【作者】 张晋；

【导师】 郑利强；

【作者基本信息】 山东大学 ， 物理化学， 2008， 博士

【摘要】 在溶剂中,两亲分子可以形成多种的缔合结构,如胶束、囊泡、溶致液晶等。溶致液晶因为相态丰富多样、结构可调控等特殊的性能而受到众多研究人员的关注,其物理化学性质以及在材料合成、萃取、催化、医药等领域的应用被广泛的研究。本论文从扩展溶致液晶在药物载体及材料制备方面的应用两个角度出发,对溶致液晶的物理化学性质进行了系列研究。首先,利用甘油单酸酯构建了类脂立方液晶,研究了多种添加剂对其物理化学性质的影响、药物分子在立方液晶中的增溶位置,同时考察了其作为药物载体在药物包载及药物控制释放方面的应用。其次,利用长链咪唑类离子液体与水和对二甲苯共同构筑了溶致液晶,研究了溶致液晶的结构参数、流变学性质与各组分含量、烷基链长之间的关系,还比较了长链咪唑类离子液体形成的溶致液晶与传统阳离子表面活性剂溶致液晶在结构及流变学性质上的差异。这为今后以咪唑类离子液体溶致液晶作为模板进行纳米材料的制备打下了理论基础。甘油单油酸酯（MO）与水形成的类脂立方液晶具有生物可降解、生物亲和度高、粘度大、有助于药物的透皮吸收等优点,因此其在药物载体领域的应用逐渐受到人们的关注。在本论文的第二章中,我们利用小角X射线散射（SAXS）、流变和傅立叶变换红外光谱（FT-IR）等技术,考察了嵌段共聚物（F-127）、药物分子（盐酸普鲁卡因,PC）对MO/水类脂立方液晶结构及流变学性质的影响。发现,F-127的加入可以引起MO/水立方液晶的结构由C_D型向C_P型转变,而盐酸普鲁卡因的加入则可以引起立方液晶由C_G型向C_D型转交。相应的,体系的流变学性质也随着立方液晶结构的变化而发生了变化。另一方面,体系流变学性质非线性变化也证实了,随着F-127和PC的加入,立方液晶内部结构的变化不是连续的,体系确实存在着相态类型的变化。利用FT-IR技术研究了盐酸普鲁卡因对立方液晶中MO分子构象的影响,结果表明,体系中加入盐酸普鲁卡因后,MO分子烷基链构象的变化较大,随着PC的加入,红外光谱的特征峰宽度变窄,说明烷基链活跃度降低,分子排列的有序性增强。同时,PC的加入更有利于立方液晶相中kink构象的形成。PC对MO分子极性头的影响主要表现在,MO分子中羰基的氢键形式加强,这是由于PC中的N^-离子上的H原子与羰基上的氧原子间形成了氢键作用。进一步证实,盐酸普鲁卡因可以增溶在MO分子形成的双层膜中,与MO共同构筑立方液晶中骨架结构。而随着PC含量的升高,MO分子中构象的不连续性变化也恰好对应于SAXS结果中表明的,MO/水立方液晶由C_G型向C_D型的结构转变。类脂立方液晶在水中的分散体系（cubosome）也是一种潜在的药物载体。在本论文的第三章中,我们用一种操作简单的前体法制备了cubosome,通过SAXS、冷冻蚀刻电镜（FF-TEM）和激光光散射（DLS）等技术考察了该分散体系颗粒的结构类型、形貌以及粒径分布。研究发现,一定量的嵌段共聚物F-127和P6100对cubosome的形貌不会产生明显的影响,分散体系仍然为不规则的立方状颗粒,但颗粒的粒径尺寸变化明显,这与嵌段共聚物可以引起体系内部结构由C_D向C_P变化有关,而且相同量的嵌段共聚物由于分子量的差异对颗粒尺寸的影响也有所不同;链长不同的三种甘油单酸酯均可以得到相应的cubosome,但其分散颗粒的粒径尺寸存在差异;由于药物分子咖啡因可以破坏MO分子极性头与水分子之间的氢键作用,因此其加入可以引起体系发生由cubosome向囊泡的相转变。两亲分子在医药领域具有广泛的应用,它不但可以起到增溶药物、保护药物、稳定药剂等的作用,而且其在溶剂中形成的多种有序结构本身即可用作药物载体。在本论文的第四章中,我们在类脂立方液晶作为药物载体方面进行了研究尝试。首先,研究了两种药物分子——盐酸普鲁卡因（PC）和盐酸环丙沙星（CF）,对两种双尾巴表面活性剂——二—（2—乙基己基）磺基琥珀酸钠（AOT）和双十二烷基二甲基溴化铵（DDAB）在水中胶束化过程热力学参数的影响,从分子层面揭示了药物分子与表面活性剂分子之间的相互作用。研究方法包括表面张力法、紫外—可见分光光度法及稳态荧光技术等。研究发现,药物分子对双尾巴表面活性剂在水溶液中的临界胶束浓度（cmc）、表面张力平衡值(γ_cmc)以及表面活性剂分子胶束化过程的热力学参数均产生了一定程度的影响,但机理有所不同。PC与AOT之间的静电引力,可以导致水溶液中AOT的cmc及γ_cmc值降低。当PC的浓度增加到一定程度时,PC可以与AOT形成混合胶束,进一步影响其胶束化行为。PC与DDAB之间的静电斥力,导致DDAB胶束排列松散,水溶液的γ_cmc升高。CF和AOT间的静电引力同样可以引起水溶液中AOT的cmc值及γ_cmc降低。另一方面,CF导致DDAB在水溶液中cmc及γ_cmc升高,则是因为CF可以破坏DDAB疏水部分周围水分子形成的“冰山”结构。同时,通过对比药物分子在水溶液及胶束溶液中光学性质的差异,也可以证实PC与AOT混合胶束的生成,并推测出CF增溶在AOT胶束的栅栏层中,而在DDAB体系中,CF位于DDAB胶束/水的界面附近。其次,在本章中,利用释放度测定法研究了PC在MO/水立方液晶中的释放行为。发现在研究的时间和浓度范围内,不同浓度的盐酸普鲁卡因均可以在MO/水立方液晶中达到缓释,t_1/2超过20小时,且释放效率超过80%,基本达到完全释放。PC在不同体系中的释放过程可分为两个阶段,第一阶段为暴释阶段,对应于自由药物分子的释放;第二阶段为载体中包结的药物分子的释放。两个阶段的释放曲线均符合Higuchi平方根定律。而第二阶段中,PC在C_D结构立方液晶中的扩散系数高于在C_G结构立方液晶中的扩散系数,说明药物释放行为的差异与载体体系的结构存在着一定的关系。最后,我们还考察了F-127的含量对氯霉素在MO/水体系形成的cubosome中释放行为的影响。发现氯霉素的释放效率与体系的结构有关,对于氯霉素这类亲油的模型药物来说,cubosome是一种暴释载体。近些年来,离子液体由于其特殊的物理化学性质,在绿色化学、合成、催化及材料制备方面逐渐受到人们的关注。在胶体与界面化学领域,离子液体除了作为传统溶剂的替代品之外,还可以通过对其分子结构的调控,使之具有一定的表面活性,进而扩展了离子液体的应用范围。