Separation of conglomerate forming enantiomers using a novel continuous preferential crystallization process

Providing enantiomerically pure products is of key importance in the fine chemicals, food, and pharmaceutical industries. A continuous preferential crystallization process is presented that allows the separation of conglomerate forming enantiomers in a stable, robust, and flexible way. This is achieved by coupling two continuous crystallizers by exchanging their clear liquid phases. Each crystallizer is connected to a suspension mill responsible for in situ seed generation through particle breakage. The dynamic and steady‐state behavior of this process is extensively analyzed for racemic feed streams through process simulations, and parameter regions, which yield pure enantiomers in both crystallizers, are identified. For enriched feed streams, it is further shown when this novel flow sheet is capable of outperforming an ideal batch process in terms of solvent consumption per unit mass of desired enantiopure product produced. © 2015 American Institute of Chemical Engineers AIChE J, 61: 2810–2823, 2015     

Diastereomeric salt crystallization of chiral molecules via sequential coupled-Batch operation

A novel process, sequential coupled-batch diastereomeric crystallization is presented for the resolution of racemic mixtures. This strategy utilized a preferential crystallization of diastereomeric salt followed by sequential coupled diastereomeric salt resolution of racemic ibuprofen with the resolving agent (S)-lysine utilizing a novel small scale pneumatic liquid exchange design to couple two batch crystallizers. Results were compared to conventional sequential resolution via seeded isothermal batch crystallization. Diastereomeric salt resolution was developed using the ternary phase diagram of the isolated (R)-ibuprofen-(S)-lysine and (S)-ibuprofen-(S)-lysine salts and optimized empirically with the aid of process analytical technology. Sequential coupled-batch crystallization was found to be capable of increasing the yield of both salts while maintaining purity. This gave an increase in both the productivity and yield (20.5% for (S)-ibuprofen-(S)-lysine) compared to the equivalent sequential batch (17.7% for (S)-ibuprofen-(S)-lysine) crystallization methodology. Single crystals of the (S)-ibuprofen-(S)-lysine were isolated, and its single crystal structure determined. © 2018 American Institute of Chemical Engineers AIChE J, 65: 604–616, 2019     

FINES DESTRUCTION DURING BATCH CRYSTALLIZATION

An analysis of the use of fines destruction during batch crystallization based on the population (number) balance is presented. The effects of operating policy and fines crystal cut size and destruction rate are examined in detail for two cases viz. natural and controlled cooling respectively. It is predicted that use of fines destruction has the potential as a control aid to significantly improve the product crystal size distribution from batch crystallizers and is supported by experimental data on the programmed cooling crystallization of potassium sulphate solutions.     

Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers

The challenges of insufficient residence time for crystal growing and transfer line blockage in conventional continuous mixed‐suspension mixed‐product removal (MSMPR) operations are still not well addressed. Periodic flow crystallization is a novel method whereby controlled periodic disruptions are applied to the inlet and outlet flows of an MSMPR crystallizer to increase its residence time. A dynamic model of residence time distribution in an MSMPR crystallizer was first developed to demonstrate the periodic flow operation. Besides, process models of periodic flow crystallizations were developed with an aim to provide a better understanding and improve the performance of the periodic flow operation, wherein the crystallization mechanisms and kinetics of the glycine‐water system were estimated from batch cooling crystallization experiments. Experiments of periodic flow crystallizations were also conducted in single‐/three‐stage MSMPR crystallizers to validate the process models and demonstrate the advantages of using periodic flow operation in MSMPR stages. © 2016 American Institute of Chemical Engineers AIChE J, 63: 1313–1327, 2017     

草甘膦连续结晶技术的开发与应用

测定了实际料液中草甘膦的溶解度和过饱和度特性,并根据此特性设计建立了由2个Krystal结晶器串联组成的年产10000t草甘膦连续结晶系统.运行结果表明:系统设计合理,达到了设计目标;连续结晶工艺相对间歇结晶工艺具有占地面积小、自动化程度高、操作简单、操作人员少、产品粒度均匀、节能降耗达50%以上等优点;系统可连续稳定运行60 d以上.     

