Characterization of the anti-solvent batch, plug flow and MSMPR crystallization of benzoic acid

Ferguson, Steven; Morris, Gary; Hao, Hongxun; Barrett, Mark; Glennon, Brian

doi:10.1016/j.ces.2013.09.006

Cited by 82 publications

(110 citation statements)

References 18 publications

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“…Plug flow crystallizers (PFC) and mixed-suspension mixed-product removal (MSMPR) crystallizers are the two main types of continuous crystallizers. Plug flow can be approximated in tubular crystallizers, which have a narrow residence time distribution and a high surface-to-volume ratio allowing precise process control, while costs are minimized due to small process equipment and straightforward scale-up [5][6][7][8][9].…”

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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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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“…39,63,64 Thompson et al 39 investigated the effect of structurally related additives on different crystal faces of form I PCM. They found that the growth of the (001) face, and hence the crystal morphology, was affected to different extents by acetanilide and metacetamol additives due to different interactions with the NHCOCH 3 and OH functional groups, respectively. The microscope images (Figure 14a,b) indicate, qualitatively, the effect HPMC additive on growth of PCM crystals in the continuous MSMPR crystallizer.…”

Section: Resultsmentioning

confidence: 99%

“…This is an important observation since many recent studies on the subject of continuous crystallization monitoring characterized steady state by relying solely on FBRM 9,18,32,49−51 and/or imaging techniques (for example, low angle light scattering (LALLS) and PVM 19,51 ) or calibrationfree spectroscopy approaches. 9 Arguably, real-time determination of concentration using multivariate models supported by online particle measurements provides a more robust measure of steady-state operation, as opposed to just tracking changes in FBRM statistics or using calibration-free methods. Since these are essentially qualitative measures, they may not reliably determine the attainment of steady-state operation.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, start-up of the MSMPR was achieved without any wash-out issues, as are often reported in the literature. 9,19 Wash-out was avoided due to the start-up strategy employed, whereby material is circulated between the dissolver and MSMPR until nucleation is detected, as opposed to starting up with a suspension already in the MSMPR. 19,51 Experiments were carried out with HPMC additive addition to further alleviate fouling and encrustation problems encountered during prolonged operation.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 The breaking off of crusts from the crystallizer walls can then lead to line blockages as well as particle settling and classification due to the difference in flow velocities in the agitated crystallizer or in transfer lines. To overcome these challenges in MSMPR operation, researchers have used different operating strategies to varying degrees of success, for example, intermittent withdrawal 9,18,19 and, more recently, periodic flow operation. 20 In this study, a two-pronged approach was taken to alleviate fouling and encrustation in MSMPR.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Monitoring Continuous Crystallization of Paracetamol in the Presence of an Additive Using an Integrated PAT Array and Multivariate Methods

Powell

Saleemi²,

Rielly

et al. 2016

Org. Process Res. Dev.

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In this study, an automated intelligent decision support (IDS) framework was applied to monitor the continuous crystallization of form I paracetamol (PCM) and determine steady-state operation. A modified single-stage mixed suspension mixed product removal (MSMPR) crystallizer was used to investigate methods to minimize early onset of fouling and encrustation by carrying out crystallizations in the presence and absence of hydroxyl propyl methyl cellulose (HPMC) additive. The effectiveness of HPMC toward controlling the crystallization process and alleviating fouling and encrustation for prolonged operation of the MSMPR was investigated over a range of concentrations. HPMC was found to suppress nucleation and growth, thereby controlling the crystallization and alleviating fouling and encrustation over extended operating periods. HPMC also affected the product crystal morphology, leading to predominantly tabular shaped crystals. Steady state in the MSMPR was characterized using the IDS, which consisted of an integrated and ancillary array of process analytical technologies (PAT), including the application of Raman spectroscopy with multivariate calibration for solution phase concentration measurement.

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Continuous Crystallisation

Brown

McGlone

Florence

2017

Continuous Manufacturing of Pharmaceuticals

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Mixing 2) Nucleation 3) Growth 4) Filter/wash/dry Required to:  Produce consistent composition  Control crystallisation driving force  Influence flow rate, shear-kinetic effects  Consistent suspension of seed and product Controlled via:  Supersaturation  High shear  External fields, e.g. ultrasound, nonphotochemical laser induced nucleation  Seed. Seeds produced via dry milling, wet media milling, precipitation, recycle, dissolution, spray drying or secondary nucleation Controlled to avoid:  Fouling  Agglomeration  Dissolution  Crystalline form transformation(s) Controlled via:  Supersaturation (typically low) via cooling, anti-solvent, evaporation  Effective heat/mass transfer Ensures:  Efficient desupersaturation Controlled to avoid:  Fouling  Agglomeration  Attrition (particle breakage)  Dissolution  Crystalline form transformation(s) Required to:  Create filter cake  Remove mother liquor and impurities  Maintain particle attributes Controlled to avoid:  Agglomeration  Attrition (particle breakage)Continuous crystallisation has been implemented for many decades in other manufacturing sectors, typically for large volume commodity chemicals, and offers a range of potential advantages [16,17] including lower operating and capital costs, reduced down time and more efficient use of energy and materials. Cooling and anti-solvent crystallisation are commonly used in industrial applications and can be readily implemented in continuous. The aim is to follow a controlled trajectory through the solubility phase diagram (section 1.2).

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Characterization of the anti-solvent batch, plug flow and MSMPR crystallization of benzoic acid

Cited by 82 publications

References 18 publications

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

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

Monitoring Continuous Crystallization of Paracetamol in the Presence of an Additive Using an Integrated PAT Array and Multivariate Methods

Continuous Crystallisation

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