溶液结晶中L-谷氨酸成核与晶型转变机理的分子模拟与实验研究

发布时间：2018-06-27 18:21

  本文选题：溶液结晶 + 分子聚集体　； 参考：《华东理工大学》2016年博士论文

【摘要】：结晶技术由于具有能耗低、效率高、产品纯度高以及操作条件温和等优势,在医药、化工、材料和生命科学等领域有着广泛的应用。其中,溶液结晶是最古老也是最常采用的一种结晶工艺。该过程虽然看似简单,但涉及复杂的晶体成核与生长过程,并受到内部和外部多重因素的制约。目前,对溶液结晶过程尤其是涉及到多晶型药物的结晶过程尚未完全理解,设计和优化结晶过程在很大程度上仍然依赖于经验。因此,为了能够有效地控制溶液结晶过程,进而获取满足不同需求的晶体产品,必须从原理上认识晶体的成核与生长机理以及晶体内部的分子排列方式和外部生长环境对晶体成核的影响机制。众多研究表明,结晶过程中的的溶剂以及过饱和度对晶体的成核与生长过程以及多晶型体系的晶型转变过程都产生了重要影响。但目前对溶剂和过饱和度这两个因素对晶型的调控以及晶型转变的作用机制尚缺乏深入系统的理解和认识。因此,本文以L-谷氨酸为研究体系,采用实验与分子模拟相结合的方法研究成核前溶液中分子聚集体的结构、过饱和度对成核及晶型转变过程的影响以及溶剂和亚稳晶型的晶面对稳定晶型成核过程的作用机制,以期为多晶型药物结晶过程提供一定的理论基础。本论文主要研究内容如下：1.利用紫外光谱分析了L-谷氨酸分子在不同溶剂中的聚集方式,并通过实验测定了其在上述溶剂中的成核诱导期,关联了不同溶剂中溶质分子的聚集方式与成核诱导期之间的关系；采用分子动力学模拟研究了水溶剂中溶质分子的聚集形式,结果表明在较高的浓度下,溶质分子倾向于形成单氢键二聚体,并可继续团聚成更大的聚集体,初步解释了紫外光谱法得到的结果。2.应用红外光谱探测了具有不同过饱和度的L-谷氨酸水溶液中的溶质分子的构象,并监测了对应的晶核的晶型,发现不同过饱和溶液中溶质分子的主要构象决定了初始结晶产品的晶型,并且在较低过饱和度的溶液中会直接生成稳定的p晶型,而在高过饱和度的溶液中,首先出现的是亚稳的a晶型,随后逐渐转变为β晶型。3.使用粉末X射线衍射对L-谷氨酸两种晶型的组成进行了定量分析,在此基础上确定了L-谷氨酸晶型转变过程中两种晶型的含量变化。利用光学显微镜在线观测了高过饱和度下L-谷氨酸的晶型转变过程,发现过饱和度的增加,改变了初始结晶的α晶型的形貌,从而大幅缩短了晶型转变的时间。4.在线观察了的L-谷氨酸过饱和溶液中的晶型转变过程,发现p晶型可以在α晶型的三个主要晶面都上成核,但成核概率按照{011}{111}{001}的顺序降低。通过分子动力学模拟考察了初始构象为α或β的单一溶质分子吸附在α晶型的三个主要晶面上的吸附情况。结果表明两种分子在晶面上的吸附能都依照{011}{111}{001}的顺序降低,且初始构象为α的溶质分子由于受到{011}晶面的诱导作用而演变为p的构象。进一步,采用单分子连续吸附模型,考察了多个初始构象为β的分子在α晶型的三个晶面上的吸附情况,发现增加吸附分子数目并不改变吸附能的大小顺序,但这些分子在a晶型不同晶面上的自组装能力不同,其中在α晶型的{011}晶面上的自组装能力最强。5.为了考察溶剂在L-谷氨酸晶型转变过程中所起到重要作用,在第4点的基础上,进一步构建了单层弛豫的界面溶剂化模型,从热力学和动力学角度分析了溶质、溶剂分子分别在晶面上的吸附及扩散行为以及溶质分子在溶液中的脱溶剂化过程。发现溶剂的存在并不改变两种分子在α晶型的不同晶面上的吸附能顺序,但会减小吸附能的相对大小,并削弱了α晶型的晶面对溶质分子构象改变的诱导作用以及构象为p的溶质分子在α晶型的不同晶面上的自组装行为。
[Abstract]:Because of the advantages of low energy consumption, high efficiency, high purity and mild operating conditions, crystallization is widely used in the fields of medicine, chemical industry, material and life science. Among them, the crystallization of solution is the oldest and most commonly used crystallization process. Although it seems simple, it involves complex crystal nucleation and production. The long process is restricted by the internal and external factors. At present, the crystallization process of the solution crystallization, especially the polycrystalline drug, is not fully understood. The design and optimization of the crystallization process are largely dependent on the experience. Therefore, in order to effectively control the crystallization process of the solution, the process of the crystallization of the solution can be obtained to meet the different needs. In order to obtain crystal products, the mechanism of nucleation and growth of crystal, the mechanism of molecular arrangement within the crystal and the influence mechanism of external growth environment on the nucleation of crystals must be understood in principle. The process has produced important effects. However, there is still a lack of understanding and understanding of the regulation of the two factors of solvent and supersaturation on the crystal form and the mechanism of the crystalline transformation. Therefore, this paper uses L- glutamic acid as the research system and studies the molecular aggregates in the pre nucleated solution by combining the experiment with the molecular simulation. Structure, the effect of supersaturation on nucleation and crystal transformation and the mechanism of solvent and metastable crystals in the process of stabilizing the nucleation process, in order to provide a theoretical basis for the crystallization of polycrystalline drugs. The main contents of this paper are as follows: 1. the L- glutamic acid molecules in different solubility were analyzed by ultraviolet spectroscopy. The nucleation induction period in the above solvent was determined by experiments, and the relationship between the aggregation mode of solute molecules in different solvents and the induction period of