Continuous reactive crystallization of pharmaceuticals using impinging jet mixers

For reactive crystallization of pharmaceuticals that show a rapid reaction rate, low solubility of active pharmaceutical ingredient and hence a large supersaturation, it was found in a recent study that a process design which integrates an impinging jet mixer and batch stirred tank produces high quality crystals. The current investigation examines if the short processing time of reactive crystallization permits the impinging jet mixer—stirred tank design to be modified to operate in a continuous mode. The new design combines an impinging jet mixer for feed introduction and reaction with a continuous stirred tank reactor (CSTR) and tubular reactor for crystal growth. A study of reactive crystallization of sodium cefuroxime (an antibiotic), using first a 1L CSTR then scaling to a 50L CSTR, found that the new design produces crystals of higher crystallinity, narrower particle size, and improved product stability, than batch crystallizers. © 2016 American Institute of Chemical Engineers AIChE J, 63: 967–974, 2017     

撞击流强化混合特性及用于制备超细粉体研究进展

撞击流以其强化微观混合的优异特性在化学反应、结晶、制备超细粉体等方面有广泛应用。本文在撞击流技术强化混合特性的基础上对近年来几种撞击流反应器制备超细粉体研究进行了综述。简述了流体流动、受限空间、喷嘴形式及结构、外部激励等因素对浸没循环撞击流反应器、受限撞击流反应器、T形撞击流反应器、微小型撞击流反应器、撞击流-旋转填料床反应器混合性能的影响。从结晶、微观混合时间等角度分析了撞击流微观混合特性对化学反应及制备超细粉体的影响。并与常规反应器及方法对比,从超细粉体的粒度大小、形貌、表面、能量、分散性、电性能及稳定性等方面进行评估。提出一种双层对置撞击流反应器用于工业上大规模制取超细粉体的中试研究,并展望了撞击流技术用于制备超细粉体的前景。     

Preparation of ferric oxide powders by ultrasonic-assisted impinging stream reaction

In this paper, Fe₃O₄ powder was prepared by the chemical precipitation method using impinging stream technology. The influences of feed flow rate, L/D, reactant concentration, ratio of iron ion concentration, reaction temperature, and impact time on the size and distribution of particles were investigated by the orthogonal experiment method. The microstructure and morphology of Fe₃O₄ powders were characterized by scanning electron microscopy, X-ray diffractometer, and granulometer. The results showed that when ratio of iron ion concentration c(Fe²⁺):c(Fe³⁺) = 0.75, reactant concentration c(Fe³⁺) = 0.4 mol · L⁻¹, feed flow rate Q = 800 L · h⁻¹, L/D = 3, reaction temperature T = 20°C, impact time t = 50 min, the prepared Fe₃O₄ had an average particle size of 1.815 μm and the most uniform distribution. The influence of ultrasonic enhancement on the mixing process and powder preparation in an impinging stream reactor was investigated. The size and distribution of the powders were significantly affected by ultrasonic enhancement. With the increase in ultrasonic power, the particle size of the powders decreased and the distribution became narrower. The particle size was reduced by 68.78%, and the particle distribution range was narrowed by 84.34% under ultrasound enhancement. This study promised the effective utilization of ultrasonic cavitation in the optimization of experimental equipment and the preparation of ultrafine powder, which provides a basis for process optimization of powder preparation.     

Analytical technology aided optimization and scale‐up of impinging jet mixer for reactive crystallization process

Reactive crystallization is widely used in the manufacture of active pharmaceutical ingredients (APIs). As APIs often have low solubility, traditional stirred tank reactors and the route of process operation and control using metastable zone width are not effective. This work investigated the integration of an impinging jet mixer and a stirred tank crystallizer that can take advantage of both the reaction and crystallization characteristics, the focus being on design optimization and scale‐up using process analytical techniques based on the Fourier transform infrared spectroscopy and focused beam reflectance measurement, as well as X‐ray diffraction and particle imaging Morphologi G3. The parameters for process operation and design of the impinging jet mixer were optimized. The research was carried out with reference to the manufacture of an antibiotic, sodium cefuroxime, first in a 1L reactor, then a 10L reactor. The crystals produced showed higher crystallinity, narrower size distribution, higher stability, and purity. © 2014 American Institute of Chemical Engineers AIChE J, 61: 503–517, 2015     

撞击流反应器制备纳米二氧化钛的实验研究

以TiCl4和(NH4)2SO4为原料,在撞击流反应器中用沉淀法制备了纳米二氧化钛。研究了工艺参数对粒径的影响,结果表明,反应物浓度1.2 mol/L,pH值为3,反应温度70℃,转速600 r/min的条件下,制得的沉淀物经600℃高温焙烧3 h,可得粒径为11.30 nm的二氧化钛颗粒,粒径均匀,不团聚。     

