Continuous crystallization using a sonicated tubular system for controlling particle size in an API manufacturing process

Furuta, Masashi; Mukai, Kouji; Cork, David G.; Mae, Kazuhiro

doi:10.1016/j.cep.2016.02.002

Cited by 42 publications

(44 citation statements)

References 35 publications

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“…12,13,18,22 First studies applying the HCT for API coating and crystal growth were published by Khinast and co-workers. 18,23,24,25,26,27 A sonicated tubular crystallizer was designed by Furuta et al 22 The HCT has not yet been investigated for crystal shape control, although the shape strongly determines API efficacy 6 as well as downstream processing. 2 Therefore, the objective of this work is to apply methods for shape control to the continuous HCT crystallizer to grow crystals with a narrow CSSD.…”

Section: Introductionmentioning

confidence: 99%

Continuous Crystallization in a Helically Coiled Flow Tube: Analysis of Flow Field, Residence Time Behavior, and Crystal Growth

Wiedmeyer

Anker

Bartsch

et al. 2017

Ind. Eng. Chem. Res.

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A continuously operated helically coiled flow tube (HCT) crystallizer is investigated for crystal growth. Inline video-imaging is used for crystal shape analysis and residence time estimation of potash alum. The main finding is that there is a size-dependent particle residence time. Large particles move faster through the HCT than small particles. Consequently, small crystals have more time to grow in the HCT. Physical reasons for this behavior are proposed, for example small-scale flow characteristics. In a direct numerical simulation of the instationary Navier-Stokes equations, velocity fluctuations and a secondary flow are identified. The presented flow field may have a different impact on the particles and cause the size-dependent particle residence time. A particle size dependent residence time may potentially narrow the crystal size and shape distribution in such a process, frequently a desired feature in solids' production.

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Section: Introductionmentioning

confidence: 99%

Continuous Crystallization in a Helically Coiled Flow Tube: Analysis of Flow Field, Residence Time Behavior, and Crystal Growth

Wiedmeyer

Anker

Bartsch

et al. 2017

Ind. Eng. Chem. Res.

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“…The most important advantages are: more reproducible PSDs, smaller particle sizes, more robust scale-up, shorter downtimes, and easier control over the supersaturation ratio by better temperature control [1,2,7,8]. These continuous crystallizers suffer, nevertheless, from clogging and blocking of their channels by the attachment of crystals to the walls or agglomeration of these crystals [1,4,5,9]. Furthermore, the total residence time which can be achieved in these crystallizers is limited by the tube length and flow rate.…”

Section: Introductionmentioning

confidence: 99%

Ultrasound Assisted Particle Size Control by Continuous Seed Generation and Batch Growth

et al. 2017

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Controlling particle size is essential for crystal quality in the chemical and pharmaceutical industry. Several articles illustrate the potential of ultrasound to tune this particle size during the crystallization process. This paper investigates how ultrasound can control the particle size distribution (PSD) of acetaminophen crystals by continuous seed generation in a tubular crystallizer followed by batch growth. It is demonstrated that the supersaturation ratio at which ultrasound starts seed generation has a substantial effect on the final PSD while the applied power is insignificant in the studied conditions. The higher the supersaturation ratio, the smaller the final crystals become up to a supersaturation ratio of 1.56. Furthermore, it was shown that ultrasound can also impact the final PSD when applied during the growth phase. Frequencies of 850 kHz or below reduce the final particle size; the lower the applied frequency, the smaller the crystals become. In conclusion, one could state that ultrasound is able to control the particle size during seed generation and subsequent growth until the final particle size.

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“…Another challenge is fouling, which eventually leads to clogging. Whilst multiple solutions to fouling are suggested in literature, they often add a lot of complexity and can only limit fouling to a certain degree [10,13,14]. A general rule to minimize fouling is to work at low supersaturations; however, this decreases nucleation rates even more, highlighting the need to enhance nucleation at low supersaturations.…”

Section: Introductionmentioning

confidence: 99%

Reducing the Induction Time Using Ultrasound and High-Shear Mixing in a Continuous Crystallization Process

et al. 2018

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Continuous crystallization in tubular crystallizers is of particular interest to the pharmaceutical industry to accurately control average particle size, particle size distribution, and (polymorphic) shape. However, these types of crystallizers require fast nucleation, and thus, short induction times at the beginning of the flow process, which is challenging for larger and complex organic molecules. High shear and/or the presence of bubbles were identified to influence the nucleation behavior. This work investigates the effects of both high-shear mixing and ultrasound on the anti-solvent crystallization of paracetamol in acetone-water. Both devices generate intense amounts of shear and gas bubbles. Generally, the results show that increasing input power decreases the induction time significantly for both the rotor-stator mixer and ultrasound probe. However, the induction time is almost independent of the supersaturation for the ultrasound probe, while the induction time significantly increases with decreasing supersaturation for the rotor-stator mixer. In contrast, the particle size distribution for the rotor-stator mixer is independent of the supersaturation, while increasing supersaturation decreases the particle size for the ultrasound probe.

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Continuous crystallization using a sonicated tubular system for controlling particle size in an API manufacturing process

Cited by 42 publications

References 35 publications

Continuous Crystallization in a Helically Coiled Flow Tube: Analysis of Flow Field, Residence Time Behavior, and Crystal Growth

Continuous Crystallization in a Helically Coiled Flow Tube: Analysis of Flow Field, Residence Time Behavior, and Crystal Growth

Ultrasound Assisted Particle Size Control by Continuous Seed Generation and Batch Growth

Reducing the Induction Time Using Ultrasound and High-Shear Mixing in a Continuous Crystallization Process

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