Overcoming the Challenges of Solid Bridging and Constriction during Pd-Catalyzed C−N Bond Formation in Microreactors

Hartman, Ryan L.; Naber, John R.; Zaborenko, Nikolay; Buchwald, Stephen L.; Jensen, Klavs F.

doi:10.1021/op100154d

Cited by 229 publications

(212 citation statements)

References 69 publications

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“…Another example of the d f impact on the operation stability of industrial units, is represented by product or by-product crystallization in microreactors, which leads to reactor clogging, of particular importance given the small reactor diameter (in the range of 10-1000 μm) [84]. The fractal dimension of the formed crystals plays a key role in this process as a low d f will cause a faster clogging.…”

Section: Coagulum Formation In Industrial Production Unitsmentioning

confidence: 99%

Fractal-like structures in colloid science

Lazzari

Nicoud

Jaquet

et al. 2016

Advances in Colloid and Interface Science

175

126

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a b s t r a c tThe present work aims at reviewing our current understanding of fractal structures in the frame of colloid aggregation as well as the possibility they offer to produce novel structured materials. In particular, the existing techniques to measure and compute the fractal dimension d f are critically discussed based on the cases of organic/inorganic particles and proteins. Then the aggregation conditions affecting d f are thoroughly analyzed, pointing out the most recent literature findings and the limitations of our current understanding. Finally, the importance of the fractal dimension in applications is discussed along with possible directions for the production of new structured materials.

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Section: Coagulum Formation In Industrial Production Unitsmentioning

confidence: 99%

Fractal-like structures in colloid science

Lazzari

Nicoud

Jaquet

et al. 2016

Advances in Colloid and Interface Science

175

126

View full text Add to dashboard Cite

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“…In contrast, in our opinion, mini-/mesoscale reaction and separation technology (mm−cm scale) have received relatively less attention, even though it is potentially possible to access some of the advantages of small scales while lowering the sensitivity to practical problems such as blockages from solids in suspension, which still form a main limitation for microreaction technology. 5, 15 Furthermore, it has been observed that fluid distribution and parallelization of microscale units is not such a straightforward task, despite expectations based on the standard scaling-out principles. 16 Thus, constructing basic units at a moderately larger scale should theoretically make scaling-up/-out an easier and smoother task.…”

Section: Introductionmentioning

confidence: 99%

Continuous Hydrolysis and Liquid–Liquid Phase Separation of an Active Pharmaceutical Ingredient Intermediate Using a Miniscale Hydrophobic Membrane Separator

Cervera-Padrell

Morthensen

Lewandowski

et al. 2012

Org. Process Res. Dev.

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Continuous hydrolysis of an active pharmaceutical ingredient intermediate, and subsequent liquid−liquid (L-L) separation of the resulting organic and aqueous phases, have been achieved using a simple PTFE tube reactor connected to a miniscale hydrophobic membrane separator. An alkoxide product, obtained in continuous mode by a Grignard reaction in THF, reacted with acidic water to produce partially miscible organic and aqueous phases containing Mg salts. Despite the partial THF− water miscibility, the two phases could be separated at total flow rates up to 40 mL/min at different flow ratios, using a PTFE membrane with 28 cm 2 of active area. A less challenging separation of water and toluene was achieved at total flow rates as high as 80 mL/min, with potential to achieve even higher flow rates. The operability and flexibility of the membrane separator and a plate coalescer were compared experimentally as well as from a physical viewpoint. Surface tension-driven L-L separation was analyzed in general terms, critically evaluating different designs. It was shown that microporous membrane L-L separation can offer very large operating windows compared to other separation devices thanks to a high capillary pressure (Laplace pressure) combined with a large number of pores per unit area offering low pressure drop. The separation device can easily be operated by means of a back-pressure regulator ensuring flow-independent separation efficiency. Simple monitoring and control strategies as well as scaling-up/out approaches are proposed, concluding that membrane-based L-L separation may become a standard unit operation for continuous pharmaceutical manufacturing.

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“…66 More trivially, clogging can be hindered by employing wide bore channels or tubing, as well as applying agitation or sonic irradiation and controlling of fluid velocity. 25,27,67 If clogging is caused by the crystallization of low melting substances, the heating of the problematic areas is an effective method. 39 In the gas-liquid two phase flow during an ozonolysis leading to drug candidate OZ439, the evaporation of the liquid phase caused clogging.…”

Section: Ensuring Stability For Continuous Productionmentioning

confidence: 99%

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

Bana

Örkényi

Lövei

et al. 2017

Bioorganic & Medicinal Chemistry

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a b s t r a c tRecent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules.

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Overcoming the Challenges of Solid Bridging and Constriction during Pd-Catalyzed C−N Bond Formation in Microreactors

Cited by 229 publications

References 69 publications

Fractal-like structures in colloid science

Fractal-like structures in colloid science

Continuous Hydrolysis and Liquid–Liquid Phase Separation of an Active Pharmaceutical Ingredient Intermediate Using a Miniscale Hydrophobic Membrane Separator

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

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