Reactive hot pressing of zirconium diboride

The reaction of zirconium and boron was investigated as a potential route to form dense monolithic zirconium diboride (ZrB₂) ceramics. Attrition milling of the precursors produced nanosized (less than 100 nm) zirconium metal particles that reacted with boron to form ZrB₂ with an average particle size of less than 100 nm at temperatures as low as 600 °C. Scanning electron microscopy of ZrB₂ compacts heated to 1450 °C and 1650 °C showed average particle sizes of 0.6 μm and 1.0 μm, respectively, suggesting that the fine particle size was maintained during densification. Ceramics with a relative density of 99% were produced by hot pressing at 2100 °C. Dense ZrB₂ produced by the reactive hot pressing process had mechanical properties that were comparable to ceramics produced by conventional processes. The four-point flexure strength of ZrB₂ produced in this study was 434 MPa.     

撞击流-沉淀法制取超细白炭黑中试研究

介绍了以工业级硫酸和工业级水玻璃为原料,利用撞击流反应-沉淀法制取超细白炭黑的中试试验。其反应过程在无旋立式循环撞击流反应器中进行。反应后物料经过陈化、过滤、洗涤,最后通过再浆进行喷雾干燥制得了超细白炭黑。用激光颗粒分析仪和比表面积-孔隙分析仪测定粒径及比表面积,结果表明:产品的平均粒径为2—3μm、比表面积高达822 m2/g,进一步证明了无旋立式循环撞击流反应器性能优越,操作稳定可靠,有利于制备超细粉体材料。     

反应结晶制备碳酸锂的粒度及形貌控制

碳酸锂的粒度及形貌决定其性能和应用。通过考察反应结晶温度、进料速率、晶种用量和搅拌速率对碳酸锂产品平均粒径的影响以及添加剂的用量对产品形貌的影响,提供了一种经过优化的制备碳酸锂的反应结晶工艺。通过正交实验确定了反应结晶制备碳酸锂的最佳实验条件：200 mL质量浓度为90 g/L的氯化锂溶液一次性加入反应结晶器内,质量浓度为260 g/L的碳酸钠溶液的加料速率为0.5 mL/min,晶种用量为2%（占碳酸锂理论产量的分数）,搅拌速率为400 r/min,反应温度为80 ℃,添加剂六偏磷酸钠用量为2%（占碳酸锂理论产量的分数）。在此条件下制得的碳酸锂为平均粒径为132 μm、变异系数为51.53%的密实球形产品。研究表明,反应温度对晶体粒度的影响最大,添加剂对晶体的粒度和形貌起到调控作用。     

Crystallization of synthetic hydrotalcite under hydrothermal conditions

The synthetic Mg–Al hydrotalcite with Mg/Al molar ratio of 2 was hydrothermally treated in autoclaves under autogenous water vapour pressure at 120–200 °C for 2–18 h. The obtained samples were characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and surface area measurements. A well-crystallized hydrotalcite-like phase was present in the coprecipitated product. No other crystalline phases were detected in the powder XRD patterns of both coprecipitated and hydrothermally treated samples. The integral intensity and full width in half maximum (FWHM) of the (003) and (006) hydrotalcite diffraction lines were evaluated in order to compare the crystallinity of samples hydrothermally treated under various conditions. The hydrothermal treatment increased the hydrotalcite content in the samples and improved significantly the hydrotalcite crystallinity. In general, the higher temperature and longer time of hydrothermal treatment, the higher hydrotalcite enrichment, as well as an increasing growth of crystallites, were observed. After the first 2–4 h, the time dependence was less evident, whereas temperature seemed to be a crucial parameter affecting the hydrothermal crystallization. The temperature of 120 °C was too low to increase significantly the sample crystallinity during several hours. According to XRD results, the marked crystallinity improvement was observed at 160 °C and higher temperatures. The hydrothermal treatment resulted in a marked decrease of surface area and a growth of hydrotalcite crystals. SEM micrographs of coprecipitated samples showed the aggregates composed of small thin crystals of ca. 0.1 μm in diameter, which were gradually transformed into thin plates with hexagonal morphology and particle size of several tenths of micrometers. Both a decrease of surface area and the crystallinity improvement of hydrothermally treated samples can be explained by the increase of hydrotalcite crystal size.     