在本论文的第五章中,我们合成了一系列不同链长的1—烷基—3—甲基澳代咪唑类离子液体（C_Nmim-Br,N=12、14、16）,并利用这几种离子液体与对二甲苯和水共同构筑了溶致液晶体系,同时应用SAXS、偏光显微镜（POM）、核磁共振（²H-NMR）等技术对离子液体溶致液晶的结构进行了表征。研究发现,溶致液晶的结构参数受到体系中离子液体的种类及各组分含量等因素的影响。在六角相中,随着离子液体含量的升高,一方面,离子液体分子在形成结构单元的棒状胶束中的聚集更加紧密;另一方面,结构单元在体系中的聚集也更加紧密。在层状相中,随着水含量的升高,溶致液晶的水通道厚度增大,相应的离子液体分子双层膜受到挤压,其厚度降低。同时,体系的流变学性质与溶致液晶的结构有关,在六角相中随着离子液体分子的聚集更加紧密,体系的稳态参数和动态模量值均增大,松弛时间缩短。在层状相中,则由于水含量的升高,体系的模量值降低。长链咪唑类离子液体形成的溶致液晶的结构参数与流变学性质随组分含量变化的规律与在传统阳离子表面活性剂CTAB形成的溶致液晶体系中的变化规律一致。但由于分子结构的不同,长链咪唑类离子液体形成的溶致液晶的结构与相同碳链长度的三甲基季铵盐体系有所差异。在C₁₂mim-Br/对二甲苯/水三元体系中,除六角相和层状相外,还利用SAXS和NMR等技术手段证实了双连续型立方相溶致液晶的存在。根据IPMS理论计算了立方液晶的结构参数,发现随着离子液体含量的升高,离子液体分子双层膜逐渐膨胀,进而挤压水通道,使水通道半径的值降低。长链咪唑类离子液体疏水烷基的长度对其形成的溶致液晶的物理化学性质也有着一定的影响,疏水烷基的长度越大,液晶的晶胞参数越大、流变学模量参数的值越高。同时,体系的流变学性质与液晶的结构有关。这部分研究丰富了溶致液晶体系,同时为离子液体在合成纳米材料、催化和萃取方面的应用进行了探索。更多还原

【Abstract】 The self-assembled structures of amphiphile molecules in solvents,such as micelle, vesicle,and lyotropic liquid crystalline phase（LLC）etc.,have attracted more and more attention.As the abundant of structures,LLC is studied widely and applied in several fields,such as synthesis,extraction,catalysis,pharmaceutics,and so on.In order to expand the application of LLC as the drug delivery system and the templates of nanomaterials,the physicochemical properties of two kinds of LLCs formed by lipid and imidazolium-type ionic liquids are studied in the present dissertation.Beside of the component effects on the physicochemical properties of the two kinds of LLCs are studied,the lipid-based LLCs are attempted to be used as drug delivery systems.In the second chapter,the effects of copolymer（F-127）and model drug（procaine hydrochloride,PC）on the structure and theological properties of the cubic LLC formed in monoolein（MO）/water systems are studied by means of Small Angle X-ray Scattering,rheology and FT-IR.It is found that the addition of F-127 could lead to the structure transition from C_D-type to C_P-type cubic phase.The structure transition from C_G-type to C_D-type could also be investigated in the MO/water cubic phase in the present of procaine hydrochloride.The phase transition could consequently induce the change of the theological properties of the cubic phases.The effect of procaine hydrochloride on molecular conformation of MO in the cubic phase is further studied by FT-IR.The results reveal that the arrangement of the hydrophobic carbon chain of MO is strongly affected by procaine hydrochloride.The spectrums of MO/PC/water mixtures are narrower than that of MO/water mixtures,which means that the order of the arrangement of MO hydrophobic carbon chain is increased.The addition of PC is favorable to the kink conformation of CH₂ group.Moreover,with the addition of PC.the H-bond C=O in the polar head group of MO is