TECHNICAL FIELD

The present invention relates to a planar flow reactor and in particular to a flow reactor suitable for multiphasic reactions and/or photochemical processes. The present invention also relates to a use of the flow reactor to produce a product stream and to a method for producing a product stream using the flow reactor.

BACKGROUND ART

Continuous manufacturing is often the most cost-effective and efficient way to produce goods. This technology was originally developed for the production of very high volumes of end products, for example in the petroleum and food industries. However, in recent times, continuous manufacturing has also been used for low volume production, for example in the chemical and pharmaceutical industries, as other benefits (e.g. safety, quality, mass and heat transfer, etc.) became apparent. Especially in the pharmaceutical industry, regulatory agencies (e.g. the FDA) prefer a switch from batch to continuous processing of active pharmaceutical ingredients (APIs). Optimized dedicated systems have been developed for continuous production of specific APIs. However, on laboratory and pilot scale, it is impractical and expensive to design and implement a suitable reactor for every specific process.

In view of this issue, a wide variety of laboratory flow reactors have been developed. Most of these laboratory reactors utilize (coiled) tubing, narrow channels or falling films of which it is known that these are difficult to scale-up. Specifically, increasing the internal volume by increasing the tube diameter or the channel cross-section results in a deteriorated process control, i.e. mass transfer, heat exchange and/or flow hydrodynamics become more difficult to control. Furthermore, increasing the tube or channel length increases the pressure drop over the length of the reactor.

The scale-up issues associated with these types of flow reactors were addressed, but not solved, in WO-A-2012/025224 which proposes a flow reactor having a planar process channel delimited by a bottom wall, a top wall and two side walls. The process channel is provided with an inlet to introduce a feed stream into the process channel and an outlet to discharge the product stream therefrom. Between the inlet and outlet, the process channel has a meander pattern, i.e. a serpentine flow reactor, which provides the necessary length of the process channel while limiting the external size of the flow reactor, which is especially beneficial for laboratory flow reactors in view of the limited available space in a laboratory. Furthermore, a plurality of static mixing elements are disposed within the process channel to locally split and recombine the fluid flow.

WO-A-2012/025224 further aims to improve the residence time distribution (RTD) of the fluid flowing through the process channel, i.e. the RTD is preferably as narrow as possible. The improvement of the RTD is achieved by reducing the dead volume of the process channel and this may be done in two ways.

In the first way disclosed in WO-A-2012/025224, the shape of the static mixing elements may be chosen to provide long laminar boundary layer flows, e.g. by using circular, elliptical or wing-shaped static mixing elements, which avoid a dead volume directly behind a static mixing element. However, this has the disadvantage that different fluids typically have a different viscosity which affects the extent of the laminar boundary layer flows generated by a specific shape of static mixing element. As such, when the flow reactor is used for different reactions, as is typically the case in a laboratory environment, the static mixing elements may need to be replaced with a different set to achieve the reduced dead volume, which is essential to control the RTD. As the mixing elements are an integral part of the flow reactor, such a replacement is not possible. Furthermore, it may even be that an entirely new shape needs to be designed for a specific fluid, which may require extensive modelling and/or simulations. Moreover, the laminar boundary layer flows provide less mixing of the fluid within the reactor.

In the second way disclosed in WO-A-2012/025224, high flow rates, i.e. a flow having a relatively high Reynolds number, may be used to create a turbulent flow which causes turbulence behind a static mixing element thus also avoiding a dead volume. Although an effective mixing can be achieved in this way, this has the disadvantage that the flow reactor needs to be sufficiently long for the fluid to have the desired residence time. Therefore, the serpentine reactors may be placed in series with the different plates of the reactor being stacked onto one another thereby creating the required length, but, as also disclosed in WO-A-2012/025224, the longer the process channel, the higher the pressure drop becomes, which is undesirable and in many cases exceed the pressure limit of the reactor or auxiliaries like pumps. Moreover, an already quite long laboratory reactor takes away the option of scaling-up by placing multiple reactors in series as the pressure drop cannot be controlled sufficiently to have a narrow RTD.