Fabrication of BaTiO3 nanopowders with high tetragonality via two-step assisted rotary furnace calcination for MLCC applications

Ultrafine ceramic powders with high tetragonality are essential for next-generation multi-layer ceramic capacitors (MLCC). The solid-state reaction synthesis commonly used in industry is challenging to prepare ultra-fine BaTiO₃ powders due to issues of the coarse crystallization at high temperature calcinations. In this study, a two-step calcination combining with the rotary furnace was innovatively used to synthesize ultra-fine BaTiO₃ powders with uniform particle and high tetragonality. Through the reaction kinetics study, it was found that the rotary furnace increases the point contact area of Ba²⁺ and Ti⁴⁺ by improving the heat transfer efficiency of the solid-phase reaction and decreases the diffusion rate of both, so that the diffusion-nucleation-growth rate is greater than the decomposition rate of BaCO₃ to improve the tetragonality of BaTiO₃ powders. The optimal process parameters were determined and the reaction mechanism was studied. Particularly, the optimized two-step assisted rotary furnace calcination had succeeded in preparing finer powders with an average particle size of 250 nm and tetragonality (c/a) of 1.0096. The BaTiO₃ ultrafine powders sintered at 1200 °C has a ceramic density of 96%, dielectric constant of 9173 at the Curie temperature point (131 °C) and a grain activation energy of 0.821 eV, representing excellent dielectric properties and reliability.     

Preparation of Ca(OH)2 nanoparticles by impinging stream reaction precipitation method

In this paper, Ca(OH)₂ nanoparticles are prepared by impinging stream co-precipitation method. The process of preparing nanoparticles by impinging stream is optimized. The influence of process variable, such as dispersant type, dispersant dosage, circulating flow rate, reactant concentration ratio of OH⁻ and Ca²⁺, reaction temperature and circulation time, on the particle size of Ca(OH)₂ nanoparticle are investigated. The results show that the concentration ratio of reactants has a significant effect on the size of Ca(OH)₂ nanoparticles. The optimal process conditions are obtained by single factor experiment, PEG6000, 3.3% dispersant dosage, Q = 1000 L · h⁻¹, C = 1.88, T = 46.68°C and t = 60 min. The average particle size of Ca(OH)₂ nanoparticles prepared under these conditions is 107.67 nm. According to the microstructure analysis, the prepared Ca(OH)₂ nanoparticles samples have high purity and a good crystal structure. The powder dispersed with a marked hexagonal crystal shape and good thermal decomposition.     

粉末PET固相缩聚的研究

系统地研究了粉末聚酯(PET)固相缩聚,得到了有效的干燥结晶条件:140℃干燥120 min,180℃再结晶45 min,切片含水率低于30μg／g;研究了反应温度,粉末粒径和N2流量对PET固相缩聚的影响,分析粉末固相缩聚存在N2流量阈值的机理。结果表明:反应温度越高,颗粒越小,固相缩聚反应速度越快;粉末 PET预聚体在一定温度下固相缩聚,存在N2流量阈值。在此流量下,达到该温度下的该粒径粉末的最大界面扩散速率和固相缩聚的最大反应速度。相同反应温度下,粉末粒径越小,阈值N2流量越大。     

均匀沉淀法制备镁铝水滑石的中试研究

对镁铝水滑石的生产进行了中试研究,获取了中试生产的工艺条件。采用尿素水解均匀沉淀法,原料配比为n(硝酸镁)∶n(硝酸铝)=3∶1,n(尿素)∶n(硝酸根)=1.5∶1,m(物料)∶m(水)=1∶2,125℃下沉淀及晶化5 h,可制备镁铝水滑石,产品收率为71%。XRD和SEM结果表明无杂相生成,产品结晶度高,呈六边形,粒径<13.0μm,平均粒径约3.7μm,提供的工艺参数对于镁铝水滑石的工业生产具有一定的实用价值。     

石灰乳中和模拟酸性废水形成的二水硫酸钙的晶粒形貌与粒度分布

实验研究了各工艺参数及废水中Mg2+与Fe3+主要杂质离子对石灰乳中和模拟酸性废水形成的二水硫酸钙晶体形貌与大小的影响. 结果表明,反应温度是主要影响因素,当其从25℃提高至70℃时,硫酸钙晶体形貌从片状和针状向棒状转变;而搅拌转速、石灰乳浓度、石灰乳加入速度对结晶过程的影响较不明显. 废水中Mg2+和Fe3+离子对硫酸钙晶体生长有抑制作用,浓度越大,抑制作用越强,Mg2+浓度达1945 mg/L时晶体由片状转变为棒状. 石灰乳二段中和模拟工业酸性重金属废水,得到团聚的针状硫酸钙晶体,废水达标排放.     

Preparation of spherical nanoparticles of LaAlO3 via the reverse microemulsion process

Spherical LaAlO₃ nanoparticles in a reverse microemulsion consisting of solution (water phase), Tween-80 and Span-80 (surfactant), n-butanol (cosurfactant, and cyclohexane (oil phase) were prepared. Precursor powders and calcined powders were characterized by differential thermal analysis (DTA), thermogravimetry analysis (TG), X-ray diffraction (XRD) and transmission electron microscopy (TEM). A pure perovskite LaAlO₃ formed when the precursor hydroxides calcined at 800 °C for 2 h. The particle size was about 50 nm and the shape of the monodisperse particles is spherical. The reverse microemulsion process can dramatically lower the crystallization temperature of LaAlO₃ about 700 °C than the classical solid-state reaction method.     

