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Recent developments of automated flow chemistry in pharmaceutical compounds synthesis 药用化合物合成中的自动化流动化学最新进展
IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2023-11-06 DOI: 10.1007/s41981-023-00285-x
Jiashu Wu, Xingxing Yang, Yourong Pan, Tao Zuo, Zuozhou Ning, Chengxi Li, Zhiguo Zhang

Recent developments in automated flow chemistry for pharmaceutical compound synthesis have garnered significant attention. Automation in synthesis represents a cutting-edge frontier in the field of chemistry, offering highly efficient, rapid, and reproducible synthetic methods that significantly shorten reaction time and reduce costs. In the realm of pharmaceutical compound synthesis, automated flow chemistry demonstrates unique importance. By utilizing flow chemistry, reactions can be performed under continuous flow conditions, enabling precise reaction control, higher yields, and increased product purity. Additionally, automated flow synthesis overcomes several challenges encountered in traditional batch synthesis, such as decreased generation of chemical waste, optimization of reaction conditions, and enhanced operational safety. This review highlights the recent developments in automated flow synthesis of various pharmaceutical compounds, including large biopharmaceutical molecules, small organic drug molecules, and carbohydrates. It covers automated iterative synthesis and the use of machine learning to enhance synthesis efficiency. Furthermore, it explores the practical application of high-throughput synthesis and screening technologies. Finally, the review offers concise perspectives on potential future developments in the field.

Graphical abstract

The development of automated flow synthesis kept breaking through new challenges for chemical reactions. Especially with the increasing demand for fast and efficient synthesis of therapeutic compounds, automated systems built a solid foundation for pharmaceutical innovation.

Solid-phase flow synthesis has been well-developed in the synthesis of large biopharmaceutical molecules; the immobilized support helps replace tedious separation and purification with a simple solvent wash. Additionally, flow-based pathways could provide convenience for automation.

High-throughput synthesis with in-line analysis offers both high-efficiency production and accurate monitoring. Therefore, this combination could be easily applied to rapid screening processes for building a large library, enhancing the performance of machine learning in reaction, and product prediction.

Artificial intelligence can be applied to self-optimized synthesis processes. Algorithm-based software could rapidly calculate and optimize insufficient reactions with a learning model built on past reactions posted in the literature. The connected robotic arm can then be automatically set to perform the optimized reaction.

用于药物化合物合成的自动化流程化学的最新发展引起了广泛关注。自动化合成是化学领域的前沿技术,它提供了高效、快速和可重复的合成方法,大大缩短了反应时间并降低了成本。在药物化合物合成领域,自动化流动化学具有独特的重要性。利用流动化学,反应可以在连续流动的条件下进行,从而实现精确的反应控制、更高的产量和更高的产品纯度。此外,自动化流动合成克服了传统批量合成中遇到的一些挑战,如减少化学废物的产生、优化反应条件和提高操作安全性。本综述重点介绍了各种药物化合物(包括大型生物制药分子、小型有机药物分子和碳水化合物)的自动化流式合成的最新进展。内容包括自动迭代合成和使用机器学习提高合成效率。此外,它还探讨了高通量合成和筛选技术的实际应用。图解摘要 自动化流程合成的发展不断突破化学反应的新挑战。固相流式合成在合成大型生物制药分子方面得到了很好的发展;固定化的支持物有助于用简单的溶剂清洗取代繁琐的分离和纯化。此外,基于流动的途径还能为自动化提供便利。高通量合成与在线分析相结合,既能实现高效生产,又能进行精确监测。人工智能可应用于自我优化的合成过程。人工智能可以应用于自我优化的合成过程。基于算法的软件可以根据文献中公布的以往反应建立学习模型,快速计算和优化不足的反应。然后,连接的机械臂可自动设置为执行优化反应。
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引用次数: 0
Perspectives on flow biocatalysis: the engine propelling enzymatic reactions 流动生物催化透视:推动酶促反应的引擎
IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2023-10-23 DOI: 10.1007/s41981-023-00283-z
Ana I. Benítez-Mateos, Francesca Paradisi

Flow biocatalysis has emerged as an empowering tool to boost the potential of enzymatic reactions towards more automatized, sustainable, and generally efficient synthetic processes. In the last fifteen years, the increasing number of biocatalytic transformations carried out in continuous flow exemplified the benefits that this technology can bring to incorporate biocatalysis into industrial operations. This perspective aims to capture in a nutshell the available methodologies for flow biocatalysis as well as to discuss the current limitations and the future directions in this field.

