was below l%(n=5).
Chapter four: A method of determination of degree of stripping(%) of Nateglinide by HPLC was developed. The chromatography conditions were as follows: column, JASCO-ODS; mobile phase, acetonitrile -methanol - NH4H2PO4(0.1 mol/1) =5:2:4(adjusted to pH 3.0 with phosphoric acid ), flow rate, 1 mL/min; detection
wavelength, 210 nm; temperature, room temperature. The degree of stripping(%) of Nateglinide was 99.9% by this method in 30 minutes.
第一章：介绍了分子烙印技术的基本知识和发展状况以及在药物分析中的应用。
第二章：以甲基丙烯酸为功能单体，乙二醇二甲基丙烯酸酯为交联剂，合成了一种氨基安替比林分子烙印聚合物。将所得聚合物用作高效液相色谱的固定相，研究了对结构类似物氨基安替比林和氨基比林的拆分能力。分析结果表明，在以甲醇：异丙醇=2：8的条件下两种结构类似物可以得到基线分离，实验还发现在以100％异丙醇为流动相时只有氨基比林被洗脱出来，而模板分子氨基安替比林完全被保留在色谱柱上。
第三章：建立了一种抗糖尿病新药那格列奈的高效液相色谱(HPLC)手性拆分的新方法。D，L-那格列奈在sumichiral OA-3300色谱柱上实现了分离。试验证明那格列奈的最佳拆分条件为0.0025 mol/L NH_4AC甲醇溶液，紫外检测波长为210nm。在此条件下，那格列奈在12min内实现了基线分离，D-那格列奈的检测限为80pg，L-那格列奈的检测限为120pg。
第四章：建立了反相高效液相色谱法测定国家二类新药那格列奈溶出度的方法。色谱条件为：色谱柱，JASCO-ODS柱；流动相，乙腈—甲醇—磷酸二氢铵(0.1mol／L)=5：2：4(以磷酸调节pH至3.0)；检测波长为210 nm；30 min内平均溶出度为99.9％。通过与进口药片对比结果显示，那格列奈的溶出度与进口片的溶出度差别不大，且不同批号之间无明显差异，稳定性较好。
Molecular imprinting polymer (MIP) has draw increasing attention in recent years. Because of its higher molecular recognition ability and stability than that of biological molecules. MIP has been used in a wide rang of applications, such as chiral separartion, solid phase extraction, sensor, immuno-analysis and has become an effective strategy to prepare stationary phase of HPLC having a specific molecular recognition. In this thesis, four chapters are consisted, the technological and development of MIP, the application of MIP in Pharmaceuticals, the chiral separation of Nateglinide and the determination of degree of stripping of Nateglinide by reverse phase high performance liquid chromatography.
Chapter one: it is an introduction of the basic knowledge of molecular imprinting and its application in pharmaceutical analysis.
Chapter two: A synthetic polymer selector for aminoantipyrine is prepared by molecular imprinting technology. Methacrylic acid and ethylene glycol dimethacrylate are copolymerised in the presence of the template aminoantipyrine. The template is extracted from the polymer leaving specific recognition sites, complementary to the template. The polymer is utilized as a stationary phase in HPLC. The mixture of the two close analogues, aminoantipyrine and aminopyrine, can be baseline separated when the mobile solution is composed of methanol: isopropanol = 2: 8. When the concentration of isopropanol is 100%, only aminopyrine is eluted and the aminoantipyrine is completely reserved by the column.
Chapter three: A high-performance liquid chromatographic method was developed for separation of a new anti-diabetic agent, N-(trans-4-isopropylcyclohexylcarbonyl)--D-phenyl- alanine, and its L-enantiomer. The separtion was performed on a Sumichiral OA-3300 column. Optimized mobile phase was 0.025 mol/L ammoniumacetate in methanol solution. UV detection was at 210nm. Baseline chiral separation was obtained within 12 minutes. The detection limits are 80 pg for D-enantiomer and 120 pg for the L-enantiomer. RSD of the method was below l%(n=5).
Chapter four: A method of determination of degree of stripping(%) of Nateglinide by HPLC was developed. The chromatography conditions were as follows: column, JASCO-ODS; mobile phase, acetonitrile -methanol - NH4H2PO4(0.1 mol/1) =5:2:4(adjusted to pH 3.0 with phosphoric acid ), flow rate, 1 mL/min; detection
wavelength, 210 nm; temperature, room temperature. The degree of stripping(%) of Nateglinide was 99.9% by this method in 30 minutes.
引文
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[2] Michael J. Whitecome, M. Esther Rodrigue, Pablo Villar, et al. A new method for the introduction of recognition site functionality into polymers prepared by molecular imprinting: synthesis and characterization of polymeric receptors for cholesterol[J]. J Am Chem Soc, 1995,117,7105-7111.
[3] Maria Kempe. Antiboty-mimicking polymers as chiral stationary phases in HPLC[J]. Anal Chem, 1996,68,1948-1953.
[4] Irene Idziak, Amina Benrebouh. A molecularly imprinted polymer for 17α-ethynlestradiol evaluated by immunoassay[J]. Analyst, 2000,125,1415-1417.
[5] Richard J, Ansell, Klaus Mosbach. Molecularly imprinted polymers by suspension polymerisaton in perfluorocarbon liquids, with emphasis on the influence of the porogenic solvent[J]. J Chromatography A, 1997,787,55-66.
[6] Maria Kempe, Klaus Mosbach. Direct resolution of naproxen on a non-covalently molecularly imprinted chiral stationary phase[J]. J Chromatography A, 1994,664,276-279.
[7] 王进防，周良模，猛子晖，等。复合碱性功能单体分子烙印手性固定相[J]。化学学报，1999，57，1147-1151。
[8] 猛子晖，周良模，王进防，等。复合作用分子烙印手性色谱固定相[J]。分析化学，1998，26(10)，1251-1253。
[9] Patrick T. Vallano, Vincent T. Remcho. Affinity screening by packed
capillary high-performance liquid chromatography using molecular imprinted sorbents Ⅰ. Demonstration of feasibility[J]. J Chromatography A, 2000,888,23-34.
[10] Leif Schweitz, Lars I. Andersson, Staffan Nilsson. Capillary electrochromatography with molecular imprinted-based selectivity for enantiomer separation of local anaesthetics[J]. J Chromatography A, 1997,792,401-409.
[11] Leif Schweitz, Lars I. Andersson, Staffan Nilsson. Capillary electrochromatography with predeterminted selectivity obtained through molecular imprinting[J]. Anal Chem, 1997,69, 1179-1183.
[12] Leif Schweitz, Lars I. Andersson, Staffan Nilsson. Molecularly imprinted microparticles for capillary electromatographic enantiomer separation of propranolol[J]. Analyst, 2000,125, 1899-1901.
[13] Lars I. Andersson. Efficient sample pre-concentriation of bupivacaine from human plasma by solid-phase extraction on molecularly imprinted polymers[J]. Analyst, 2000,125,1515-1517.
[14] 刘勤，周永新，猛子晖，等。分子烙印固相萃取-毛细管电泳法分析大米中的神经性毒剂降解产物[J]．分析化学，2001，29(4)，387-390．
[15] Tatiana A. Sergeyeva, Heike Matuschewski, Sergiy A. Piletsky, et al. Molecularly imprinted polymer membranes for substance-selecttive solid-phase extraction from water by sufance photo-grafting polymerization[J]. J Chromatography A, 2001,907,89-99.
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