【作者】 陈佩丽；

【导师】 胡小莉；

【作者基本信息】 西南大学 ， 无机化学， 2011， 硕士

【摘要】 法莫替丁和吩噻嗪类药物在药用性质方面,具有其独特的地位。本文主要以法莫替丁(FMTD)、盐酸氯丙嗪(CPZ)和盐酸异丙嗪(PMZ)为研究对象,研究、发展和建立简便快速测定法莫替丁和吩噻嗪类药物的共振瑞利散射(Resonance Rayleigh Scattering, RRS)、二级散射(Second-Order Scattering, SOS)和倍频散射(Frequency Doubling Scattering, FDS)方法,并将这些方法运用于药物制剂和动物肉类食品的检测。研究体系如下：1.钯(Ⅱ)与法莫替丁和卤代荧光素染料三元离子缔合物纳米微粒的共振瑞利散射和共振非线性散射光谱及其分析应用研究在pH 3.5～4.7 NaAc-HAc的缓冲溶液中,法莫替丁(FMTD)与Pd(Ⅱ)形成五元环螯合阳离子([Pd(FMTD)]2+),再与二氯荧光素(DCF)、二溴荧光素(DBF)、二碘荧光素(DIF)、赤鲜红(ER)、曙红Y(EY)、乙基曙红(EE)等卤代荧光素(HF)反应形成1：1：2的三元离子缔合物[Pd(FMTD)]·(HF)2。[Pd(FMTD)]·(HF)2在疏水作用和范德华力的作用下进一步聚集形成平均粒径为9 nm左右的纳米微粒,此时将引起体系吸收光谱变化、荧光猝灭和共振瑞利散射(RRS)、二级散射(SOS)和倍频散射(FDS)急剧增强。[Pd(FMTD)]·(HF)2的最大吸收峰位于476 nm (DCF体系)、540 nm (DBF体系)、553 nm (DIF体系)、560 nm (ER体系)、547 nm (EY体系)、549 nm (EE体系),最大散射波长分别位于302～361 nm(RRS法)、544～644 nm(SOS法)和320～390 nm (FDS法),3种散射增强程度(△I)在一定的范围内与FMTD的浓度成良好的线性关系,检出限为1.0～2.6 ng/mL(RRS法)、4.2～13.0 ng/mL (SOS法)和3.6～10.7 ng/mL (FDS法)。据此提出了灵敏度高、选择性好、快速准确测定FMTD的分子光谱新方法。适用于片剂、胶囊和注射液等药物制剂的测定。文中研究了反应的适宜条件、影响因素和分析化学特性,并结合吸收、荧光光谱的变化和纳米微粒的形成,讨论了反应机理和散射增强的原因。2.汞(Ⅱ)与法莫替丁和阴离子表面活性剂三元混配物的共振瑞利散射,二级散射和倍频散射光谱及其分析应用在pH 5.9 NaAc-HAc的缓冲溶液中,FMTD与Hg(Ⅱ)形成五元环螯合阳离子([Hg(FMTD)]2+),再进一步与十二烷基硫酸钠(SLS),十二烷基苯磺酸钠(SDBS)和十二烷基磺酸钠(SDS)等阴离子表面活性剂(AS)反应形成1：1：2的三元混配物([Hg(FMTD)(AS)2])。此时,RRS、SOS和FDS的显著增强。最大的散射波长位于345～352 nm (RRS法)、544 nm (SOS法)和352 nm (FDS法),3种散射强度(△I)的顺序均为SLS>SDS>SDBS,在一定范围内△I与FMTD的浓度成良好的线性关系,检出限为3.3～3.9 ng/mL (RRS法)、14.6～16.3 ng/mL (SOS法)和7.0～8.5 ng/mL(FDS法)。据此提出了灵敏度高、选择性好、快速准确测定FMTD的光散射新方法。适用于注射液、血清和尿样中FMTD含量的测定。文中探讨了[Hg(FMTD)(AS)2]的形成对吸收和RRS光谱的影响及引起RRS增强的原因。3.荧光光谱法研究法莫替丁-钯(Ⅱ)-卤代荧光素染料的相互作用及其分析应用在pH 3.2～4.1 NaAc-HAc介质中,FMTD与Pd(Ⅱ)形成螯合阳离子,它能进一步与二溴荧光素(DBF)、曙红Y(EY)、乙基伊红(EE)和荧光桃红(TCBF)等卤代荧光素(HF)类染料反应形成三元离子缔合物[Pd(FMTD)]·(HF)2,引起DBF、EY、EE和TCBF吸收光谱变化和荧光猝灭。离子缔合物的最大吸收峰位于541 nm(DBF体系)、547 nm (EY体系)、549 nm (EE体系)、558 nm (TCBF体系),最大荧光发射波长(λem)在513～540 nm范围内,荧光猝灭程度(△F)顺序为DBF>EY>EE>TCBF。△F在一定的范围内与FMTD的浓度成正比,检出限为13.6-29.6 ng/mL。据此提出了灵敏度高、选择性好、快速准确测定FMTD的荧光光谱新方法。可用于服用FMTD后尿药浓度的测定,为FMTD药代动力学研究提供借鉴。文中还对三元离子缔合物的组成、结构和荧光猝灭机理进行了讨论。4.流动注射-共振瑞利散射法测定盐酸氯丙嗪和盐酸异丙嗪在HCl介质中,12-钨磷酸(TP)分别与盐酸氯丙嗪(CPZ)和盐酸异丙嗪(PMZ)反应形成离子缔合物,导致溶液的RRS显著增强,并产生新的RRS光谱。它们的最大RRS峰位于359 nm (TP-CPZ)和346 nm (TP-PMZ),并且在一射定范围内,CPZ和PMZ的浓度与散射强度呈线性关系,据此提出流动注射-共振瑞利散射(FIA-RRS)联用技术测定CPZ和PMZ的新方法,CPZ和PMZ的检出限分别为1.7 ng/mL和3.0 ng/mL。实验优化了流动注射(FIA)参数和反应条件,并以灵敏度较高的CPZ为例,考察了共存物质的影响。本方法具有良好的选择性和重复性；用于药片和猪肝中CPZ的测定,结果满意。5.盐酸异丙嗪和盐酸氯丙嗪与12-钨磷酸相互作用的共振非线性散射光谱及其分析应用在pH=1.0的盐酸介质中,TP分别与PMZ和CPZ反应形成离子缔合物时,吸收光谱仅发生微小变化,而SOS和FDS却发生明显的增强。它们的最大SOS峰位于585 nm (TP-PMZ)、588 nm (TP-CPZ),最大的FDS峰位于388nm(TP-PMZ)、329 nm (TP-CPZ)附近。其中SOS法较灵敏,它对PMZ和CPZ的检测限分别为2.0 ng/mL和3.1 ng/mL。本文以灵敏度最高的PMZ为例,试验了共存物质的影响及分析应用,表明方法具有良好的选择性和较高的重复性。文中还根据这2种药物的电荷分布,摩尔比法和连续变化法探讨了反应机理,并且讨论了SOS和FDS光谱产生和增强的原因。更多还原

【Abstract】 Famotidine and thiadiazide in the medicinal properties, have unique position. New RRS, SOS and FDS methods for the determination of famotidine (FMTD), chlorpromazine hydrochloride (CPZ) and promethazine hydrochloride (PMZ) have been established and developed. It can be used in the determination of trace drugs in the pharmaceutical preparation and food. Main investigated systems are listed as follow:1. Study on the ternary ion-association complex nanoparticles of palladium(Ⅱ)-famotidine and halogen-fluorescein dyes by the resonance Rayleigh scattering and resonance nonlinear scattering spectra and their applicationIn pH 3.5-4.7 NaAc-HAc buffer medium, famotidine (FMTD) reacted with palladium (Ⅱ) (Pd (Ⅱ)) to form chelate cation, which further reacted with halogen-fluorescein dyes (HF) such as dichlorofluorescein (DCF), dibromofluorescein (DBF), diiodofluorescein (DIF), erythrosine (ER), eosine (EY) and eosin (EE) to form ternary ion-association complex [Pd(FMTD)]·(HF)2. The Pd(FMTD)·(HF)2 further aggregate to form average diameter of about 9 nm nanoparticles by hydrophobic forces and Van der Waals forces. As a result, the absorption bands of DCF, DBF, DIF, ER, EY, EE were shifted, the fluorescences of them were quenched and the resonance Rayleigh scattering (RRS), second-order scattering (SOS) and frequency doubling scattering (FDS) were enhanced greatly. The maximum absorption wavelengths of [Pd(FMTD)·(HF)2] were located at 476 nm (DCF system),540 nm (DBF system),553 nm (DIF system),560 nm (ER system),547 nm (EY system),549 nm (EE system) and the maximum RRS, SOS and FDS wavelengths of those were located at 302～361 nm, 536～564 nm and 320～390 nm, respectively. The three△I were proportional to the FMTD concentration in a certain range and the detection limits were 1.0～2.6 ng/mL (RRS method),4.2～13.0 ng/mL (SOS method) and 3.6～10.7 ng/mL (FDS method), respectively. Based on it, a high sensitive, good selective, rapid and new molecular spectrum method had been proposed to determine FMTD. It can be applied to determine FMTD in pharmaceutical preparation such as tablets, gelatin capsule and injection. In this work, the optimum reaction conditions, the influences of coexisting substances and the properties of analytical chemistry are investigated, and the mechanism of ion-association reaction and the reasons of enhancement for RRS are also discussed by the change of UV, F and the formation of nanoparticles.2. Study on the ternary mixed ligand complex of Hg(Ⅱ)-famotidine and anionic surfactant by the resonance Rayleigh scattering, second-order scattering and frequency doubling scattering spectra and their analytical applicationsIn pH 5.9 NaAc-HAc buffer medium, FMTD reacted with Hg(Ⅱ) to form chelate cation ([Hg(FMTD)]2+), which further reacted with anionic surfactants (AS) such as sodium dodecylsulfate (SLS), sodium dodecylbenzene sulfonate (SDBS) and sodium dodecylsulphate (SDS) to form ternary mixed ligand complex ([Hg(FMTD)(AS)2]). As a result, RRS, SOS and FDS were enhanced greatly. Their maximum wavelengths were located at 345～352 nm,544 nm and 352 nm, respectively. The three scattering intensity (△I) were proportional to the FMTD concentration in a certain range, and their detection limits were 3.3～3.9 ng/mL (RRS method),14.6～16.3 ng/mL (SOS method) and 7.0～8.5 ng/mL (FDS method). Based on it, the simple, rapid, accurate and sensitive light scattering methods had been proposed to determine FMTD in injection, serum and urine sample. The effects of formation of [Hg(FMTD)(AS)2] on absorption and RRS spectra were investigated, and the reasons of enhancement for RRS were also discussed.3. Study on the interaction between palladium(Ⅱ)-famotidine and halogen-fluorescein dyes by fluorescence quenching method and their analytical applicationsThe interaction between palladium(Ⅱ)-famotidine and halogen-fluorescein dyes (HF) was investigated by fluorescence and absorption spectrum. In pH 3.2～4.1 NaAc-HAc buffer medium, FMTD reacted with palladium(Ⅱ) (Pd(Ⅱ)) to form chelate cation, which further reacted with dibromofluorescein (DBF), eosine (EY), eosin (EE) and tetrabromotetrachloroflurescein (TCBF) to form ternary ion-association complexes [Pd(FMTD)]·(HF)2. As a result, the absorption bands of DBF, EY, EE, TCBF were shifted and the fluorescences of them were quenched. The maximum absorption wavelengths of [Pd(FMTD)]·(HF)2 were located at 541 nm (DBF system),547 nm (EY system),549 nm (EE system),558 nm (TCBF system) and the maximum fluorescence emission wavelengths of them were located at 513～540 nm, the order of quenching values (△F) was DBF>EY>EE>TCBF. The△F was proportional to the FMTD concentration in a certain range and the detection limit was 13.6～29.6 ng/mL. Based on it, a high sensitive, good selective, simple, rapid and new fluorescence quenching method had been proposed to determine FMTD. It can be applied to determine metabolites of FMTD in human urine, which provide reference for pharmacokinetics of the FMTD. The composition and structure of [Pd(FMTD)]·(HF)2 and fluorescence quenching mechanism were fully discussed.4. Determination of chlorpromazine hydrochloride and promethazine hydrochloride by resonance Rayleigh scattering method coupled with flow injection techniqueIn pH 1.0 HCl medium,12-tungstophosphoric acid (TP) reacted with chlorpromazine hydrochloride (CPZ) or promethazine hydrochloride (PMZ) to form ion-association complexes, respectively, which resulted in significant enhancement of the RRS intensity. The maximum peaks were located at 359 nm (TP-CPZ) and 346 nm (TP-PMZ). In a certain range, the RRS intensity was proportional to the concentration of CPZ or PMZ. Based on it, a flow injection analysis (FIA) coupled to resonance Rayleigh scattering (RRS) method was developed for the determination of CPZ and PMZ. The detection limits were 1.7 ng/mL for CPZ and 3.0 ng/mL for PMZ. The reaction conditions and FIA parameters for the systems were optimized. Take TP-CPZ system with high sensitivity as an example, the effect of coexisting substances was investigated, which showed that the method had good selectivity. The proposed method was used for the determination of CPZ in the pharmaceutical formulation and in pig liver with satisfactory results.5. Study on the resonance nonlinear scattering spectra of the interactions of promethazine hydrochloride and chlorpromazine hydrochloride with 12-tungstophosphoric acid and their analytical applicationsIn pH 1.0 HCl medium, TP reacted with PMZ and CPZ to form ion-association complexes respectively, which led to a great enhancement of the resonance nonlinear scattering such as SOS and FDS. Their maximum SOS and FDS peaks were located at 585 nm (TP-PMZ),584 nm (TP-CPZ) and 388 nm (TP-PMZ),329 nm (TP-CPZ), respectively. These results provided some indication for the determination of PMZ and CPZ by SOS and FDS methods. The linear range of TP-PMZ and TP-CPZ systems were 0.0069～2.5μg/mL,0.102～5.0μg/mL (SOS) and 0.079～6.0μg/mL,0.0133～5.0μg/mL (FDS), respectively. The detection limits (3σ) of PMZ and CPZ were 2.08 ng/mL,3.07 ng/mL (SOS) and 2.22 ng/mL,3.98 ng/mL (FDS), respectively. In this work, the optimum reaction conditions, the influences of coexisting substances and ionic strength and analytical application were investigated. The methods have been successfully applied to determination of PMZ and CPZ in tablets. In addition, the composition of ion-association complexes and the reaction mechanism were also discussed.更多还原