Graphical abstract

流式生物催化技术已成为一种强大的工具,可提高酶促反应的潜力,使合成过程更加自动化、可持续和普遍高效。在过去的十五年中,越来越多的生物催化转化在连续流中进行,这充分证明了这项技术在将生物催化融入工业操作方面所能带来的益处。本视角旨在概括现有的流动生物催化方法,并讨论该领域当前的局限性和未来的发展方向。
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引用次数: 0
Development of an automated flow chemistry affinity-based purification process for DNA-encoded chemistry 为 DNA 编码化学开发基于亲和力的自动流动化学纯化流程
IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2023-09-26 DOI: 10.1007/s41981-023-00282-0
Robin Dinter, Katharina Götte, Franziska Gronke, Leon Justen, Andreas Brunschweiger, Norbert Kockmann

An automated flow chemistry platform for DNA-encoded library (DEL) technologies requires the integration of a purification process for DNA-tagged substrates. It facilitates the development of further DEL reactions, building block rehearsal, and library synthesis. Therefore, a recently developed, manual affinity-based batch purification process for DNA-tagged substrates based on dispersive solid-phase extraction (DSPE) was transferred to automated flow chemistry using tailored 3D-printed microfluidic devices and open-source lab automation equipment. The immobilization and purification steps use Watson–Crick base pairing for a compound-encoding single-stranded DNA, which allows for the thorough removal of impurities and contaminations by washing steps and operationally simple recovery of the purified DNA-encoded compounds. This work optimized the annealing step for flow incubation and DNA purification was accomplished by flow DSPE washing/elution steps. The manually performed batch affinity-based purification process was compared with the microfluidic process by determining qualitative and quantitative DNA recovery parameters. It aimed at comparing batch and flow purification processes with regard to DNA recovery and purity to benefit from the high potential for automation, precise process control, and higher information density of the microfluidic purification process for DNA-tagged substrates. Manual operations were minimized by applying an automation strategy to demonstrate the potential for integrating the microfluidic affinity-based purification process for DNA-tagged substrates into an automated DNA-encoded flow chemistry platform.

Graphical Abstract

用于 DNA 编码文库(DEL)技术的自动化流程化学平台需要整合 DNA 标记底物的纯化过程。这有助于进一步开发 DEL 反应、构件排演和文库合成。因此,利用定制的三维打印微流控装置和开源实验室自动化设备,将最近开发的基于分散固相萃取(DSPE)的DNA标记底物人工亲和批量纯化流程转移到自动化流化学中。固定和纯化步骤使用化合物编码单链 DNA 的 Watson-Crick 碱基配对,这样就可以通过洗涤步骤彻底清除杂质和污染物,并在操作上简单地回收纯化的 DNA 编码化合物。这项工作优化了流式孵育的退火步骤,并通过流式 DSPE 水洗/淘洗步骤完成 DNA 纯化。通过确定定性和定量的 DNA 回收参数,将人工批量亲和纯化过程与微流控过程进行了比较。其目的是比较批次和流动纯化过程的 DNA 回收率和纯度,以受益于微流体纯化过程在自动化、精确过程控制和更高信息密度方面的巨大潜力。通过采用自动化策略,最大限度地减少了人工操作,从而展示了将基于亲和力的DNA标记底物微流控纯化工艺整合到自动化DNA编码流动化学平台的潜力。
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引用次数: 0
Droplet generation at T-junctions in parallelized microchannels 平行微通道中t型结的液滴生成
IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2023-08-16 DOI: 10.1007/s41981-023-00281-1
Zhongdong Wang, Xingyu Xiang, Sajawal Raza, Asad Ullah, Chunying Zhu, Tianyang Feng, Youguang Ma, Taotao Fu