Microreactor-assisted synthesis of α-alumina nanoparticles

In this paper, nanosized α-Al₂O₃ powders were synthesized with the aid of a high throughput impinging stream microreactor. It was demonstrated that the as-prepared powders exhibited better dispersity and more homogeneous distribution of particle size than that prepared by conventional parallel flow precipitation method due to the drastic collisions and homogeneous explosive nucleation in microchannel during the precipitation process. The effects of calcinating temperature and time on the morphology, phase composition and particle size of α-Al₂O₃ were systematically studied. Comparatively well dispersed and crystallized α-Al₂O₃ powders with higher sintering activity were obtained by calcinating the as-prepared precursors at 1200 °C for 2 h in air. The specific surface area of α-Al₂O₃ powders was above 20 m² g⁻¹ and average particle size was about 110 nm with higher sintering behavior. From room temperature to 1520 °C, the green compact exhibited shrinkage of 19.34%. This work opens a door for developing ultrafine α-Al₂O₃ powders with uniform size distribution, high crystallinity, and excellent thermal expansion property.     

镍铝水滑石的合成及其剥离表征

通过控制变量如镍铝摩尔比、镍铝与尿素的摩尔比、反应时间、反应温度,利用尿素法合成了一系列镍铝水滑石,旨在找到适合于剥片的水滑石;并且研究了剥离后水滑石的形态和光学特性。借助XRD和SEM分析发现,在n(Ni)∶n(Al)∶n(尿素)=3∶1∶9、反应温度为180℃、反应时间为24 h时,能得到规整度最好、粒径最大的水滑石样品。同时对在该反应条件下得到的样品进行振荡剥离,用AFM表征其剥离厚度为1.5~4.0 nm、粒径约为20 nm;同时,利用UV-Vis测定剥离胶体样品的光学特性,发现胶体质量浓度与吸光度之间符合线性规律。     

New hydroxyapatite–hydrotalcite composites I. synthesis

The synthesis and characterization of original materials, composed by hydrotalcite and hydroxyapatite, is discussed. All the syntheses were carried out in presence of microwave irradiation during the crystallization step. The interactions between the two compounds depend on the synthesis procedure. If hydroxyapatite is incorporated to hydrotalcite, the first compound is encapsulated by hydrotalcite. Instead, if hydroxyapatite is first prepared, the resulting solid is essentially a hydrotalcite with interlayered hydroxyapatite. When the composite material is synthesized by a simultaneous coprecipitation, the small clusters of hydroxyapatite and hydrotalcite are homogeneously dispersed. Consequently, the specific surface area and the particle size vary.     

Properties of toughened poly(butylene terephthalate) by blending with reactive ultra-fine full-vulcanized acrylonitrile butadiene rubber particles (UFNBRP)

The nano-sized ultra-fine full-vulcanized acrylonitrile butadiene rubber particles (UFNBRP) functionalized with carboxyl groups were used to toughen poly(butylene terephthalate) (PBT) through compatibilization of the two components via reactive extrusion in a twin-screw extruder. The impact strength of PBT was greatly improved with the nano-sized UFNBRP which may be attributed to its small particle size and the reactive compatibilization. Reactions between carboxyl groups on the surface of UFNBRP and hydroxyl end groups of PBT were proved with FT-IR spectra. In addition, UFNBRP also exhibited good nucleation effect and promoted the crystallization kinetics of PBT. Incorporation of small amounts of UFNBRP was found to be enough to improve the thermal stability. The maximum temperature of decomposition was increased by 25 °C at 1 wt% UFNBRP in comparison with that of pure PBT.     

流动结构对化学反应速率的影响

介绍了具有新型流场结构的"空化撞击流"的概念及其提出的背景;阐述了"空化撞击流"的三大特性;分析了空化撞击流技术对反应动力学的促进作用;用实验的方法研究了空化撞击流流场结构对化学反应动力学的影响规律。通过实验验证了关于空化撞击流流场对化学反应速率影响的推断。实验依次在普通喷嘴撞击流反应装置、空化自激脉冲喷嘴空化撞击流反应装置、低速搅拌反应装置和高速搅拌反应装置中进行。由实验结果可见,使用空化撞击流反应器时,反应速率常数分别比使用撞击流反应器、高速搅拌反应器和低速搅拌反应器高出13.42%、27.46%和33.82%,而且空化撞击流反应器的能耗更低。因此,利用空化撞击流技术确实可以有效提高化学反应速率。