本文選題：溶液結(jié)晶 + 分子聚集體　； 參考：《華東理工大學(xué)》2016年博士論文

【摘要】：結(jié)晶技術(shù)由于具有能耗低、效率高、產(chǎn)品純度高以及操作條件溫和等優(yōu)勢(shì),在醫(yī)藥、化工、材料和生命科學(xué)等領(lǐng)域有著廣泛的應(yīng)用。其中,溶液結(jié)晶是最古老也是最常采用的一種結(jié)晶工藝。該過程雖然看似簡(jiǎn)單,但涉及復(fù)雜的晶體成核與生長(zhǎng)過程,并受到內(nèi)部和外部多重因素的制約。目前,對(duì)溶液結(jié)晶過程尤其是涉及到多晶型藥物的結(jié)晶過程尚未完全理解,設(shè)計(jì)和優(yōu)化結(jié)晶過程在很大程度上仍然依賴于經(jīng)驗(yàn)。因此,為了能夠有效地控制溶液結(jié)晶過程,進(jìn)而獲取滿足不同需求的晶體產(chǎn)品,必須從原理上認(rèn)識(shí)晶體的成核與生長(zhǎng)機(jī)理以及晶體內(nèi)部的分子排列方式和外部生長(zhǎng)環(huán)境對(duì)晶體成核的影響機(jī)制。眾多研究表明,結(jié)晶過程中的的溶劑以及過飽和度對(duì)晶體的成核與生長(zhǎng)過程以及多晶型體系的晶型轉(zhuǎn)變過程都產(chǎn)生了重要影響。但目前對(duì)溶劑和過飽和度這兩個(gè)因素對(duì)晶型的調(diào)控以及晶型轉(zhuǎn)變的作用機(jī)制尚缺乏深入系統(tǒng)的理解和認(rèn)識(shí)。因此,本文以L-谷氨酸為研究體系,采用實(shí)驗(yàn)與分子模擬相結(jié)合的方法研究成核前溶液中分子聚集體的結(jié)構(gòu)、過飽和度對(duì)成核及晶型轉(zhuǎn)變過程的影響以及溶劑和亞穩(wěn)晶型的晶面對(duì)穩(wěn)定晶型成核過程的作用機(jī)制,以期為多晶型藥物結(jié)晶過程提供一定的理論基礎(chǔ)。本論文主要研究?jī)?nèi)容如下：1.利用紫外光譜分析了L-谷氨酸分子在不同溶劑中的聚集方式,并通過實(shí)驗(yàn)測(cè)定了其在上述溶劑中的成核誘導(dǎo)期,關(guān)聯(lián)了不同溶劑中溶質(zhì)分子的聚集方式與成核誘導(dǎo)期之間的關(guān)系；采用分子動(dòng)力學(xué)模擬研究了水溶劑中溶質(zhì)分子的聚集形式,結(jié)果表明在較高的濃度下,溶質(zhì)分子傾向于形成單氫鍵二聚體,并可繼續(xù)團(tuán)聚成更大的聚集體,初步解釋了紫外光譜法得到的結(jié)果。2.應(yīng)用紅外光譜探測(cè)了具有不同過飽和度的L-谷氨酸水溶液中的溶質(zhì)分子的構(gòu)象,并監(jiān)測(cè)了對(duì)應(yīng)的晶核的晶型,發(fā)現(xiàn)不同過飽和溶液中溶質(zhì)分子的主要構(gòu)象決定了初始結(jié)晶產(chǎn)品的晶型,并且在較低過飽和度的溶液中會(huì)直接生成穩(wěn)定的p晶型,而在高過飽和度的溶液中,首先出現(xiàn)的是亞穩(wěn)的a晶型,隨后逐漸轉(zhuǎn)變?yōu)棣戮汀?.使用粉末X射線衍射對(duì)L-谷氨酸兩種晶型的組成進(jìn)行了定量分析,在此基礎(chǔ)上確定了L-谷氨酸晶型轉(zhuǎn)變過程中兩種晶型的含量變化。利用光學(xué)顯微鏡在線觀測(cè)了高過飽和度下L-谷氨酸的晶型轉(zhuǎn)變過程,發(fā)現(xiàn)過飽和度的增加,改變了初始結(jié)晶的α晶型的形貌,從而大幅縮短了晶型轉(zhuǎn)變的時(shí)間。4.在線觀察了的L-谷氨酸過飽和溶液中的晶型轉(zhuǎn)變過程,發(fā)現(xiàn)p晶型可以在α晶型的三個(gè)主要晶面都上成核,但成核概率按照{(diào)011}{111}{001}的順序降低。通過分子動(dòng)力學(xué)模擬考察了初始構(gòu)象為α或β的單一溶質(zhì)分子吸附在α晶型的三個(gè)主要晶面上的吸附情況。結(jié)果表明兩種分子在晶面上的吸附能都依照{(diào)011}{111}{001}的順序降低,且初始構(gòu)象為α的溶質(zhì)分子由于受到{011}晶面的誘導(dǎo)作用而演變?yōu)閜的構(gòu)象。進(jìn)一步,采用單分子連續(xù)吸附模型,考察了多個(gè)初始構(gòu)象為β的分子在α晶型的三個(gè)晶面上的吸附情況,發(fā)現(xiàn)增加吸附分子數(shù)目并不改變吸附能的大小順序,但這些分子在a晶型不同晶面上的自組裝能力不同,其中在α晶型的{011}晶面上的自組裝能力最強(qiáng)。5.為了考察溶劑在L-谷氨酸晶型轉(zhuǎn)變過程中所起到重要作用,在第4點(diǎn)的基礎(chǔ)上,進(jìn)一步構(gòu)建了單層弛豫的界面溶劑化模型,從熱力學(xué)和動(dòng)力學(xué)角度分析了溶質(zhì)、溶劑分子分別在晶面上的吸附及擴(kuò)散行為以及溶質(zhì)分子在溶液中的脫溶劑化過程。發(fā)現(xiàn)溶劑的存在并不改變兩種分子在α晶型的不同晶面上的吸附能順序,但會(huì)減小吸附能的相對(duì)大小,并削弱了α晶型的晶面對(duì)溶質(zhì)分子構(gòu)象改變的誘導(dǎo)作用以及構(gòu)象為p的溶質(zhì)分子在α晶型的不同晶面上的自組裝行為。
[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.
【學(xué)位授予單位】：華東理工大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：TQ026.5;O629.71
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本文編號(hào)：2074804