有机膜精确调控传质的新型溶析结晶及过程强化

溶析结晶是一种环保、高效的结晶方法,在温敏性、低溶解度物系的晶体生产领域具有不可替代的重要作用。但是,传统溶析结晶过程中溶液过饱和度的时空均一性差,传质调控为微米级尺度,容易爆发成核,是亟待解决的关键问题。本文提出利用聚醚砜（PES）中空纤维膜,为溶析剂与结晶溶液之间的传质提供均匀稳定的界面,实现结晶溶液与溶析剂的精确混合和结晶过程强化,开发了一种新型的溶析结晶传质调控技术。溶析剂在压力差驱动下均匀渗透通过有机膜,在结晶溶液一侧的膜外表面形成溶析剂液膜层,通过表面液膜的不断更新,将传统溶析结晶的毫米级宏观混合转变为亚微米级尺度的微观混合,实现过饱和度的均匀分布。同时,这层液膜的存在,避免了结晶溶液直接接触膜表面,有效地解决了异相成核附着导致膜污染的问题。实验中,对壳程流速做出周期性改变后,渗透通量可即时发生一致的线性响应变化,证实有机膜调控传质过程的精确性和灵敏性。PES膜重复使用多次后,渗透通量仍可以保持稳定。相比传统的滴加式溶析结晶,在相同的溶析剂传质速率下,有机膜调控过程制备的晶体产品,形貌更加规整、粒径分布更集中。因此,在溶析剂精确传质和抗污染方面,有机膜调控的溶析结晶过程均表现出良好的性能,为药物、大分子结晶的高效工业化制备开拓了新的思路。     

A stochastic formulation for the description of the crystal size distribution in antisolvent crystallization processes

A stochastic approach to describe the crystal size distribution dynamics in antisolvent based crystal growth processes is here introduced. Fluctuations in the process dynamics are taken into account by embedding a deterministic model into a Fokker‐Planck equation, which describes the evolution in time of the particle size distribution. The deterministic model used in this application is based on the logistic model, which shows to be adequate to suit the dynamics characteristic of the growth process. Validations against experimental data are presented for the NaCl–water–ethanol antisolvent crystallization system in a bench‐scale fed‐batch crystallization unit. © 2009 American Institute of Chemical Engineers AIChE J, 2010     

A novel hollow fiber membrane-assisted antisolvent crystallization for enhanced mass transfer process control

Herein, a novel hollow fiber membrane-assisted antisolvent crystallization (MAAC) was proposed to enhance the mass transfer control over the antisolvent crystallization. A polyethersulfone membrane module was introduced as the key device for antisolvent transfer and solution mixing. An antisolvent liquid film layer was formed on the membrane surface and mixed with the solution. The liquid film also prevented the membrane from directly contacting with crystallization solution. By controlling both the shell side flow velocity and the antisolvent transfer, the antisolvent permeation rate achieved sensitive, stable, and accurate control during long-term and repeated utilization. The interfacial mass transfer rate of MAAC was 0.66 mg cm⁻² s⁻¹, which was only 1/50 that of conventional droplet antisolvent crystallization. MAAC also provided crystal products with better morphologies and narrower size distributions than the conventional process. The stable performances of MAAC in terms of its accurate antisolvent mass transfer and antifouling capabilities were also highlighted. © 2018 American Institute of Chemical Engineers AIChE J, 65: 734–744, 2019     

反应与溶析结晶过程强化及数值模拟研究进展

反应与溶析结晶技术被广泛地用于无机与有机化学品的生产，如催化剂和药物活性组分。反应与溶析结晶过程通常是在高过饱和度条件下进行，具有快速的成核与生长速率，因此需要在结晶过程开始前实现不同反应物或溶析剂与溶液之间快速充分的混合，以避免不良混合造成过饱和度的空间不均匀分布，破坏晶体产品的性质。模型和数值模拟方法的分析和预测能力可以加深对过程现象的机理认识，促进结晶设备和操作条件的优化设计。本文综述了反应与溶析结晶的过程强化方法和数值模拟的研究进展。首先从结晶设备、外加能量场和膜技术辅助结晶三个方面对过程强化研究进行了阐述；然后介绍了数值模拟中常用的微观混合模型，包括涡流卷吸模型和基于联合组成概率密度函数的微观混合模型；最后对文献中的液液反应结晶、气液反应结晶和溶析结晶的数值模拟进行了总结与分析。针对已有研究的不足，提出了未来发展方向的一些展望。     