Antisolvent crystallization in porous hollow fiber devices

This paper examines antisolvent crystallization under a new perspective and in the unique environment offered by porous hollow fiber membrane devices. The latter are compact, extremely efficient on a volumetric basis, easy to scale up and control. Their inherent characteristics promote the creation of homogeneous concentration conditions on a scale considerably smaller than existing industrial crystallizers without the necessity of a large energy input, properties that are desirable but rarely achieved in industrial crystallizers.Mixing studies were performed to examine the maximum achievable supersaturation in porous hollow fiber devices. It was shown that they are able to offer the supersaturation levels necessary to perform antisolvent crystallization. Moreover, supersaturation is created uniformly due to the large number of feed introduction points, the membrane pores. In addition, radial mixing is substantial in contrast with traditional tubular devices and the characteristic time involved in this process is comparable to the device residence time.Porous hollow fiber antisolvent crystallization of aqueous L-asparagine monohydrate systems proved successful. Mean crystal sizes up to two times smaller compared to batch stirred crystallizers were obtained in standalone membrane hollow fiber crystallizers (MHFC) and their combinations with completely stirred tanks. The CSD was confined below for the former and for the latter, levels that are sufficient for most pharmaceutical crystalline products, for which bioavailability and formulation concerns dictate the desired CSD. In addition, porous hollow fiber devices achieved comparable or slightly higher nucleation rates with respect to batch stirred crystallizers and similar values compared to tubular precipitators. Considerable improvements can be obtained by carefully designing membrane hollow fiber crystallizers.     

Programmed cooling of batch crystallizers

An analysis of the programmed cooling of batch crystallizers, starting with the solution of the momentum equations of the population balance, is presented. Based on a general solution, conditions are discussed leading to limiting equations which had been published earlier. The model described in this paper determines the optimum cooling curve for a batch crystallizer with an arbitrary seeding and nucleation ratio, hence a more detailed analysis of the physical conditions of the process and a better comparison of the theory with experiment are possible. Kinetic data of crystallization can also be obtained from batch experiments.     

Thermal analysis of failed-batch palm oil by differential scanning calorimetry

Thermal behavior of palm oil samples drawn from the batch crystallizers that failed during crystallization and of a control oil that was drawn from a batch that produced good crystallization were analyzed by differential scanning calorimetry under constant heating and cooling conditions. Four polymorphs—β’₂, α, β’₁, and β₁—were observed, and their temperatures were tabulated. A rapid and sudden surge of heat demand was observed for samples from failed crystallizers. Less supercooling values were obtained from the control oil compared to the higher values for samples from failed crystallizers. In crystallization thermograms, a sharp high-temperature exotherm (high-T peak) and a broad low-temperature exotherm (low-T peak) were observed. Low-T peaks were found almost invariably stationary at −5.1 to −5.6°C, and high-T peaks varied depending on the saturation level of the oil. A new peak, sandwiched between the high-T and low-T peaks, was observed for the control oil.     

Crystallization and Precipitation: The Optimal Supersaturation

In this article optimal supersaturation for cooling and evaporation crystallization are presented. This information is based on a simplified model which describes the metastable zone width of activated nucleation. The model assumes that the nucleation step is very fast and the occurrence of the shower of nuclei which is used to define the metastable zone width is caused by the growth of activated nuclei. In future new sensors for the measurement of supersaturation will help to operate batch crystallizers at the optimal supersaturation during the entire batch time.     

ANALYSIS OF BATCH CRYSTALLIZATION PROCESSES

The analysis of batch crystallization processes normally requires the consideration of the time-dependent, batch conservation equations (e.g., population, mass, and energy balances), together with appropriate nucleation and growth kinetic equations. The solution of these integro-differential equations is relatively difficult, even by numerical techniques. This review outlines the advances that have been made in the experimental techniques and data analyses which can be used to study the crystallization kinetics and the crystal size distribution (CSD) in batch suspension crystallizers. Several simple and useful methods are discussed which include characterization of CSD maximum, cumulative CSD approach, SSBCR crystallizer, thermal response technique, maximum allowable growth rate, and desupersaturation curve technique.     

