Continuous chemical processing apparatus and method

Abstract

An apparatus for carrying out continuous precipitation or chemical reaction involving solids is provided. The apparatus includes a plurality of serially connected chambers. One or more of the chambers includes a volume reducer for decreasing and increasing the volume of a chamber to produce a pulse of fluid to downstream chambers.

Description

ZFT00005WQU1CONTINUOUS CHEMICAL PROCESSING APPARATUS AND METHODTECHNICAL FIELD

[0001] The present disclosure generally relates to precipitation of compounds from a fluid and continuous chemical reactions involving solids. Specifically, the present disclosure is directed to temperature control of zones in an apparatus for performing continuous precipitation as well as continuous chemical reactions.BACKGROUND

[0002] Precipitation of solutes from solution has been used to produce and purify both organic and inorganic compounds. Precipitation or specifically crystallization can be done using continuous or batch methods, and both techniques have been used in the pharmaceutical industry. Temperature profiles of purification devices can be selected by controlling the heat flux between chambers of the device.SUMMARY

[0003] In one aspect, a continuous chemical processing apparatus is provided, the apparatus including a housing defining a linear plurality of chambers in fluid communication with each other, a fluid transfer region in the housing, the fluid transfer region connecting adjacent chambers and providing a pathway for fluid transfer from a first chamber to an adjacent second chamber, and a cavity in the fluid transfer region of the housing, the cavity isolated from the pathway for fluid transfer, wherein a cross-section of the housing across the transfer region includes less area than does a cross-section of the housing across a midpoint of an adjacent chamber. In some cases, the fluid transfer region defines a channel connecting adjacent chambers and / or the fluid transfer chamber comprises an intersection of two adjacent chambers. In the apparatus, heat can be transferred more efficiently through a housing section including the chambers than through a housing section including the transfer region. In some cases, the cross-sectional area across the transfer region is less than half the cross-sectional area across the adjacent chamber. The apparatus can include a plurality of agitators, each of the plurality of agitators disposed in one of the plurality of chambers. The plurality of chambers can include a volume modulator wherein the volume modulator is configured and arranged to change theZFT00005WQU1volume of the chamber. The apparatus can include at least 3 chambers, at least 5 chambers, at least 10 chambers or at least 20 chambers, and one or more of the chambers can be substantially spherical. The serial chambers of the apparatus can be fluidly connected by a passageway connecting one chamber to a next chamber or via direct overlap of the chambers. The volume of at least one of the chambers, or each of the chambers, can be less than 100 L, less than 10 L, less than 1 L, less than 500 mL, less than 250 mL, less than 100 mL, less than 50 mL, less than 25 mL, greater than 1 mL, greater than 5 mL, greater than 10 mL, greater than 50 mL, greater than 100 mL, greater than 500 mL, greater than 1 L, greater than 5 L or greater than 10 L. The apparatus can include a volume modulator configured and arranged to change either the first volume, the second volume, or both, and a volume modulator can change a first volume or a second volume in a first chamber, a final chamber or an intermediate chamber. The apparatus can include a heat exchanger in thermal communication with one or more chambers. The apparatus can be a unitary device that is fashioned from a monolith.

[0004] In another aspect, a method of segmenting temperature in at least n chambers of a chemical processor having a plurality of serially connected chambers in fluid communication with each other is provided. The method includes heating or cooling a first end of the chemical processor to provide a temperature differential T between the first end and a second end of the chemical processor, T being greater than 5°C, and flowing a fluid from the first end to the second end through the plurality of connected chambers, the connected chambers being physically and fluidly connected by a series of fluid transfer regions, wherein the temperature difference at steady state between an nth chamber and an (n+1)th chamber is T / n + / - 5%, + / -10%, or + / - 20%. The method can include examples wherein n is at least 5. The method can use a processor wherein there are no heaters or coolers acting between the first and second ends. The cross-sectional area of the fluid transfer region of the device being used can be less than ½ the cross-sectional area of a chamber. The heat flux through a transfer region can be less than ½ the heat flux through a chamber. The transfer regions can be made of the same material as the chambers. The method can flow fluid at a rate equal to or greater than 0.05 chamber volumes per minute. Adjacent chambers can be separated by less than ’A of the chamber length. The chambers can be essentially spherical, and the volume of at least one of the plurality of chambers can be modulated.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] FIG. 1 is a schematic diagram of an embodiment of a continuous precipitation apparatus;ZFT00005WQU1