Microchemical technology is an advanced chemical production technology and the large-scale production for industrial applications is realized by parallelization of microchannels. In this paper, the emulsification process and numbering-up of droplets in asymmetric parallelized microchannels with T-junction are investigated, and the effects of fluid properties and operating conditions on droplet size are analyzed. The droplet generation process is divided into waiting stage, filling stage, necking stage, and pinch-off stage, according to the variation of the characteristic length scale during droplet generation. The flow patterns of droplet swarm in cavities and their influence on fluid distribution are analyzed. The droplet size prediction equation and fluid distribution model in asymmetric parallelized microchannel are constructed. The phenomenon of droplet asynchronous generation due to the coupling of parallelized microchannels during the numbering-up process is analyzed. The effect of asynchronous generation on droplet monodispersity is investigated and the mothod for the prevention of this effect is proposed.

Graphical abstract

微化工技术是一种先进的化工生产技术,通过微通道并行化实现了工业应用的大规模生产。本文研究了带 T 型接头的非对称并行微通道中的乳化过程和液滴编号,分析了流体性质和操作条件对液滴大小的影响。根据液滴生成过程中特征长度尺度的变化,将液滴生成过程分为等待阶段、填充阶段、缩颈阶段和掐断阶段。分析了液滴群在空腔中的流动模式及其对流体分布的影响。构建了非对称并行微通道中液滴大小预测方程和流体分布模型。分析了在编号过程中由于并行微通道的耦合而导致的液滴异步生成现象。研究了异步生成对液滴单分散性的影响,并提出了防止这种影响的方法。
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引用次数: 0
Continuous-flow synthesis of 7-methoxy-1-tetralone: an important intermediate of (-)-Dezocine 7-甲氧基-1-四氢萘酮的连续流动合成
IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2023-07-27 DOI: 10.1007/s41981-023-00274-0
Liangchuan Lai, Liang Gao, Minjie Liu, Yongxing Guo, Dang Cheng, Meifen Jiang, Fener Chen

Continuous flow technology has been widely adopted in manufacturing active pharmaceutical ingredients (APIs). Herein, we report an expeditious multi-step continuous-flow strategy for an efficient and highly productive flow synthesis of 7-methoxy-1-tetralone, which is an essential intermediate for the opioid analgesic drug (-)-dezocine. Compared with the traditional batch operation, this work presents significant advantages of continuous-flow chemistry with dramatically reduced reaction time, highly improved reaction efficiency, good controls over reaction optimizing conditions, etc. The flow protocol in this work provided the desired product in an overall yield of up to 76.6% with 99% purity, much higher than those from batch process (i.e., 50% yield, 92% purity). Moreover, reaction efficiency is highly improved with a throughput of 0.49 g/h, the total reaction time is markedly reduced from hours in batch to minutes in flow process.

Graphical abstract

连续流技术已被广泛应用于活性药物成分(API)的生产。在此,我们报告了一种快速的多步连续流策略,用于高效、高产地流动合成 7-甲氧基-1-四氢萘酮,它是阿片类镇痛药 (-)-dezocine 的重要中间体。与传统的间歇式操作相比,这项工作体现了连续流化学的显著优势,如反应时间大大缩短、反应效率大幅提高、反应优化条件控制良好等。与间歇式工艺(即产率 50%、纯度 92%)相比,该工作中的流式方案可提供高达 76.6% 的所需产物,纯度高达 99%。此外,反应效率也大大提高,产量为 0.49 克/小时,总反应时间从间歇式工艺的数小时明显缩短到流式工艺的数分钟。
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引用次数: 0
Safe and on-demand protocol for the continuous generation of SO2 and Cl2 for subsequent utilization in organic synthesis 安全的和按需的方案连续生成SO2和Cl2用于随后的有机合成利用
IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2023-07-24 DOI: 10.1007/s41981-023-00280-2
Gulice Yiu Chung Leung, Shannon Thoi Rui Ying, Edwin Chia, Anqi Chen, Gabriel Loh, Balamurugan Ramalingam