enhanced.It results from the H-bond between C=O and the N⁺-H in the polar head group of PC.From the change of the FT-IR spectrums,it could be concluded that PC could anticipate forming the lipid bilayer together with MO in the cubic phase.Meanwhile,the discontinuous change of the conformation of MO molecules is corresponding to the structure transition of cubic LLC which is confirmed by SAXS.It is well known that the aqueous dispersion of cubic LLC（cubosome）formed from monoglyceride can be used for the development of drug delivery systems.The cubosome formed based on monoglycerides are obtained by precursor method in the third chapter.The internal structures,morphologies and sizes of the dispersed particles are studied by means of SAXS,electronic microscopy and Dynamic Light Scattering （DLS）.It is found that the sizes of the cubosomes are dependent on the carbon chains of the monoglycerides.As the phase transition induced by F-127 in the cubic LLCs.a discontinuous change of the cubosome sizes also could be investigated.In additional, the model drug,caffeine,could induce the phase transition from cubosome to vesicle, because it could destroy the H-bond between head polar group of MO and water molecules.The elementary studies on cubic LLC used as drug delivery systems are involved in the fourth chapter.Firstly,the effects of model drugs,procaine hydrochloride（PC）and ciprofloxacin hydrochloride（CF）on the micellization of two double tailed surfactants. sodium bis（2-ethyl-1-hexyl）sulfosuccinate（AOT）and didodecyldimethylammonium bromide（DDAB）,in the aqueous solution are studied in order to reveal the interaction between drug molecules and amphiphiles on molecular level.It is found that the electrostatic attraction between PC and AOT could lead to the reduction of the cmc and equilibrium surface tension of AOT in aqueous solution.The PC-AOT mixed micelle could be formed when the concentration of PC increased to 0.5mmol/L.On the contrary. the electrostatic repulsion between PC and DDAB leads to the incompact package of DDAB molecules in micelle,and the surface tension of aqueous DDAB solutions are slightly increased.The different electrostatic actions between CF and two surfactants cause that the effect on surface properties and the standard thermodynamic functions of micelle formation are different.The electrostatic attraction between CF and AOT could lead to the reduction of cmc of AOT and surface tension in AOT/CF solution,but the increase of the cmc and surface tension in DDAB solution.From the UV results,it reveals that CF is localized in the palisade layer of AOT micelle but the water/micelle interface of DDAB micelle.Secondly,the controlled release of PC from MO/water cubic