Antisolvent crystallization and solid‐state polymerization of bisphenol‐A polycarbonate

Bisphenol‐A polycarbonate (BAPC) was synthesized by solid‐state polymerization (SSP) using a semicrystalline prepolymer crystallized by antisolvent method. The antisolvent crystallization was investigated as a function of antisolvent types using X‐ray diffraction (XRD), different scanning calorimetry (DSC), and scanning electron microscopes (SEM). The results showed antisolvent types had a significant effect on the crystallization of BAPC. Prepolymer induced by acetone as an antisolvent gained a higher crystallinity of 37.0%, more uniform particle size, and mature crystal structure compared with the samples crystallized by methanol and ethanol. Then crystallization of BAPC by acetone was carried out at crystallization temperature in the range of 40–80 °C for 1–5 h. A high crystallinity of 42.0% was acquired with the crystallization conducted at 70 °C for 2 h. Prepolymer with appropriate crystallinity of 37.8% resulted in high‐molecular‐weight polymer of 57,411 via SSP due to the effect of crystallinity and plasticization of residual solvent. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43636.     

Evaluation of Ultrasonic Treatment for the Size Reduction of HNS and HMX in Comparison to Solvent‐Antisolvent Crystallization

The paper presents and compares two methods for the synthesis of fine particles of the high explosives HNS and HMX by ultrasonic treatment and solvent/antisolvent crystallization. The effect of ultrasonic treatment on the particle size of explosives was studied by varying the amplitude and frequency of ultrasonication for different time periods using an ultrasonic probe and an ultrasonic bath. Solvent/antisolvent recrystallization was performed by varying the process parameters including stirring rate, antisolvent temperature etc. In addition to FT‐IR spectroscopy and thermal analysis by TGA/DSC; the particle size and shape of fine powders of the explosives HMX and HNS were determined using particle size analysis and scanning electron microscopy (SEM). Ultrasonic treatment of the probes resulted in the finer grains of HMX compared to solvent‐antisolvent crystallization. However in the case of HNS, solvent‐antisolvent crystallization produced finer particles compared to ultrasonication.     

Liquid Antisolvent Recrystallization of Phenylbutazone and the Effect of Process Parameters

Phenylbutazone was crystallized from solutions by the liquid antisolvent recrystallization technique. Acetone was used as a solvent, and distilled water was selected as an antisolvent. The influence of processing parameters, such as drug concentration, temperature, injection rate of drug solution, and mixing method of drug solution with antisolvent, on the particle size distribution were investigated. Furthermore, to examine the variation of resulting particle size in the presence of the ultrasound, the ultrasonic wave was applied to all experiments. Larger crystals were obtained when crystallization took place at higher temperatures. The enhancement of drug concentration favored decreased particle size. Regarding the mixing method of the drug solution and antisolvent, smaller particles were produced when the drug solution was injected into antisolvent, and larger crystals were obtained when the antisolvent was injected into drug solutions. As the injection rate of the drug solution increased, the average particle size decreased. The processed particles consistently exhibited an acicular crystal habit. The presence of ultrasound caused a reduction of particle size under all operational conditions.     

Influence of Solvents on Solution‐Mediated Polymorphic Transformation of the Polymorphs of L‐Histidine

Solution‐mediated polymorphic transformation (SMPT) of the metastable polymorph B of L‐histidine (L‐his) into the stable polymorph A in water‐antisolvent solutions was performed. Methanol, acetone, and acetonitrile served as antisolvents. The SMPT was studied via nucleated batch antisolvent crystallization process by determining the change of the fraction of the stable polymorph A of L‐his in the crystal phase with time during the crystallization process. The fraction of the stable polymorph A of L‐his was assessed offline by Raman spectroscopy. The transformation time depended on the fractions of form A obtained at the initial stage of crystallization. The transformation rate of the metastable polymorph B into the stable polymorph A at lower antisolvent volume fraction was faster than at higher antisolvent volume fraction. The transformation time of polymorph B into polymorph A in water‐acetonitrile solution was the shortest compared to the other solutions.     