Hazardous reagents such as sulfur dioxide (SO2) and chlorine (Cl2) are powerful and atom-efficient reagents for respectively introducing the ‘SO2’ moiety and ‘Cl’ atom into organic molecules. However, their use is limited due to a lack of protocols and methods to access them in laboratories readily. This article describes the development of a prototype, method, and process for accessing hazardous gaseous reagents safely on demand continuously for further utilization in organic synthesis. The prototype was validated by producing SO2 from readily accessible laboratory reagents sodium sulfite (Na2SO3) and sulfuric acid (H2SO4). The generated SO2 was successfully utilized for the synthesis of aryl sulfinate salts, which were subsequently converted to sulfonamides and sulfone-containing bicalutamide drugs. The broader applicability of the reactor prototype has also been demonstrated in the generation of chlorine gas from bleach (NaOCl) and hydrochloric acid (HCl), followed by the separation of chlorine gas from an acidic aqueous reaction mixture. The utilization of the separated chlorine gas was demonstrated in the synthesis of silyl chlorides in both batch and continuous manners. The present reactor prototype not only enables safe and convenient access to highly hazardous gaseous reagents for facile organic synthesis in laboratories, but also eliminates the risks in handling, storage, and transportation of hazardous gaseous reagents in cylinders.

Graphical abstract

二氧化硫(SO2)和氯气(Cl2)等危险试剂是分别将 "SO2 "分子和 "Cl "原子引入有机分子的强效原子高效试剂。然而,由于缺乏在实验室中随时使用它们的规程和方法,它们的使用受到了限制。本文介绍了一种原型、方法和流程的开发,该原型、方法和流程可按需安全地持续获取危险气态试剂,以便在有机合成中进一步利用。该原型通过利用实验室现成试剂亚硫酸钠 (Na2SO3) 和硫酸 (H2SO4) 生产二氧化硫进行了验证。生成的二氧化硫被成功用于合成芳基硫酸酯盐,随后转化为磺胺类药物和含砜的比卡鲁胺药物。该反应器原型的广泛适用性还体现在从漂白剂(NaOCl)和盐酸(HCl)中生成氯气,然后从酸性水反应混合物中分离出氯气。分离出的氯气在间歇式和连续式合成硅基氯化物的过程中都得到了验证。本反应器原型不仅可以安全方便地获取高危气态试剂,在实验室中进行简单的有机合成,而且消除了处理、储存和运输装在气瓶中的危险气态试剂的风险。
{"title":"Safe and on-demand protocol for the continuous generation of SO2 and Cl2 for subsequent utilization in organic synthesis","authors":"Gulice Yiu Chung Leung,&nbsp;Shannon Thoi Rui Ying,&nbsp;Edwin Chia,&nbsp;Anqi Chen,&nbsp;Gabriel Loh,&nbsp;Balamurugan Ramalingam","doi":"10.1007/s41981-023-00280-2","DOIUrl":"10.1007/s41981-023-00280-2","url":null,"abstract":"<div><p>Hazardous reagents such as sulfur dioxide (SO<sub>2</sub>) and chlorine (Cl<sub>2</sub>) are powerful and atom-efficient reagents for respectively introducing the ‘SO<sub>2</sub>’ moiety and ‘Cl’ atom into organic molecules. However, their use is limited due to a lack of protocols and methods to access them in laboratories readily. This article describes the development of a prototype, method, and process for accessing hazardous gaseous reagents safely on demand continuously for further utilization in organic synthesis. The prototype was validated by producing SO<sub>2</sub> from readily accessible laboratory reagents sodium sulfite (Na<sub>2</sub>SO<sub>3</sub>) and sulfuric acid (H<sub>2</sub>SO<sub>4</sub>). The generated SO<sub>2</sub> was successfully utilized for the synthesis of aryl sulfinate salts, which were subsequently converted to sulfonamides and sulfone-containing bicalutamide drugs. The broader applicability of the reactor prototype has also been demonstrated in the generation of chlorine gas from bleach (NaOCl) and hydrochloric acid (HCl), followed by the separation of chlorine gas from an acidic aqueous reaction mixture. The utilization of the separated chlorine gas was demonstrated in the synthesis of silyl chlorides in both batch and continuous manners. The present reactor prototype not only enables safe and convenient access to highly hazardous gaseous reagents for facile organic synthesis in laboratories, but also eliminates the risks in handling, storage, and transportation of hazardous gaseous reagents in cylinders.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2023-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42193973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enantioselective catalytic Strecker reaction on cyclic (Z)-aldimines in flow: reaction optimization and sustainability aspects 流动中环状(Z)-醛亚胺对映选择性催化Strecker反应:反应优化和可持续性
IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2023-07-19 DOI: 10.1007/s41981-023-00279-9
Antonella Ilenia Alfano, Andrea Sorato, Alessia Ciogli, Heiko Lange, Margherita Brindisi

