Development of an automated multi-stage continuous reactive crystallization system with in-line PATs for high viscosity process

Hu, Chuntian; Finkelstein, Joshua E.; Wu, Wei; Shvedova, Khrystyna; Testa, Christopher J.; Born, Stephen C.; Takizawa, Bayan; O’Connor, Thomas; Yang, Xiaochuan; Ramanujam, Sukumar; Mascia, Salvatore

doi:10.1039/c8re00078f

Cited by 18 publications

(29 citation statements)

References 67 publications

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“…By approximating a PFR with a four-stage CSTRs-in-series, the volume is reduced from 12.4 L to 2 L [8]. The Damkӧhler number, Da, which is defined as the ratio of the reaction rate of A to the convective transport rate of A at the entrance of the reactor, is often used to estimate the degree of conversion achieved in continuous reactors [20].…”

Section: Cstrs-in-seriesmentioning

confidence: 99%

“…7d is adapt from Ref. [8] with permission from the Royal Society of Chemistry) reaction; however, the heat dissipation capacity was low. As better mixing and a longer residence time facilitate the reaction conversion, a combination of a PFR-3 CSTRs-in-series system was used.…”

Section: Cstrs-in-seriesmentioning

confidence: 99%

“…ReactIR is a real-time, in situ mid-infrared based system that enables tracking of soluble reactants, intermediates, products and by-products during the reaction process. This provides useful information about initiation, conversion, intermediates and endpoints of a reaction [8,16,[91][92][93]. A ReactIR probe could be located in a batch reactor, a CSTR, or any stage of a CSTRs-in-series, while a ReactIR flow cell can be placed at the exit of a PFR [94].…”

Section: Selected Pats In Continuous Reactorsmentioning

confidence: 99%

“…FBRM is a probe-based instrument that tracks changing particle size and counts in real-time, and has been widely used in: 1) developing and optimizing crystallization process [95][96][97][98][99], 2) tracking and troubleshooting crystallizer systems [100][101][102][103][104][105], and 3) even monitoring polymorphic forms [103,106]. The FBRM probe could be located in a batch crystallizer, or in CSTRs-in-series systems for reactive crystallization processes [8,16]. For example, Hu et al [8,16]used FBRM in the last stage of CSTRs-in-series to track changing chord length in real time.…”

Section: Selected Pats In Continuous Reactorsmentioning

confidence: 99%

“…Motivated by the benefits shown in Fig. 1 [6][7][8][9][10], the pharmaceutical industry is transitioning to continuous processes, including end-to-end integrated continuous manufacturing (ICM) approaches [1,6,8,[10][11][12][13][14][15][16][17][18]. A first-of-its-kind research demonstration of an end-to-end ICM line was unveiled by MIT in 2011 [13].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Cstrs-in-seriesmentioning

confidence: 99%

Section: Cstrs-in-seriesmentioning

confidence: 99%

Section: Selected Pats In Continuous Reactorsmentioning

confidence: 99%

Section: Selected Pats In Continuous Reactorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reactor design and selection for effective continuous manufacturing of pharmaceuticals

2021

J Flow Chem

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Comparative Study of Preprocessing on an ATR‐FTIR Calibration Model for In Situ Monitoring of Solution Concentration in Cooling Crystallization

Zhang

Guo

et al. 2021

Chem Eng & Technol

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The effect of data preprocessing on a calibration model based on attenuated total reflectance-Fourier transform infrared spectroscopy was investigated for in situ measurements of the solution concentration during cooling crystallization. L-Glutamic acid cooling crystallization was taken as a case study. It was found that smoothing and derivative is a superior preprocessing method for model calibration, which can effectively remove spectral nonlinearity, improve the prediction accuracy of the calibration model, and enhance model robustness in detecting faults. Verification experiments demonstrated the effectiveness of the established calibration models. These models also show better performance in detecting the generation of crystal nuclei in the probe window, which is of great significance to eliminate the fatal probe fouling.

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Continuous Reactive Crystallization in a Mesoscale Oscillatory Baffled Reactor

et al. 2023

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Continuous reactive crystallization was carried out in a mesoscale oscillatory baffled reactor (meso‐OBR), using calcium carbonate as a case study to demonstrate the ability of high solid loadings and to examine the fouling potential in continuous processes. Plug flow behavior was easily achieved in reactive solid‐liquid phase reaction systems, as evidenced by the rapid establishment of a steady state. Effects of the operating conditions (reactant concentration, mixing conditions, and temperature) on the yield, particle size, and particle size distribution were studied. Increasing the reactant concentration and oscillation conditions reduced the particle size whereas increasing the operating temperature led to a large particle size. The meso‐OBR produced uniformly shaped spherical crystals, with a 35 % reduction in average particle size and high purity compared to conventional stirred tanks. The meso‐OBR could be used continuously for up to 6 h with less than 1 wt % of fouling (product loss).

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Development of an automated multi-stage continuous reactive crystallization system with in-line PATs for high viscosity process

Abstract: Lower E-factor was obtained in an automated multi-stage continuous reactive-crystallization system.

Cited by 18 publications

References 67 publications

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Comparative Study of Preprocessing on an ATR‐FTIR Calibration Model for In Situ Monitoring of Solution Concentration in Cooling Crystallization

Continuous Reactive Crystallization in a Mesoscale Oscillatory Baffled Reactor

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