phases could be achieved because t_1/2is more than 20h,and the release efficiency could attain up to 80%in different systems.The release profiles of PC could be divided into two stages.The release in the two stages both follow the Higuchi quadratic root law. Finally,the effects of copolymers on the drug release behavior from cubosome formed from MO/water systems are also studied.It is found that the release efficiency of Chloramphenicol is dependent on the structure of cubosome,and cubosome is a burst drug release system for lipophilic drugs.In the fifth chapter,the structures of the LLCs formed in 1-alkyl-3-methylimidazolium bromide（C_Nmim-Br,N=12,14,16）/p-Xylene/water mixtures are characterized by Small Angle X-ray Scattering（SAXS）,Polarized Optical Microscopy （POM）and ²H-NMR technologies.There are two phases in all of the three systems with different carbon number of the hydrophobic group of C_Nmim-Br,hexagonal and lamellar LLCs,respectively.The structural parameters of the two LLCs are found to be dependent on the carbon number of the hydrophobic group of C_Nmim-Br and the components content.For hexagonal phase,at higher surfactant content,the surfactant molecules aggregate more densely in the cylinder unit of the hexagonal phase;while the cylinder units aggregate more densely in the hexagonal phase.For lamellar phase,the increase of the water content leads to the water channel swell,and the surfactant bilayer is compressed.Meanwhile,the rheological properties of the LLCs are related to the phase structures.In the hexagonal phase,the sample with higher surfactant content has a higher zero-rate viscosity,zero-rate stress and dynamic modulus,which is due to the more dense aggregation of surfactant molecules in the membranes.The viscosity of lamellar phase is dependent on the component contents.Samples with higher content of surfactant or lower water content have the higher viscosity and dynamic modulus. Besides of hexagonal and lamellar phases,there is a bicontinuous cubic phase in the C₁₂mim-Br system,which is investigated by SAXS,POM and ²H-NMR experiments. Moreover,the structural parameters and rheological properties of the C_Nmim-Br-based LLCs are compared with that of the traditional cationic surfactant cetyltrimethylammonium bromide（CTAB）system.It is found that the effects of components content on the LLCs formed from the two kinds of amphiphile molecules are similar.However,the structural parameters and rheological properties of the two systems are different because of the different molecular structure.The studies of the physicochemical properties of LLC formed based on ionic liquid are helpful to the further application of LLC in the nanomaterials preparation.更多还原