[0006] FIG. 2 is a schematic diagram of a second embodiment of a continuous precipitation apparatus;

[0007] FIG. 3 is a schematic diagram of a third embodiment of a continuous precipitation apparatus; and

[0008] FIG. 4 is a flow chart illustrating one embodiment of a process for continuous precipitation.

[0009] FIG. 5 is a diagram illustrating the dimensions of a cavity in one embodiment;

[0010] FIG. 6 is a thermal image of a simulation of temperature distribution;

[0011] FIG. 7 is a thermal image showing temperature distribution of another embodiment;

[0012] FIG. 8 is a thermal image showing temperature distribution of another embodiment;

[0013] FIG. 9 is view of one embodiment of a chemical processing apparatus;

[0014] FIGS. 10 A- 10C provide thermal images of a simulated experiment;

[0015] FIGS. 11A-11C provide thermal images of another simulated experiment;

[0016] FIGS. 12A-12C provide thermal images of a simulated experiment on a device with no material removed;

[0017] FIG. 13 provides a graph indicating the temperature in each chamber of a multi-chamber apparatus;

[0018] FIG. 14 provides a graph showing chamber temperatures at different bottom temperatures;

[0019] FIG. 15 provides a graph showing temperatures in various chambers with water flowing through the apparatus;

[0020] FIG. 16 provides a graph showing temperatures in various chambers at different flow rates;

[0021] FIG. 17A provides a cross-sectional view of a device having several different types of cavities;

[0022] FIGS. 17B-17D illustrate the cross-sectional structure at three points taken from FIG. 17A.

[0023] FIGS. 18A-18D provide various temperature profiles that are available with different embodiments.

[0024] The figures depict various embodiments of the present disclosure for purposes of illustration only. Numerous variations, configurations, and other embodiments will be apparent from the following detailed discussion.ZFT00005WQU1DETAILED DESCRIPTION

[0025] In one aspect, a continuous crystallizer is disclosed that can be scaled up to production size or down to laboratory scale and can maximize retention time while maintaining a high level of crystal purity. The continuous crystallizer can be used in a number of industries including pharmaceuticals, fine and specialty chemicals, natural products, biologies, food and beverage and chemical synthesis and purification. The system can be used with different fluids including liquids, solutions and mixtures.

[0026] In one set of embodiments, the device can include a set of linked chambers that are in serial fluid communication. The chambers can be of a same or similar shape and volume and can have an absence of comers. For instance, the chambers can be spherical, or egg shaped. One or more chambers can be of variable volume. For example, a chamber can include a movable surface such as a diaphragm or a piston that can be activated to move inwardly and thereby reduce the volume of the chamber. This reduction in volume can cause a sudden increase in flow (pulse) from the chamber to a second (and third and fourth and more) chamber that is in fluid communication with the first chamber. An absence of headspace in the chamber(s) dictates that a decrease in volume results in an instantaneous outflow of fluid, such as water. This pulse of liquid and suspended solids can help transport solution and precipitate to the next chamber without clogging. After the pulse of flow, the diaphragm or piston can be retracted, resulting in an increase in volume of the chamber, typically back to its original volume. The increase in volume of the chamber can be made up by solution or other liquid that is fed to the first chamber through an orifice, passageway or valve.

[0027] In other embodiments, the device is used to carry out a chemical reaction that produces solids or that needs a solid reagent. The controlled reduction of volume in the first chamber allows for movement of the slurry within the device. Reagents can be mixed in the first chamber, or in one or more of the other chambers.