ANALYSIS OF BATCH CRYSTALLIZATION PROCESSES

The analysis of batch crystallization processes normally requires the consideration of the time-dependent, batch conservation equations (e.g., population, mass, and energy balances), together with appropriate nucleation and growth kinetic equations. The solution of these integro-differential equations is relatively difficult, even by numerical techniques. This review outlines the advances that have been made in the experimental techniques and data analyses which can be used to study the crystallization kinetics and the crystal size distribution (CSD) in batch suspension crystallizers. Several simple and useful methods are discussed which include characterization of CSD maximum, cumulative CSD approach, SSBCR crystallizer, thermal response technique, maximum allowable growth rate, and desupersaturation curve technique.     

crystSim: A software environment for modelling industrial batch cooling crystallization

Crystallization modelling is limited by the availability of methods to reliably predict mixing, temperature and concentration distributions, supersaturation, nucleation and growth kinetics for crystallization systems of industrial size. A new software environment for modelling batch cooling crystallization has been developed integrating crystallization and fluid dynamics. The mathematical model can reliably predict mixing in stirred vessels of a given geometry and its effect on the crystallization kinetics and crystal product properties thus reducing the cost and time required for the design and scale-up of industrial crystallizers. The paper describes the development and application of crystSim for modelling industrial crystallization in stirred tanks. The software is developed in Visual C# making full use of Object Oriented Programming (OOP) and multithreading.     

Tools for Design and Control of Industrial Crystallizers – State of Art and Future Needs

The design and control of industrial crystallizers continues to be a tremendous challenge. The tendency to move away from base‐chemicals towards fine‐chemicals will give a new impulse to the utilisation of crystallization technology for the separation and the formulation of particulate products. This paper reviews the most recent developments in the design industrial crystallizers and the development of novel crystallization processes. Furthermore it discusses emerging modeling tools needed for a flexible design and operation of crystallizers and crystallization processes that meet rapid changing product yield and specifications. Finally a new approach towards model‐based predictive control of crystallization processes is presented.     

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     

翅片式结晶器在硝基氯苯生产中的应用

介绍了硝基氯苯常用结晶器的结构形式,详细分析了翅片式结晶器的结构特征。通过分析开车数据,对翅片式结晶器与卧式结晶器的结晶效率、结晶电耗进行比较。运行表明,采用翅片式结晶器,结晶周期缩短32％;相同装料体积的结晶器,装机容量减少59．5％;结晶效率提高134．0％;吨产品结晶电耗下降83．5％,效果显著。     

Kristallisation aus Schmelzen

Crystallization from melts . Equipment for crystallization from melts differs considerably from the solution crystallizer. The article discusses: Trough crystallizers, belt crystallizers, pastillators, flakers, screw crystallizers, and prilling towers. The kinetics of melt crystallization is simpler than that from solution, and the secondary nucleation becomes less important. Environmentally, crystallization from melts is more attractive because absence of solvent obviates waste products. Dust problems are avoidable by flaking, pastillizing, and prilling.     

维生素C结晶物系相图的测定

采用差式扫描量热仪测得维生素Ｃ结晶物系的ＤＳＣ谱图,根据谱图数据提出了维生素Ｃ－水－乙醇物系的固液相图,并结合定量分析,计算其结晶热,对结晶工艺条件的确定以及结晶器的设计具有指导意义。     

Preferential crystallization: Multi‐objective optimization framework

A four objective optimization framework for preferential crystallization of D‐L threonine solution is presented. The objectives are maximization of average crystal size and productivity, and minimization of batch time and the coefficient of variation at the desired purity while respecting design and operating constraints. The cooling rate, enantiomeric excess of the preferred enantiomer, and the mass of seeds are used as the decision variables. The optimization problem is solved by using adaptation of the nondominated sorting genetic algorithm. The results obtained clearly distinguish different regimes of interest during preferential crystallization. The multi‐objective analysis presented in this study is generic and gives a simplified picture in terms of three zones of operations obtained because of relative importance of nucleation and growth. Such analysis is of great importance in providing better insight for design and decision making, and improving the performance of the preferential crystallization that is considered as a promising future alternative to chromatographic separation of enantiomers. © 2009 American Institute of Chemical Engineers AIChE J, 2009