Continuous Crystallization System Research Articles

Multi‐objective optimization of cane sugar continuous crystallization system design based on computational fluid dynamics

This work focused on improving circulation and mixing of the massecuite and reducing the energy loss in the cane sugar continuous crystallization system. The developed Computational Fluid Dynamics (CFD) model is based on the continuous crystallization system of a sugarcane mill in Guangxi, China and verified with the actual operation data. The calculated entropy production and pressure drop of the system are used as indices for assessing the performance of the system. Next, 350 CFD simulations are conducted in the parametric experiment platform with 9 parameters and produces a collection of data. Then based on the CFD data set, the data-driven model is employed for regression of the relations between key parameters and indices. The implemented data-driven model is used for Non-dominated Sorting Genetic Algorithm (NSGA-II) to obtain the optimal result of Pareto frontier. CFD simulation with the optimized parameters reduces entropy by 9.76% and reduces pressure drop by 11.52%. Novelty impact statement Multi-objective optimization of cane sugar continuous crystallization system is performed. The entropy is reduced by 9.76% and the pressure drop is reduced up to 11.52%. The proposed method show the good applicability.

Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine

Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and the understanding of the impact on product quality is currently evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical properties of drug substance and is considered a critical process step in achieving the continuous manufacturing of drug substances. Although many publications previously focused on various innovative techniques to continuously make crystals with desired properties, engineering difficulties such as system design, automation, and integration with process analytical technology (PAT) tools have not been thoroughly discussed. Here, we focus on how to develop a continuous crystallization system, from the perspective of process engineering, and the related risk considerations on product quality. Specifically, we designed and built an automated two-stage mixed suspension mixed product removal (MSMPR) crystallization platform for a model compound (carbamazepine, CBZ) that exhibits multiple polymorphs. The crystallization process includes the integration of PAT tools (online Raman microscopy and focused beam reflectance microscopy, FBRM) for real-time monitoring. A series of case studies were done to evaluate the performance of the continuous system and PAT tools. Specifically, the drawing schemes, slurry transport, and variations on process variables are considered as the three key risk areas for continuous crystallization process development. Our proof-of-concept continuous crystallization system uses feedback/feedforward controls to achieve constant levels in crystallizers, a centralized automation program coded in LabVIEW, and PAT monitoring for polymorphs and particle size distribution (Raman and FBRM). To the best of our knowledge, this is also the first study on continuous crystallization of carbamazepine for form III and its polymorphic transition (between form II and form III).

Continuous Crystallization of Proteins in a Stirred Classified Product Removal Tank with a Tubular Reactor in Bypass

A lab-scale stirred tank with a cooled tubular reactor in bypass was applied for continuous crystallization of lysozyme and a full-length therapeutic monoclonal antibody. The stirred tank was operated as a mixed suspension classified product removal crystallizer. Lysozyme was crystallized by a combination of cooling crystallization and salting-out. The antibody was crystallized by a combination of cooling crystallization and isoelectric crystallization. It was deduced that nucleation rates were enhanced when the protein solutions passed through the cooled tubular bypass. It was further deduced that crystal growth rates were enhanced in the stirred tank which was operated at a higher temperature compared to the tubular reactor. Classified product removal was possible by controlled sedimentation of protein crystals. The continuous crystallization system allowed a targeted control of crystal morphology and size. No sedimentation occurred in the tubular reactor and precipitation was avoided at all times. High...

Continuous crystallization of carbamazepine

As continuous manufacturing makes inroads in drug production, the process of continuous crystallization—in which active pharmaceutical ingredients are purified via solidification from a liquid phase—has proven to be a major roadblock. Looking to understand the risks involved with such systems and how they might be mitigated, scientists led by Celia N. Cruz at the U.S. Food & Drug Administration’s Office of Pharmaceutical Quality designed and built a lab-scale continuous crystallization platform for the anticonvulsant compound carbamazepine (Org. Process Res. Dev. 2017, DOI: 10.1021/acs.oprd.7b00130). Carbamazepine has four crystalline polymorphs, making it a good model compound for troubleshooting. The continuous crystallization system uses an automated, two-stage mixed-suspension and mixed-product removal platform and integrates two process analytical technology tools, Raman microscopy and focused-beam reflectance microscopy, to monitor the crystallization process in real time. The researchers were able ...