[0028] In other embodiments, the device can be constructed and arranged to deliver a favorable temperature gradient to the chambers of the device. The temperature gradient within the chambers can be smaller while the temperature gradients between chambers is larger. One embodiment to provide this improved temperature distribution is to reduce the amount of mass between the various chambers. By reducing the amount of material that connects the chambers, the heat flux through the connecting section is reduced, and the temperature of the chambers themselvesZFT00005WQU1become more consistent throughout each individual chamber. In addition, the temperature gradient between multiple chambers can be linear without the need for heating or cooling other than at the ends of the device. Other non-linear temperature gradients can also be formed by varying the amount of material between chambers. The amount of material between chambers can be the same or can be varied throughout the apparatus. By controlling heat conduction by limiting the mass of material between chambers, the device can achieve a stepwise temperature gradient using a single heater or cooler, positioned at one end of the apparatus, or can employ a heater at one end and a cooler at the opposed end.

[0029] “Precipitation,” as used herein, includes initial formation and / or growth of a solid material. Precipitation can be “seeded” (where there is initially a solid present, and that solid grows via subsequent deposition of solid material on the initial material to form a larger solid material) or “unseeded” (where there is initially no solid present, but solid forms from solubilized or otherwise non-solid components of an initial solution or other precursor-containing liquid). “Crystallization” is a subset of precipitation that involves the initial formation and / or growth of crystalline solid material. Crystallization can be seeded or unseeded. Crystallization can result in the formation of a polycrystalline material or single crystalline particles. In some cases, both crystalline and amorphous material can be formed.

[0030] Continuous precipitation processes differ from batch precipitation. In continuous precipitation a solution of the product to be precipitated is fed into the system, while concurrently precipitate, such as crystals, is removed from the system such that the total volume of the liquid being processed is essentially constant. For instance, during continuous precipitation, the volume of the system may vary by less than 1%, less than 5%, less than 10%, less than 20% or less than 30% during the process. In batch crystallization the inflows and outflows are not concurrent. Continuous processes can avoid batch-to-batch variability but typically produce lower yields than do batch processes. The quality of the precipitate, e.g., a crystallized material, is evaluated by measuring a number of features including, for example, purity, particle size, morphology, polymorphism, optical density, chirality and yield. Continuous tubular crystallizers can be categorized as plug flow, segment flow, or oscillatory baffled crystallizers. Segment flow and plug flow have not been shown to work well on a smaller laboratory scale (e.g., less than IL). Oscillation techniques can theoretically work on a laboratory scale, but, to date, oscillation techniques and apparatuses have been unsuccessful at achieving consistent laboratory scale practice. The apparatuses and techniques described herein provide scalable methods for efficientZFT00005WQU1crystallization that can improve, for example, yield, purity, particle size and morphology when compared to these known techniques.OVERVIEW

[0031] A schematic diagram of one embodiment of a continuous precipitation apparatus 100 is illustrated in FIG. 1. The figure includes a housing 102 that defines spherical chambers 110, 120, 130 and 140. Also shown are inlets 114 and 124, 134, 144 as well as outlet 170. Piston 180 is slidably movable and its movement into and out of the chamber can decrease and increase the volume of first chamber 110. Agitators, in this case impellers 112, 122, 132 and 142, are disposed in chambers 110, 120, 130 and 140 respectively. The impellers may be driven individually and can be driven by common driveshaft 160. As shown, fluid can pass upwardly from chamber 110 to 120 to 130 to 140. As shown, the chambers are in direct fluid communication with each other and do not require optional transfer tubes in order to move material from one chamber to the next.

[0032] Housing 102 can be made from any material capable of containing the chambers and supporting the impellers, pumps, pistons and other ancillary parts. It can be any shape that supports the chambers and as shown in FIG. 1 can be cylindrical. The material can be corrosion resistant and should be free of substances that can contaminate the solution that flows through the chambers. Appropriate materials include metals, alloys, ceramics, glass, polymers and reinforced polymers. Specific examples include stainless steel, steel alloys, Hastelloy, aluminum, titanium, PTFE, ETFE, PVDF, PP, PEEK, FEP, PF A, glass reinforced polymers, glass and ceramics. The housing can be molded or can be machined from a block of material. In some embodiments it can be 3D printed. The chambers may be molded or machined into the material and may include surface treatments such as anodization, electrodeposition, electropolishing, painting and coating with specialty materials or polymers.