nucleation was related. The aggregation form of solute molecules in water solvent was studied by molecular dynamics simulation. The results showed that the solute molecules tilting at a higher concentration. In order to form a mono hydrogen bond two polymer and continue to be reunited into a larger aggregate, the result of ultraviolet spectroscopy has been explained preliminarily by.2.. The conformation of the solute molecules in a solution of L- glutamic acid with different supersaturation is detected by infrared spectroscopy, and the crystal forms of the corresponding nuclei are monitored, and the solute in different supersaturated solutions is found. The main conformation determines the crystal form of the initial crystalline product and produces a stable P crystal in the low supersaturation solution, while in the high supersaturation solution, the metastable a crystal is first appeared, and then gradually converted to the beta crystalline.3. by powder X ray diffraction, the composition of the two crystalline forms of L- Glutamic acid is determined. On the basis of the quantitative analysis, the content changes of the two crystalline forms during the crystalline transformation of L- glutamic acid are determined. The crystal transformation process of L- glutamic acid under high supersaturation is observed on line by optical microscope, and the increase of supersaturation is found, which changes the shape appearance of the initial crystalline form of the alpha crystal, thus greatly shortens the time of.4. in the crystalline transition. The transformation process of the L- glutamic acid supersaturated solution was observed. It was found that the P crystal could be nucleated on the three main crystal surfaces of the alpha crystal, but the nucleation probability was reduced in the order of {011}{111}{001}. By molecular dynamics simulation, a single solute molecule with the initial conformation of alpha or beta was adsorbed on the three main crystal surfaces of the alpha crystal. The results show that the adsorption energy of the two molecules on the crystal surface decreases in the order of {011}{111}{001}, and the initial conformation of the solute molecules of alpha is transformed into the conformation of P due to the induction of {011} crystal surface. Further, the single molecule continuous adsorption model is used to investigate the alpha crystal of the molecules with several initial conformations of beta. It is found that the increase of the number of adsorbate molecules does not change the order of adsorption energy, but the self-assembly ability of these molecules on the a crystal surface is different, and the strongest self assembly ability.5. on the {011} crystal surface of the alpha crystal is.5. in order to investigate the important role of the solvent in the transition process of L- glutamic acid crystal. On the basis of fourth points, the monolayer relaxation interfacial solvation model is further constructed. The adsorption and diffusion behavior of solute molecules on the crystal surface and the dehydration process of solute molecules in the solution are analyzed from the thermodynamic and kinetic angles. It is found that the existence of the solvent does not change the difference between the two molecules in the alpha crystalline form. The adsorption energy sequence on the crystal surface reduces the relative size of the adsorption energy, and weakens the inducement of the crystal form of the crystal in the face of the conformation change of the solute molecules and the self assembly of the solute molecules of the conformation of P on the different crystal surfaces of the alpha crystal.
【学位授予单位】：华东理工大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：TQ026.5;O629.71
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本文编号：2074804