Another downside of the serpentine flow reactor disclosed in WO-A-2012/025224 is that the static mixing elements create very narrow fluid passages between them, typically having a dimension in the sub-millimetre range, i.e. the static mixing elements form micro-fluidic channels. Such small channels provide only a limited useable reactor volume (e.g. according to the disclosure in WO-A-2012/025224 the mixing elements take up between 40% and 60% of the total process channel volume) which naturally limits production capacity per channel. Moreover the channel volume per plate is then limited e.g. between 5 and 40% per plate. While WO-A-2012/025224 discloses that multiple serpentine flow reactors may be placed in parallel to scale-up the production capacity, the low volume of the micro-fluidic channels effectively reduces the production capacity by such an amount that the number of flow reactors needed for actual production becomes high, which leads to issues in process control, i.e. it becomes very difficult to monitor and control the process parameters in the various parallel flow reactors which may lead to quality differences between the product streams of the various parallel reactors.

It is also known in the art to provide flow reactors having a planar process channel which are totally transparent or have parts that are transparent. Transparency is typically desired for visual inspection and is required for photochemical reactions. For example, WO-A-2015/148279 discloses a transparent modular serpentine flow reactor having a central planar process fluid layer and two outer planar thermal control fluid layers. The process channel forms a microchannel which follows a meander pattern. Similar serpentine flow reactors are disclosed in US-A-2014/050630, DE-A-10209898 and US-A-2012/122224.

A downside of these flow reactors is that the small volume of the process channel is problematic for high-throughput. Moreover, the single microchannel that forms the process channel may easily get blocked due to clogging, which blockage may lead to a failure of the flow reactor. In addition, employing solids (e.g. catalysts, reagents, etc.) is difficult in single process channels in the sub-millimetre range.

Another disadvantage of the serpentine flow reactors is that the channel volume and thus also the surface per plate is limited to less than 50% and in many cases to less than 10%. Larger surfaces are especially important in the case of photochemical reactors since most photons are wasted on wall material instead of reaction fluids.

Another disadvantage of the serpentine flow reactors is that they cannot easily be scaled up by increasing the cross-sectional size of the process channel since such a scale-up generates a different hydrodynamic behavior, especially as a result of the curves. Specifically, due to the presence of curves, the cross-sectional size of the process channel can be increased by expanding the plate reactor in two dimensions, which automatically also increases the length of the process channel. As a result, in order to obtain the same residence time for the reaction, the flow rate has to be increased, thus affecting the hydrodynamic behavior of the flow.

In the art there have also been studies of other ways to influence the generation of turbulence in flow reactors. For example, the paper by A. P. Harvey, M. R. Mackley and P. Stonestreet titled “Operation and optimization of an oscillatory flow continuous reactor”, Ind. Eng. Chem. Res. 2001, 40, 5371-5377 discloses a tubular process channel with periodically spaced baffles, i.e. annular obstructions extending from the wall of the process channel inwards. A net flow is generated through the process channel in combination with an oscillatory flow, i.e. a pulsatile flow is generated. The oscillatory flow results in a turbulent flow even for a moderate speed net flow, i.e. a net Reynolds number of around 100 with an oscillatory Reynolds number of 100 to 1000. Consequently, long residence times are possible with a process channel having a reduced length-to-diameter ratio. EP-A-0540180, WO-A-2008/047166, WO-A-87/00079 and EP-A-0631809 each disclose a similar flow reactor having a tubular process channel with periodically spaced baffles.

However, as already described above, it is not easy to scale-up such a tubular process channel. In particular, increasing the diameter results in a deteriorated process control, while increasing the channel length also increases the pressure drop.

WO-A-2017/175207 discloses a plate reactor with a serpentine process channel having periodically baffled side walls. A pulsatile flow is generated to induce turbulence to improve the mixing of the fluid within the process channel.