Catalytic enantioselective Strecker reactions on an achiral substrate using sub-stoichiometric amounts of a chiral catalyst represent an evolving key strategy for the effective synthesis of α-amino nitriles. We herein disclosed the set-up of a flow-based methodology for enantioselective Strecker, employing ethyl cyanoformate as a relatively safe cyanide source, a cinchona-based catalyst, and methanol as additive. A thorough exploration of key parameters allowed the identification of the most efficient reagent mixing mode, the optimum solvent for the flow synthesis, minimum catalyst loading, additive, temperature, and residence time. The newly developed method allows straightforward reaction channeling towards the fast and complete formation of the α-amino nitrile products, thus reducing the yield drop due to indolenine degradation during long-lasting batch-wise reactions. Moreover, we herein provide preliminary hints for sustainability, by proposing a simple procedure for catalyst recycling, thus opening the way for further optimization of the proposed methodology.

Graphical Abstract

使用亚几何量的手性催化剂在非手性底物上进行催化对映选择性 Strecker 反应,是有效合成 α 氨基腈的一个不断发展的关键策略。我们在此披露了一种基于流程的对映选择性 Strecker 方法,该方法采用氰基甲酸乙酯作为相对安全的氰化源、金鸡纳树基催化剂和甲醇作为添加剂。通过对关键参数的深入探讨,确定了最有效的试剂混合模式、流动合成的最佳溶剂、催化剂的最小负载量、添加剂、温度和停留时间。新开发的方法可以直接引导反应,快速、完全地形成α-氨基腈产物,从而减少了在长期批量反应过程中由于吲哚啉降解而导致的产率下降。此外,我们在此提出了催化剂回收的简单程序,从而为进一步优化所建议的方法提供了可持续发展的初步提示。
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引用次数: 0
Continuous flow process development for the synthesis of an industrial raw material via solvent-free aromatic Claisen rearrangement 无溶剂芳香族克拉森重排法合成工业原料的连续流工艺开发
IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2023-07-14 DOI: 10.1007/s41981-023-00275-z
Nikola Petrovic, Sándor B. Ötvös, C. Oliver Kappe

A high-temperature continuous flow protocol is reported for the intensified synthesis of an important industrial raw material via aromatic Claisen rearrangement of the corresponding diallyl ether precursor. The process takes advantage of solvent-free conditions, thereby maximizing productivity whilst reducing cost and environmental impact. By precise control over reaction temperature and residence times, a high-yielding and selective synthesis is achieved that ensures improved safety and scalability of the exothermic transformation compared with earlier batch methodologies.