Custom-Built Miniature Continuous Crystallization System with Pressure-Driven Suspension Transfer

At the bench scale, the transfer of solid–liquid streams between reaction vessels or crystallizers that operate continuously poses a significant problem. Reduced equipment size of pumps and valves (i.e., approaching that on the microfluidic scale) means even further reduced orifices in which suspensions must attempt to flow. It forces bridging of solids and leads to blockages in flow. This study presents a new pressure-driven flow crystallizer (PDFC) with a custom-built suspension transfer pumping system. In the system, a dip tube is used to carry suspension between crystallizers by controlling the pressure differences of the crystallizers. This novel system has a small footprint on the scale of similar benchtop flow synthesis systems and has been demonstrated to operate continuously with intermittent withdrawal for at least 24 h. The system accommodates both cooling and antisolvent crystallization. It is compatible with a variety of solvents, can handle crystals with large and small aspect ratios, and ca...

Crystallization of Cyclosporine in a Multistage Continuous MSMPR Crystallizer

Crystallization processes can be batch or continuous. Potential advantages such as operating at steady state, small equipment size (relative to batch), and ability to recycle are encouraging the pharmaceutical industry to investigate continuous processes. In this work, a continuous cooling crystallization process for the immunosuppressant drug cyclosporine was developed. A multistage mixed suspension mixed product removal (MSMPR) crystallizer was employed which allowed simple analysis of kinetic parameters employing the population balance. Experimentally, the continuous crystallization system was able to operate without any clogging issues for more than four residence times. The experimental yield and purity of the crystals was determined as 71% and 96%, respectively (without recycle) and 87% and 94%, respectively (with recycle). In a batch cooling crystallization experiment, carried out under conditions similar to those of the continuous experiment without recycle, the experimental yield and purity of th...

Effect of ultrasonic irradiation on crystallization kinetics of potassium dihydrogen phosphate

The ultrasound effect applied on potassium dihydrogen phosphate was investigated in a continuous crystallization system. The studied process variables were ultrasonic power (W) and residence time. The crystal size distributions of the final products obtained with and without ultrasonic power were determined and the data were evaluated by using modified form of Abegg, Stevens and Larson (ASL) model. The supersaturation limit decreased with ultrasonic waves and the crystal morphology was modified. The average crystal size decreased in the presence of ultrasonic power. An abrasive effect was observed at a high ultrasonic power input.

Fisher Information on the Performance of Dynamic Systems

Recent attempts to develop sustainability theory propose the use of Fisher information as a sustainability index. The approach has been shown to be suitable for the analysis of ecological models, including dynamic simulations as well as optimal control problems where the objective function involves maximizing or minimizing Fisher information. Nevertheless, Fisher information can also be interpreted as a measure of the degree of variability of a dynamic system. The goal of this work is two-fold. First, we study the scope of using the concept of Fisher information as a sustainability index in dynamic systems different in nature from ecological systems. Then we study the behavior of Fisher information in terms of the variability and performance of the dynamic system rather than using it as a sustainability index. The results of three case studies are presented, including two chemical engineering applications (a continuous crystallization system and a series of three continuous stirred tank reactors) and a dynamic model of immunotherapy (therapeutic optimization). We perform parametric analyses, evaluating the behavior of the value of Fisher information against significant model parameters. In general, although its usefulness as a sustainability index might be difficult to interpret and elucidate in some cases, Fisher information not only can indeed be related to the degree of variability of any dynamic system, but also provides useful insights with potential application in process control.

A laboratory continuous crystallization system for aluminium hydroxide precipitation studies

A mechanically agitated laboratory continuous crystallization system of capacity 1 litre has been developed with special application to the precipitation of aluminium hydroxide. It consists of continuous liquor and seed feeding arrangements and semi-continuous product evacuation as recommended by Randolph and Larson [Theory of Particulate Processes, 2nd ed. (Academic Press, London, 1988)] [1]. A study of the particle dynamics and the solid and liquid residence time distributions has shown that the set-up represents a normal continuous mixed suspension mixed product removal (CMSMPR) system. It was found that the liquor concentration achieved steady state after 2 to 3 residence times and the slurry density, after 4 residence times; however, it was difficult to attain an absolute steady state for the solid CSD.