Upscaling the flow reactor disclosed in WO-A-2017/175207 is not straightforward for several reasons. First, as described above, the serpentine layout of the process channel means that upscaling the reactor will increase its length. As such, in order to obtain the same residence time for the reaction, the flow rate has to be increased, thus affecting the hydrodynamic behavior of the flow. Second, varying the cross-section of the process channel (e.g. increasing the width) results, as for a tubular process channel, in a deteriorated process control. Moreover, varying the cross-section of the process channel may also lead to changes in the baffle shape and/or periodicity.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide a flow reactor having improved scalability.

This object is achieved according to the present invention with a flow reactor comprising: a substantially straight planar process channel having a longitudinal direction and being delimited by a bottom wall, a top wall, two side walls, a first end wall and, a second end wall which is opposite to said first end wall along said longitudinal direction, the process channel comprising at least one inlet at said first end wall configured to introduce at least one feed stream into said process channel and at least one outlet at said second end wall configured to discharge at least one product stream from said process channel; a flow generator configured to generate a pulsatile flow within said process channel, the pulsatile flow comprising a unidirectional net flow through said process channel along said longitudinal direction and an oscillatory flow superposed on said net flow; and a plurality of static mixing elements disposed within said process channel and configured to locally split and recombine said flow. The static mixing elements are in other words each configured to split the flow approaching the mixing element into at least two streams, one of which passes the mixing element along one side of the mixing element, in particular along the right side thereof, and the other one of which passes the mixing element along the opposite side of the mixing element, in particular along the left side thereof.

By providing a substantially straight planar process channel through which a net unidirectional flow can be generated from the inlet to the outlet, a flow pattern is generated that is largely independent of the width of the process channel. In other words, changing the width of the process channel has no significant influence on the flow pattern within the process channel in case the flow parameters of the pulsatile flow (e.g. the flow velocity and oscillation centre-to-peak amplitude) are kept constant. Consequently, process parameters and resulting reactor performance, such as the RTD, are largely unaffected when varying the width of process channel. As such, in order to scale-up the flow reactor, the width of the flow reactor can be enlarged, thus providing a larger volume and thus a larger throughput, i.e. an increase in production capacity, without significantly affecting process parameters such as the pressure drop and the flow behaviour and, as a consequence, the RTD, mass and/or heat transfer.

Furthermore, by creating a pulsatile flow, i.e. a resultant periodic flow of the superposition of a unidirectional net flow along said process channel and a periodic oscillatory flow, irrespective of the amplitude of the oscillatory flow, within the process channel, turbulence and/or chaotic fluid flows may be generated even at low net flow rates, i.e. low net Reynolds numbers, without requiring a large volume of static mixing elements, thereby losing a relatively large portion of the reactor volume, as in the serpentine flow reactor disclosed in WO-A-2012/025224. Therefore, the size and/or placement of the static mixing elements can be modified, without decreasing the needed turbulence, thus resulting in an increase in the maximal fluid volume within the process channel, thereby increasing the production capacity.

Moreover, the higher level of turbulence created by the oscillatory flow component also has advantages, such as an improvement in the RTD and the generation of a sufficient and/or increased mixing of the fluid within the process channel. The sufficient and/or increased mixing is advantageous in most reactions or unit operations and in particular for multiphasic reactions and/or photochemical processes. In case of multiphasic reactions the higher level of turbulence created by the oscillatory flow component creates remixing and constant redispersion of the immiscible phases thus creating larger surface areas that improve overall mass transfer.

While a pulsatile flow is known in the art as described above, such a flow is typically used for cylindrical process channels provided with baffles, i.e. local constrictions of the channel in the form of annular rings (orifices) such as disclosed in EP-A-0540180, WO-A-2008/047166, WO-A-87/00079 and EP-A-0631809. Also the reactor disclosed in WO-A-2017/175207 utilizes local constrictions applied to the side walls, i.e. no static mixing elements are used. Consequently, a person skilled in the art would not consider generating a pulsatile flow within the known planar serpentine flow reactor disclosed in WO-A-2012/025224 which is provided with static mixing elements to create the required turbulence.