Graphical Abstract

报告采用高温连续流方案,通过相应二烯丙基醚前体的芳香族克莱森重排,强化合成一种重要的工业原料。该工艺利用了无溶剂条件的优势,从而最大限度地提高了生产率,同时降低了成本和对环境的影响。通过精确控制反应温度和停留时间,实现了高产和高选择性合成,与早期的批量方法相比,确保了放热转化的安全性和可扩展性。
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引用次数: 0
3D printed reactors and Kessil lamp holders for flow photochemistry: design and system standardization 用于流动光化学的3D打印反应器和Kessil灯座:设计和系统标准化
IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2023-07-05 DOI: 10.1007/s41981-023-00278-w
Matthew R. Penny, Stephen T. Hilton

A low-cost 3D printed standardized flow-photochemistry setup has been designed and developed for use with a pressure-driven flow system using photochemistry lamps available in most laboratories. In this research, photochemical reactors were 3D printed from polypropylene which facilitated rapid optimization of both reactor geometry and experimental setup of the lamp housing system. To exemplify the rapidity of this approach to optimization, a Kessil LED lamp was used in the bromination of a range of toluenes in the 3D printed reactors in good yields with residence times as low as 27 s. The reaction compared favorably with the batch photochemical procedure and was able to be scaled up to a productivity of 75 mmol h−1.

设计和开发了一种低成本的3D打印标准化流动光化学装置,用于大多数实验室使用的光化学灯的压力驱动流动系统。在这项研究中,光化学反应器是用聚丙烯3D打印的,这有助于快速优化反应器的几何形状和灯罩系统的实验设置。为了证明这种优化方法的快速性,在3D打印反应器中,将Kessil LED灯用于一系列甲苯的溴化,收率高,停留时间低至27秒。该反应与间歇光化学反应相比较有利,并且能够扩大到75 mmol h−1的产率。
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引用次数: 0
Continuous morphology-controllable precipitation strategy for europium oxalate hydrates via microchannel reactor 微通道反应器连续形态可控的草酸铕水合物沉淀策略
IF 2.7 4区 化学 Q2 Chemical Engineering Pub Date : 2023-06-30 DOI: 10.1007/s41981-023-00277-x
Keyu Tao, Hao Li, Junjie Cheng, Zhi Cao, Yefan Li

A flow chemistry based continuous morphology-controllable precipitation strategy was successfully developed for synthesis of europium oxalate hydrate microparticles. The effects of flow ratio between raw materials within microchannels on the crystal structure, morphology and particle size distribution of the precipitated products were firstly studied. The results shown that both high yield and controllable morphology were achieved for Eu3+ precipitation reactions under its low concentration condition. The effects of supersaturation, mixing intensity, and reaction temperatures were also investigated in detail, which proved the continuous preparation of layered microparticles with concentrated size distribution can be achieved by this strategy. Multiple characterizations and comparison experiment synergistically reveal that the feed flow ratios of nitric acid and oxalic acid determines the morphology and particle size distribution due to affecting the mixing degree and phase composition of the precipitation reaction. In addition, the phase and morphology conversion of precipitates after calcination treatment were also studied, the as-calcined metal oxide powder exhibited a decent photoluminescence characteristic. In summary, this work demonstrates a promising precipitation strategy within micro-channels for mass controllable production of high-quality metal oxide materials.

Graphical abstract

成功地开发了基于流动化学的连续形态可控沉淀策略,用于合成草酸铕水合物微粒。首先研究了微通道内物料流动比对析出产物晶体结构、形貌和粒度分布的影响。结果表明,在低浓度条件下,Eu3+的沉淀反应既能获得较高的收率,又能获得可控的形貌。研究了过饱和度、混合强度和反应温度的影响,证明了该策略可以连续制备具有集中粒度分布的层状微颗粒。多种表征和对比实验协同表明,硝酸和草酸的进料流量比通过影响沉淀反应的混合程度和相组成,决定了产物的形貌和粒度分布。此外,还研究了煅烧处理后析出相的物相和形貌变化,煅烧后的金属氧化物粉末具有良好的光致发光特性。总之,这项工作展示了一种在微通道内大规模可控生产高质量金属氧化物材料的有前途的沉淀策略。图形抽象
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引用次数: 0
期刊
Journal of Flow Chemistry
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