Modeling and Growth Kinetics of Antisolvent Crystallization Applied to the Pharmaceutical Industry

With the aim of simulating the product crystal size, which is one of the important physical properties for active pharmaceutical ingredients, an antisolvent crystallization model is proposed, including only six experimentally determined kinetic parameters to develop a concise model. As a first step, the methodology to assess the growth rate parameters, which are some of the six kinetic parameters, is discussed. An approach for appropriately treating the size distribution data obtained by means of the laser diffraction/scattering method is suggested. The determined growth rate parameters could be used to simulate the crystal size indicating that the simulation by crystallization modeling is a practical application for the pharmaceutical industry.     

Relative Supersaturation Ratio and Separation Factor in Crystallization with High Pressure C02

Crystallization in the presence of high pressure gas as antisolvent could be applied for the recovery of valuable compounds from liquid solution. A study of separation behavior is presented here for a mixture of anthracene (AN) and anthraquinone (AQ) in cyclohexanone (CX) expanded with a gaseous antisolvent, CO₂. The pressure range was 0.1 to 12 MPa; the temperature was either 292 or 313K. Separation factors were obtained from the measured salted-out yields and the supersaturation of each solute could be also obtained for this pressure-tuning crystallization. The separation factor varies almost linearly with relative supersaturation ratio in the crystallization of anthracene-anthraquinone from cyclohexanone and CO₂.     

超临界流体结晶技术研究进展

综述了超临界流体结晶技术的理论和应用进展，重点介绍了三种超临界流体结晶技术：超临界溶液快速膨胀结晶法，超临界流体抗溶剂结晶法和超临界流体梯度结晶分离法，并指出了它们的研究方向。     

Prediction model,experimental optimization,and verification for yield of high-pressure crystallization: a case study of citric acid

ABSTRACT

Yield is one of the most important quality indexes for the crystal produced by high-pressure crystallization such as supercritical antisolvent (SAS) crystallization. In this study, a prediction model of yield of the SAS crystallization was proposed in the first place. Then, an experiment that prepares the citric acid particle crystallization was conducted through SAS batch device. With the help of a uniform design method, the maximum yield (0.86) was obtained under the combination of process parameters (the initial concentration of solution 0.35 g/mL, the operating temperature of 33°C, the operating pressure of 12.5 MPa, and the holding time of 3.5 h), the regression equation between yield of crystallization and four factors was obtained, and the effects of each factor on the yield are as follows: initial solution concentration > operating pressure > operating temperature > holding time. Finally, the prediction model was verified by an experiment, and the results show that the average relative error between the values calculated by prediction model and the experimental ones is 9.77%.     

Antisolvent crystallization of carbamazepine from organic solutions

Carbamazepine was crystallized from organic solutions using an antisolvent crystallization technique. Ethanol was used as a solvent for the carbamazepine and distilled water was used as an antisolvent. The carbamazepine was dissolved in the solvent, and the drug solution was injected into the antisolvent causing the particle precipitation. During the crystallization experiments, the effects of the process parameters such as solution concentration, temperature, injection rate of the solution, and the presence of ultrasound, were investigated. An analysis of the produced particles showed that external characteristics such as particle size and its distribution were a strong function of the process parameters, while the internal structures such as crystallinity and thermal stability were nearly unaffected. Smaller particles were obtained when solutions with high drug concentrations were used. Higher temperature resulted in larger crystals. Particle size was also influenced by the injection rate of the drug solutions. Carbamazepine particle size was significantly reduced when the ultrasonic wave was selectively applied.     

