Continuous crystallization and its potential use in drug substance Manufacture: A review

Eren, Ayşe; Civati, Francesco; Ma, Wenchuan; Gamekkanda, Janaka C.; Myerson, Allan S.

doi:10.1016/j.jcrysgro.2022.126958

Cited by 14 publications

(14 citation statements)

References 81 publications

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“…The MSMPR crystallizers are very similar to continuous stirred tank reactors (CSTRs). [ 25 ] These are jacketed vessels with agitators designed to achieve homogeneous mixing across the liquid bulk. Materials are fed into the tank through one or multiple inlets and removed from the outlet.…”

Section: Continuous Crystallizer Overviewmentioning

confidence: 99%

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Recent Advancements in Continuous Crystallization of Proteins

Vikram,

Yadav

2023

Cryst. Res. Technol.

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Recently, there have been many studies and reports on various continuous protein crystallization processes. Due to the increasing demand for pharmaceutical proteins such as insulin and monoclonal antibodies, it has become essential to optimize the current industrial processes to meet these demands. There are various comparisons to be made between current batch crystallization processes and continuous processes for proteins. This review paper aims to review the recent advancements in continuous protein crystallization processes, such as slug flow crystallizers, oscillatory baffled crystallizers, and mixed suspension mixed product removal (MSMPR) crystallizers.

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Section: Continuous Crystallizer Overviewmentioning

confidence: 99%

“…Recycling solids is a potential solution to increasing yield in cases where the protein has low growth rates. [ 25 ] The increase in yield can be attributed to the increase in surface area provided by the recycled crystals. This also has the effect of reducing secondary nucleation since growth is promoted.…”

Section: Continuous Crystallizer Overviewmentioning

confidence: 99%

Recent Advancements in Continuous Crystallization of Proteins

Vikram,

Yadav

2023

Cryst. Res. Technol.

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“…Continuous crystallizers can be divided into mixed suspension mixed product removal crystallizers, , continuous oscillatory baffled crystallizers, − and tubular flow crystallizers (TFCs) . Several recent reviews discuss the advantages of continuous crystallization in more detail, − such as consistent production and no batch-to-batch variability. One type of TFC is the continuous microcrystallizer.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Modular Microfluidic Section for Seeded Nucleation in Multiphase Flow

Devos

Brozzi

Gerven

et al. 2023

Org. Process Res. Dev.

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We present a proof-of-concept modular nucleation section for seeded multiphase flow crystallization of an active pharmaceutical ingredient. The setup can be used in four different modes of operation (with or without off-line prepared seeds and with or without a stream of microbubbles). The setup is characterized to provide insights into the design and operation of crystallization processes. First, the performance of the off-line continuous seeding platform is established via the seed delivery efficiency for constant and oscillatory flows. Second, the yields of seeded and unseeded crystallization are evaluated in the presence and absence of microbubbles. A statistically significant increase in the net crystal mass and net yield was measured when comparing unseeded and seeded crystallization, which can be attributed to the increased nucleation rates as a result of secondary nucleation. Third, the clogging behavior of the presented continuous microcrystallizer is discussed. Finally, also the crystal size distribution is analyzed: the mean crystal size decreases for both single- and two-phase flow when seeds are introduced. The presence of microbubbles resulted in a higher net yield and slightly smaller crystals compared to that of the single-phase flow. This work highlights the importance of a holistic characterization approach for continuous microfluidic crystallizers.

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“…The mixed suspension mixed product removal (MSMPR) crystallizer, analogous to the well-known continuous stirred tank reactor (CSTR), stands as the most popular continuous crystallization formalism. 7 This type of design offers flexibility in terms of residence time and mixing intensity�the former tunable by changing the inlet and outlet streams' flow rates or the operating volume, and the latter by adjusting the impeller's stirring rate. However, the working principle of the MSMPR differs considerably from that of the batch formalism, hence preventing a straightforward transfer of process knowledge from one formalism to the other.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Continuous crystallizers on the other hand have much milder scale up requirements since extending the operating time increases the throughput. The mixed suspension mixed product removal (MSMPR) crystallizer, analogous to the well-known continuous stirred tank reactor (CSTR), stands as the most popular continuous crystallization formalism . This type of design offers flexibility in terms of residence time and mixing intensitythe former tunable by changing the inlet and outlet streams’ flow rates or the operating volume, and the latter by adjusting the impeller’s stirring rate.…”

Section: Introductionmentioning

confidence: 99%

Loop-Configuration for Plug Flow Crystallization Process Development

Aprile,

Pandit,

Albertazzi

et al. 2023

Crystal Growth & Design

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Continuous crystallization plays a pivotal role in the transition to continuous manufacturing that the pharmaceutical industry is currently undertaking. Alas, the development of a continuous crystallization process using data from continuous operation is prohibitively material-intensive. Given the state of control nature of the continuous formalism, experimental design spaces entail several experiments, in which up to ten residence times are required to assess an experimental condition at steady state. Furthermore, transferring batch kinetics determined from batch experiments to a continuous crystallizer, despite being common practice, adds undesirable uncertainty to the development endeavors due to equipment-dependent mass and heat transfer. In this work, we present a novel configuration of a tubular crystallizer, capable of characterizing a system with a few experiments, curbing the reactor footprint, and abating the development's raw material requirements. A stream of crystallizing material, flowing inside a tubular crystallizer equipped with Kenics static mixers, was fully recirculated, implementing a looped plug flow configuration, and its evolution was monitored in-line continuously by means of in situ Process Analytical Technologies. This allows effective mimicking of long residence times (which correspond to large process volumes) in a short plug flow crystallizer while maintaining plug flow conditions and screening a process from nucleation to equilibrium. Computational fluid dynamics simulations supported the assumption of negligible back mixing and aided the comparison of the mixing with that of a cascade of continuous stirred tank reactors. The use of the novel configuration is showcased for the antisolvent crystallizations of ketoconazole, azithromycin, and glycine. Using this approach, we show reductions in raw material requirements from 50 to 98%, compared with an equivalent standard plug flow crystallizer. Naturally, the configuration can also be employed for manufacturing in a semicontinuous manner.

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Continuous crystallization and its potential use in drug substance Manufacture: A review

Cited by 14 publications

References 81 publications

Recent Advancements in Continuous Crystallization of Proteins

Recent Advancements in Continuous Crystallization of Proteins

Characterization of a Modular Microfluidic Section for Seeded Nucleation in Multiphase Flow

Loop-Configuration for Plug Flow Crystallization Process Development

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