Multistep Continuous‐Flow Microchemical Synthesis Involving Multiple Reactions and Separations

Sahoo, Hemantkumar R.; Kralj, Jason G.; Jensen, Klavs F.

doi:10.1002/ange.200701434

Cited by 152 publications

(82 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Just recently, the focus has been set also on separations [43][44][45][46][47][48]. Besides chemical applications, energy generation is a major application, in particular concerning fuel processing to make hydrogen for fuel cells [25,26,49,50].…”

Section: Milli-and Micro-process Technologiesmentioning

confidence: 99%

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

2009

View full text Add to dashboard Cite

Driven by the economics of scale, the size of reaction vessels as the major processing apparatus of the chemical industry has became bigger and bigger [1,2]. Consequently, the efforts for ensuring mixing and heat transfer have also increased, as these are scale dependent. This has brought vessel operation to (partly severe) technical limits, especially when controlling harsh conditions, e.g., due to large heat releases. Accordingly, processing at a very large scale has resulted in taming of the chemistry involved in order to slow it down to a technically controllable level. Therefore, reaction paths that already turned out too aggressive at the laboratory scale are automatically excluded for later scale-up, which constitutes a common everyday confinement in exploiting chemical transformations. Organic chemists are barely conscious that even the small-scale laboratory protocols in their textbooks contain many slow, disciplined chemical reactions. Operations such as adding a reactant drop by drop in a large diluted solvent volume have become second nature, but are not intrinsic to the good engineering of chemical reactions. These are intrinsic to the chemical apparatus used in the past. In contrast, today's process intensification [3][4][5][6][7][8][9][10][11][12] and the new flow-chemistry reactors on the micro-and milli-scale allow such limitations to be overcome, and thus, enable a complete, ab-initio type rethinking of the processes themselves. In this way, space-time yields and the productivity of the reactor can be increased by orders of magnitude and other dramatic performance step changes can be achieved. A hand-in-hand design of the reactors and process re-thinking is required to enable chemistry rather than subduing chemistry around the reactor [40]. This often leads to making use of process conditions far from conventional practice, under harsh environments, a procedure named here as Novel Process Windows. Starting Point: Novel Process WindowsIntensify Rather than OptimizeThe aim of the following introductory remarks, and the paper as whole, is to make sensible -while everyone in the field would agree that microstructured reactors and micro-process technology [3-12] form a major direction within process intensification -that the exploitation of such innovation can still profit considerably by joining both concepts. It is frequently thought that the use of a microstructured reactor automatically and implicitly results in process intensification; simply because this is a major direction within process intensification and since the latter is also concerned with apparatus developments. This is only partly true and actually ignores significant chances for process breakthrough. In many investigations, the use of a microstructured reactor is still more concerned with process optimization, which is involves a slight to moderate improvement of processes using classical paths, in particular with the same or similar chemical and processing protocol. Often, the most radical and innovative step is the

show abstract

Section: Milli-and Micro-process Technologiesmentioning

confidence: 99%

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

2009

View full text Add to dashboard Cite

show abstract

“…12 In this context, microreaction technology and microbased separations (μm scale) have rapidly developed in recent years, 5 providing the basic tools to achieve multistep organic synthesis in continuous mode. 13,14 The miniaturization of reaction and separation devices is especially advantageous in process development studies and high-throughput screening (where reagents and catalysts may be scarce, harmful and/or expensive), motivating the expansion of microfluidic devices and techniques. 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.…”

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.

View full text Add to dashboard Cite

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.

show abstract

“…[2b, 8] These include development of flow chemistry transformations, difficulties with processing dry solids and solid-laden fluids, lack of equipment at bench and pilot scale, development of control methodologies to guarantee product quality, and breaks in the process, especially between synthesis and formulation. Many examples have been reported of continuous processes for chemical synthesis in flow, [9] reactions with workup, [10] continuous crystallization, [10b, 11] drying, [12] powder blending, [13] and tableting; [13d, 14] however, only few others have considered multistep portions of a process.…”

mentioning

confidence: 99%

End‐to‐End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation

et al. 2013

View full text Add to dashboard Cite

show abstract

Multistep Continuous‐Flow Microchemical Synthesis Involving Multiple Reactions and Separations

Cited by 152 publications

References 41 publications

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

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

End‐to‐End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation

Contact Info

Product

Resources

About