Integrated solvent and process design for continuous crystallization and solvent recycling using PC‐SAFT

Solvent usage is a major source of environmental waste in pharmaceutical industry. The current paradigm shift toward continuous manufacturing in pharmaceutical industry has renewed the interest in continuous crystallization, which offers the prospect of easy solvent recycling. However, the selection of solvents for an integrated crystallization processes is nontrivial due to the likely trade‐off between optimal solvent properties for crystallization and solvent separation and recycling. A systematic approach for the simultaneous optimization of process conditions and solvent selection for continuous crystallization including solvent recycling is presented. A unified perturbed‐chain statistical associating fluid theory model framework is applied to predict thermodynamic properties related to solubility and vapor‐liquid equilibrium, which is integrated with a process model. A continuous mapping procedure is adopted to solve the optimization problem effectively. A case study based on continuous antisolvent crystallization of paracetamol with solvent separation via flash demonstrates the approach. © 2017 American Institute of Chemical Engineers AIChE J, 64: 1205–1216, 2018     

Antisolvent Crystallization of Sulfa Drugs and the Effect of Process Parameters

Abstract

Three sulfa drugs (sulfathiazole, sulfamethizole, and sulfabenzamide) were crystallized using carbon dioxide and water as antisolvents, and the effects of the type of solvent, the crystallization temperature, and the antisolvent injection rate were investigated. Sulfathiazole crystallized in granulate form from acetone, but it was crystallized in acicular form from methanol. Sulfamethizole was crystallized in tabulate form from acetone and as plates from DMF. Sulfabenzamide was precipitated in the form of prisms from acetone and of aciculates from ethyl acetate. As the crystallization temperature increased from 30 to 50°C, the average particle size increased from 6.5 to 10.5 µm for sulfathiazole, 29.5 to 53.1 µm for sulfamethizole, and 33.0 to 59.8 µm for sulfabenzamide. The crystal habit tended to become more needle‐like as the antisolvent injection rate increased. Larger particles were produced when the antisolvent was changed from carbon dioxide to water.     

Experiments and Correlations of the Solubility of γ-DL-Methionine in Binary Solvent Mixtures

Antisolvents increase the supersaturation in the crystallization process which can enhance the product yield. The effect of an antisolvent on the solubility of γ-DL-methionine (γ-DL-met) in aqueous solution was investigated. The solubility of γ-DL-met was measured with various binary solvent mixtures. It improved with higher temperature but decreased with increasing the antisolvent mass fraction. Acetone showed the highest efficiency to reduce the solubility. The solubilities were correlated with the van't Hoff-Jouyban-Acree model and the modified Apelblat-Jouyban-Acree model. Both models fitted to the experimental results with high accuracy. Enthalpy, entropy, and Gibbs free energy of dissolution were determined by van't Hoff analysis. The thermodynamic properties indicated that the dissolution process is endothermic and entropy-driven.     

Separation and purification of two isomorphic steroids by a novel extractive drowning out crystallization

A novel extraction drowning out crystallization technology was brought forward for separation and purification of two isomorphic steroid pharmaceutical intermediates. In this process, extraction and crystallization are conducted in the same crystallizer simultaneously. The two immiscible (partial miscible) liquid phases were achieved by adding water into the toluene–DMF system. The role played by water is both as an antisolvent for a crystallization and a trigger to generate two immiscible phases for extraction. The advantage of this method is that two relative pure product can be achieved in a crystallization process. The experimental result shows a good prospect of this method for industrial separation of the studied two isomorphic steroids.     

硝酸钙-磷酸-水-异丙醇体系中溶析结晶工艺研究

酸解液中氮磷的高效分离是发展硝酸法湿法磷酸的关键技术之一。提出采用溶析结晶使酸解液中磷以磷酸钙盐形式析出从而达到氮磷分离的研究思路。以异丙醇为溶析剂,通过单因素实验考察了溶析剂加入比（异丙醇与模拟酸解液质量比）、温度、五氧化二磷质量分数、溶析时间对析出晶体物相结构以及磷析出率的影响。结果表明,溶析时间不会影响析出晶体物相结构,增大溶析剂加入比、升高温度、降低五氧化二磷质量分数都会使得析出的晶体由磷酸二氢钙转变成磷酸氢钙。通过对比磷析出率得出适宜的工艺条件：溶析剂加入比为3∶1、温度为5.0 ℃、五氧化二磷质量分数为30%、溶析时间为1.0 h,在此条件下磷析出率可达73.58%。