In an embodiment of the present invention, said flow generator is configured to generate said pulsatile flow with a normalised oscillatory Reynolds number that is at least 5v, preferably at least 25v, more preferably at least 50v, advantageously at least 75v and most advantageously at least 100v, where v is the kinematic viscosity of the material in the process channel. Advantageously, said flow generator is configured to generate said pulsatile flow with a velocity ratio of at least 1, preferably at least 5, more preferably at least 10, advantageously at least 15 and more advantageously at least 20, where the velocity ratio is the ratio of the oscillatory Reynolds number to the net Reynolds number and is given by 2πfx0/u where u is the velocity of the net flow component, f is the frequency of the oscillatory flow component and x0is the centre-to-peak amplitude of the oscillatory flow component. Advantageously, said flow generator is configured to generate said pulsatile flow with a normalised net Reynolds number that is at most 200 v, preferably at most 100v, more preferably at most 50v, most preferably at most 20v, advantageously at most 10v, more advantageously at most 5v and most advantageously at most 0.5v, where v is the kinematic viscosity of the material in the process channel.

It has been found that a flow having such high normalised oscillatory Reynolds numbers (i.e. having an oscillatory Reynolds number that is at least 5 irrespective of the viscosity of the fluid within the process channel) is subject to turbulence and/or chaotic motions even for relatively low net flow rates. In other words, a sufficiently mixed flow can still be obtained even when the net flow rate as required by the RTD for a fixed reactor length is low (i.e. in case a relatively long residence time is required) as the oscillatory Reynolds number can be easily increased. Consequently, for processes requiring a large residence time, the reactor length can still be kept relatively short as low net flow rates are now feasible with sufficient mixing.

In an embodiment of the present invention, said mixing elements are further configured to generate vertical vortices within said flow.

Such vertical vortices further increase the turbulence and/or chaotic fluid behaviour, thereby improving various aspects, such as the mixing of the fluid, the RTD, mass and/or heat transfer and film renewal at the top wall.

In an embodiment of the present invention, said top wall comprises at least one transparent part, said transparent part being preferably manufactured from one of: laboratory glass (e.g. borosilicate, Pyrex®, Vycor®), fused silica, quartz and polymers, such as PMMA, COC, etc.

In this embodiment the flow reactor is also suitable for photochemistry, i.e. reactions that are triggered by irradiation (e.g. UV or visible light) as the necessary rays can now penetrate the top wall to irradiate the flow within the process channel. Furthermore, the transparency of the top wall allows for a visual inspection of the reaction and/or process within the process channel. Consequently, it can be visually observed whether there is adequate mixing in for example liquid-liquid reactions of immiscible fluids and/or other multiphasic reaction mixtures. Similarly, it can be visually checked whether precipitation occurs as desired (e.g. in crystallisations) or whether solid particles (e.g. heterogeneous catalysts) are smoothly transferred through the reactor channel. It is also possible to visually check for one or more areas within the process channel whether unexpected precipitation or clogging has occurred.

In a preferred embodiment of the present invention, a transparent protective cover is provided on the inside of said top wall, said protective cover protecting at least said transparent part, said protective cover comprising, in particular, a polyfluorinated material.

In this way at least the transparent parts are protected from potential chemical damage that may result from the process streams within the process channel. In addition, said transparent protective cover can act as a protective barrier that prevents leaching of any material into the reaction. The protective cover may be conveniently replaced when needed.

In a further preferred embodiment of the present invention, the flow reactor further comprises at least one irradiation source configured to irradiate the material inside the process channel through said transparent part, preferably at least one cooling means being provided configured to cool said irradiation source, preferably to cool the region between said irradiation source and said transparent part and more preferably to cool the transparent part.

By providing an irradiation source, the flow reactor becomes suitable for photochemical reactions that require non-visual radiation, e.g. UV radiation.

In an embodiment of the present invention, the reactor further comprises a heat exchanger in thermal connection with said process channel.

The heat exchanger provides the capability of controlling the temperature within the process channel by heating or cooling. This is advantageous as it enables to set the temperature within the process channel depending on the process.

In a preferred embodiment of the present invention, said bottom wall and/or said mixing elements are manufactured from laboratory glass, polymers, ceramic or metal.

