The coupling of in-flow reaction with continuous flow seedless tubular crystallization

Rimez, Bart; Septavaux, Jean; Scheid, Benoît

doi:10.1039/c8re00313k

Cited by 12 publications

(13 citation statements)

References 33 publications

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“…In 2019, Rimez et al published a two-step continuous tubular system incorporating a synthetic step and plug flow crystallization for the production of ASA crystals in 2019. 129 They further examined the crystallization step in a subsequent study, which might be ready for the connection to other flow chemical processes. 130 In the research area of flow syntheses coupled to continuous workup procedures, a great work was accomplished by Ely Lilly and Company.…”

Section: Recent Progress In Continuous Pharmaceutical Technologiesmentioning

confidence: 99%

“…Thus, after the scale-up of the flow synthesis to relevant flow rates for continuous crystallization, the two developed processes could be run in an integrated fashion. In 2019, Rimez et al published a two-step continuous tubular system incorporating a synthetic step and plug flow crystallization for the production of ASA crystals in 2019 . They further examined the crystallization step in a subsequent study, which might be ready for the connection to other flow chemical processes …”

Section: Recent Progress In Continuous Pharmaceutical Technologiesmentioning

confidence: 99%

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Integrated Continuous Pharmaceutical Technologies—A Review

Domokos

Nagy

Szilágyi

et al. 2021

Org. Process Res. Dev.

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Innovation in the pharmaceutical industry has been limited for a long time to the research and development of new active compounds; meanwhile, the structure of the production, dominated by batchwise technologies, has not changed to date. As has already been demonstrated in several other industrial sectors, continuous manufacturing (CM) has many advantages over batch processes. Faster, cheaper, and more flexible production can be developed with a significantly higher level of quality assurance. In the recent years the main regulatory agencies recognized the need for a change in drug production and started to promote continuous technologies and encourage pharmaceutical companies to develop and adapt such processes. As a result, by today extensive research was conducted in the various fields of pharmaceutical technologies from drug substance to drug product manufacturing. Many publications deal with synthetic steps carried out in flow reactors and crystallizations implemented in a continuous manner, and on the formulation side continuous filtration, drying, granulation, and blending have all been studied to a lesser or greater extent. Moreover, besides the modification of these traditional processes to continuous operation, novel, intrinsically continuous technologies are being studied as well. In order to entirely exploit the advantages of CM, the mainly separately developed processes need to be integrated to form end-to-end systems from the raw materials to the final dosage forms. However, even the integration of two technological steps is a challenging task. The development of end-to-end systems requires deep process understanding and a holistic approach toward process development and optimization. The aim of this work is to give insight into the state-of-the-art and new directions in integrated continuous pharmaceutical technologies by critically reviewing the recent literature of the broad field.

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Section: Recent Progress In Continuous Pharmaceutical Technologiesmentioning

confidence: 99%

Section: Recent Progress In Continuous Pharmaceutical Technologiesmentioning

confidence: 99%

Integrated Continuous Pharmaceutical Technologies—A Review

Domokos

Nagy

Szilágyi

et al. 2021

Org. Process Res. Dev.

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show abstract

“…After the exit of the growing nuclei out of the reactor further crystal growth is reported to be conducted in storage vessels, tubing, or directly casted on filters, both for direct nucleation in one single solvent or by addition of antisolvent. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

“…[22] As a consequence, the size of the crystalline material obtained afterwards results directly from the ruling elevated nucleation rates. [24,25].…”

Section: Introductionmentioning

confidence: 99%

On the effect of flow restrictions on the nucleation behavior of molecules in tubular flow Nucleators

2020

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This paper discusses theoretical and experimental considerations of organic molecules nucleating inside tubular reactors or nucleators. Temperature evolution of these liquid systems is experimentally shown for different flow rates as a function of distance when these nucleators are immersed into a water bath set at spontaneous nucleating conditions. When different restrictions in the flow path are introduced before the cooling phase of the liquid; important differences on the nucleation rates are observed. For this study, Aspirin was dissolved in a blend of water and ethanol in a 50/50 vol%. At a concentration of 200 mg/mL and a nucleation temperature of 10°C, demonstrated to be close to the metastable zonewidth, these flow restrictions show an antagonistic effect on the nucleation rate. One restriction, placed right before the nucleator enters the cooling bath, induces a reduction in nucleation rate. Putting more restrictions into the flow path with an equal separation of 5 cm in between, the nucleation recovers back to its initial value when a second restriction of an expansion ratio 2 is applied. Restrictions with an expansion ratio of 4 exceed this nucleation rate up to an order of magnitude when more than 2 restrictions are put in place.At a higher kinetic driving force defined KDF, at a concentration of 300 mg/mL of Aspirin, the influence of the restriction becomes invariant as a function of the expansion ratio. For all experiments, the nucleation rates is highly increased with the number of restrictions introduced into the flow path. A thermal gradient difference by using the restrictions on the cooling rate of the liquid flowing inside the tubing was not observed experimentally. Therefore only hydrodynamic changes of the flow seems a plausible cause for this nucleation rate -restriction dependence as it is expected that finite amplitude perturbations, amplified by the use of restrictions, cause vortex shedding in current experimental setup.

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“…The main reason is the lack of control of the suitable conditions, so that nucleation gets out of hand resulting in retrieved cakes inside the reactors [20]. The use of milli-and micro-metric tubular reactors to perform crystal nucleation may overcome this drawback as residence times at nucleating conditions are drastically reduced; despite the reached high supersaturation values that ensure high nucleation rates [21,22].…”

Section: Introductionmentioning

confidence: 99%

The creation and testing of a fully continuous tubular crystallization device suited for incorporation into flow chemistry setups

et al. 2019

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The study presents the use of a continuous crystallization device that can be directly incorporated into flow chemistry setups. Inside this device spontaneous nucleation and growth of organic molecules are controlled and maintained, using Aspirin as model molecule. The identification of the optimal crystallization scenario is discussed in view of the chemical stability of Aspirin and based on the determination of the solubility and the metastable zone width corresponding to the presented experimental setups. Physicochemical analyses combined with heat transfer modeling of the solution whilst flowing through a capillary placed inside a thermostated water bath provide the desired cooling profile and hence the degree of supersaturation along the system. The crystalline quality and stability of the crystalline output is evidenced for two different pump setups having distinguished flow patterns to show the independence on the flow stability, an important parameter for the success rate of the complete reaction scheme and in the perspective of operation scale-up. Reproducible output of material with narrow size distributions is obtained throughout all experiments.

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The coupling of in-flow reaction with continuous flow seedless tubular crystallization

Cited by 12 publications

References 33 publications

Integrated Continuous Pharmaceutical Technologies—A Review

Integrated Continuous Pharmaceutical Technologies—A Review

On the effect of flow restrictions on the nucleation behavior of molecules in tubular flow Nucleators

The creation and testing of a fully continuous tubular crystallization device suited for incorporation into flow chemistry setups

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