Encrustation in Continuous Pharmaceutical Crystallization Processes—A Review

Acevedo, David; Yang, Xiaochuan; Liu, Yiqing C.; O’Connor, Thomas; Koswara, Andy; Nagy, Zoltán K.; Madurawe, Rapti D.; Cruz, Celia N.

doi:10.1021/acs.oprd.9b00072

Cited by 35 publications

(34 citation statements)

References 54 publications

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“…In order to utilize these advantages, however, the steady state must first be reached and then maintained [3]. Here, encrustation and blockage of the continuous crystallizers still remain a major challenge [5].…”

Section: Introductionmentioning

confidence: 99%

Flow Map for Hydrodynamics and Suspension Behavior in a Continuous Archimedes Tube Crystallizer

et al. 2021

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The Archimedes Tube Crystallizer (ATC) is a small-scale coiled tubular crystallizer operated with air-segmented flow. As individual liquid segments are moved through the apparatus by rotation, the ATC operates as a pump. Thus, the ATC overcomes pressure drop limitations of other continuous crystallizers, allowing for longer residence times and crystal growth phases. Understanding continuous crystallizer phenomena is the basis for a well-designed crystallization process, especially for small-scale applications in the pharmaceutical and fine chemical industry. Hydrodynamics and suspension behavior, for example, affect agglomeration, breakage, attrition, and ultimately crystallizer blockage. In practice, however, it is time-consuming to investigate these phenomena experimentally for each new material system. In this contribution, a flow map is developed in five steps through a combination of experiments, CFD simulations, and dimensionless numbers. Accordingly, operating parameters can be specified depending on ATC design and material system used, where suspension behavior is suitable for high-quality crystalline products.

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Section: Introductionmentioning

confidence: 99%

Flow Map for Hydrodynamics and Suspension Behavior in a Continuous Archimedes Tube Crystallizer

et al. 2021

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“…Fouling on the vessel walls will reduce the heat transfer, which could influence the reaction rate, resulting in decreased yield. Many strategies [99,[108][109][110][111][112][113][114] have been developed to avoid fouling in continuous crystallization, which can also be used in reactive crystallization processes, including: (1) mechanical devices (e.g., addition of baffles, scrapes, rotating shafts), (2) surface energy or roughness modification via coating (e.g., gold), (3) operating conditions (e.g., mixing, supersaturation level, flow rate, seeding), (4) process dynamics (e.g., use of ultrasonic vibrations, temperature cycling), ( 5) polymeric excipients (e.g., hydroxylpropyl methylcellulose (HPMC)), ( 6) model-based strategies, and (7) PAT-based strategies.…”

Section: Clogging and Foulingmentioning

confidence: 99%

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

2021

J Flow Chem

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Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large part motivated by the many advantages of continuous manufacturing (e.g., low cost, quality assurance, shortened lead time). As chemical reactions are fundamental to any drug production process, the selection of reactor and its design are critical to enhanced performance such as improved selectivity and yield. In this article, relevant theories, and models, as well as their required input data are summarized to assist the reader in these tasks, focusing on continuous reactions. Selected examples that describe the application of plug flow reactors (PFRs) and continuous-stirred tank reactors (CSTRs)-in-series within the pharmaceutical industry are provided. Process analytical technologies (PATs), which are important tools that provide real-time in-line continuous monitoring of reactions, are recommended to be considered during the reactor design process (e.g., port design for the PAT probe). Finally, other important points, such as density change caused by thermal expansion or solid precipitation, clogging/fouling, and scaling-up, are discussed.

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“…Even though a lot of research has been performed on tubular crystallizers, most research does not mention how long the crystallizer can run without fouling or clogging [1]. Many solutions have been proposed to solve fouling, however these often lack experimental validation [7]. One solution showing promising results are tubular crystallizers that are sonicated from front to end as shown by Furuta et al, .…”

Section: Introductionmentioning

confidence: 99%

Continuous Crystallization Using Ultrasound Assisted Nucleation, Cubic Cooling Profiles and Oscillatory Flow

et al. 2021

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Continuous tubular crystallizers have the potential to reduce manufacturing costs and increase product quality. However, designing tubular crystallizers is a complex and challenging task as crystallization is a complex, multiphase process with a propensity for fouling and clogging. While several designs have been proposed to overcome these issues, these designs are either unproven or poorly scalable and complex. In this work a continuous crystallizer is designed and evaluated to mitigate these issues. The tubular crystallizer combines a novel method to obtain a cubic cooling profile to control the supersaturation, ultrasound to induce nucleation and oscillatory flow to improve mixing and minimize fouling and sedimentation. The results show that the crystallizer was able to operate for more than 4 h without clogging, with high yields and a narrow particle size distribution. The design proposed here is therefore considered a viable approach for continuous crystallizers.

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Encrustation in Continuous Pharmaceutical Crystallization Processes—A Review

Cited by 35 publications

References 54 publications

Flow Map for Hydrodynamics and Suspension Behavior in a Continuous Archimedes Tube Crystallizer

Flow Map for Hydrodynamics and Suspension Behavior in a Continuous Archimedes Tube Crystallizer

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Continuous Crystallization Using Ultrasound Assisted Nucleation, Cubic Cooling Profiles and Oscillatory Flow

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