In a more preferred embodiment of the present invention said bottom wall is manufactured from a thermally conductive material having, in particular, a thermal conductivity of at least 5 W/mK, the bottom wall being part of said heat exchanger, preferably said mixing elements being part of said heat exchanger and being manufactured from a thermally conductive material having, in particular, a thermal conductivity of at least 5 W/mK, more preferably said bottom wall and mixing elements are integrally formed.

By using the mixing elements as a part of the heat exchanger, the surface to volume ratio (i.e. the ratio of the contact surface area between the heat exchanger and the material within the process channel to the volume of the fluid within the process channel) is increased which allows for an improved heat transfer between the fluid within the process channel and the heat exchanger.

In an embodiment of the present invention, at least one of said side walls comprises a plurality of deflector elements configured to locally deflect said flow.

The provision of deflector elements, such as baffles, avoids that a laminar flow would occur near the side walls, which laminar flow is undesirable as it leads to parts of the flow that are not sufficiently mixed and/or have a different residence time.

In an embodiment of the present invention, at least said top wall of the process channel is removably attached to the side walls and the end walls of the process channel, at least one sealing member preferably being provided between said top wall on the one hand and said side walls, said first end wall and said second end wall on the other hand.

By having a removable top wall, the internal volume of the process channel may be easily cleaned and/or parts replaced.

In an embodiment of the present invention, one or more of said top wall, said bottom wall, said side walls, said first end wall, said second end wall and said mixing elements are provided with a coating.

Such a coating may be used for a variety of reasons, such as an additional protective layer (for use in aggressive or corrosive media), catalytic properties (for catalytic solid-liquid reactions), improvement of the flow properties by changing surface tension, and/or surface area and/or surface roughness, and/or different reflection properties.

In an embodiment of the present invention, said mixing elements are formed by at least one removable inlay disposed within the process channel.

A separate inlay has the benefit that the same process channel can be used with a variety of inlays having differently shaped mixing elements and/or being manufactured from different materials and/or being conveniently coated with different coatings as described above. Moreover, inlays are a convenient way to modify the flow behaviour within the process channel. Furthermore, in case the mixing elements are damaged (e.g. due to abrasion) the inlay can be easily replaced.

In an embodiment of the present invention, said process channel is provided with at least one further inlet connected to a gas chamber, said at least one further inlet comprising a semipermeable membrane, the semipermeable membrane preferably forming the top wall of said process channel.

In this embodiment, the flow reactor is especially suited for gas-liquid reactions. Specifically, as the top wall is preferably formed by the semipermeable membrane, which corresponds to the gas inlet, the gas from the gas chamber is fed into the process channel over a large surface area which aids in controlling the dosage based on the applied pressure and the properties of the semipermeable membrane (e.g. the thickness, composition, porosity etc.). Furthermore, the pulsatile flow ensures a sufficient fluid renewal near the top wall thereby alleviating saturation effects of the fluid near the top thus increasing the gas absorption efficiency.

In this embodiment, the flow reactor is particular suited for removal of gas from the reaction medium. Therefore, the described gas chamber needs to be under reduced pressure compared to the reactor chamber.

In an embodiment of the present invention, said process channel can be fed with a multiphasic mixtures including partially miscible gases (e.g. gas-liquid or gas-liquid-solid mixtures). In this case the reactor can be tilted and thus the undissolved gas will progress upwards. This can improve gas hold-up depending on the angle of tilting. The oscillatory motion can improve the specific interfacial area by the reduction of mean bubble diameter of the gas bubbles.

It is a further object of the present invention to provide a method for producing a product stream having improved scalability.

This object is achieved according to the present invention with a method comprising: providing a flow reactor as described above; continuously introducing a feed stream into the flow reactor; generating a pulsating flow within said process channel; and removing a product stream from said flow reactor.

This object is also achieved by using a flow reactor as described above to produce a product stream.

By using the flow reactor as described above to produce the product stream, the improved scalability of the flow reactor naturally results in a production method having an improved scalability.