[0033] Housing 102 can include any number of chambers such as 110, 120, 130 and 140. The chambers may be linearly arranged and can be similarly or identically sized to promote consistent residence time in each. Linearly arranged means that the output from one chamber leads to an input of a second chamber, the output from the second chamber leads to an input of a third chamber and continues in this manner until the nthchamber. Chamber size can be varied when, for instance, residence time should be varied. As the number of chambers increases, the residence time distribution (RTD) becomes tighter. In various embodiments, the apparatus can include greater than 2, greater than 3, greater than 5, greater than 10, greater than 15, greater than 20 or greaterZFT00005WQU1than 25 chambers. Chambers can be arranged vertically, as shown in FIG. 1, can be arranged horizontally as shown in the embodiment of FIG. 2, or can be arranged in a combination of vertical and horizontal, an embodiment of which is illustrated in FIG.3. In some cases, all chambers are arranged horizontally. In other cases all chambers are arranged vertically. In one embodiment the chambers are individual modules and can be joined vertically or horizontally in different arrays like building blocks. In some embodiments, adjacent chambers are in fluid communication with each other, and there is zero distance between adjacent chambers. This geometry can provide for the elimination of transfer tubes, passageways or channels that can clog or retard the flow of crystals or other precipitate from one chamber to the next. During operation, chambers may include little or no headspace. In some cases, all chambers, except optionally the final dispensing chamber, may be void of headspace, and there may be no headspace during operation from the entrance point of the solution up to the final chamber (crystal exit).

[0034] Housing 102 can include observation window 172 in or adjacent to one, two or more of the chambers. To improve observation, a light can be positioned to illuminate at least a portion of the chamber, for example, opposite the observation window. In addition, one or more of the chambers can include sensors to provide real time analysis of the process. Parameters that can be measured before, during and / or after precipitation or reaction include, for example, flow, temperature, pressure, turbidity, particle count and particle size. To enable real time monitoring of the process, one or more chambers may include lights, lasers, optical sensors, thermometers, pressure sensors, flow meters, particle counters, PAT probes, particle size analyzers and turbidity sensors.

[0035] In some embodiments, the housing can include a liner that provides a barrier between the wall of one or more chambers and the inner space of the chamber where fluid is processed. Liners can be individual liners that are placed in each chamber separately or can be a single liner that lines multiple chambers. In some cases, the liner can act as a diaphragm or bladder and be used to modulate the volume of the chamber. The liner can be of inert material that prevents the solution from contacting the inner surface of the chamber and / or reacting with the liner material. This can provide a sterile, clean, inert surface that can contact compounds such as pharmaceuticals that may be subject to stringent manufacturing requirements. A liner also allows for a quick change between different precipitation runs without the need for cleaning or sterilizing the apparatus. Different liner materials can also exhibit various surface energies and hydrophobicity / hydrophilicity that may be less likely to retain crystals when compared to the metallic surface of a chamber. In someZFT00005WQU1cases, liners are flexible and resilient enough that they can withstand repeated flexing from a piston, diaphragm, air pressure, or other volume modulator. The composition of a liner can be tailored for the specific precipitation that is being run. Liners can be, for example, molded, extruded, stamped or die pressed. Appropriate liner materials include flexible materials such as polymer films and injection molded polymers. Examples of specific materials include inert polymers such as PTFE, PPS, PEEK, FEP, PF A, ETFE, POM, EPDM, FKM and FFKM and combinations of these and other polymers.

[0036] The individual chambers can be shaped to avoid geometries that might retain crystals / solids or interfere with mixing. For instance, the chambers may include few corners, for example, fewer than eight, fewer than four, fewer than two, or zero. The chambers may also be void of planar walls and may comprise one continuous rounded wall. The wall can include orifices for various inputs and outputs. In various embodiments, one or more of the chambers can be spheroidal, ovoidal and / or ellipsoidal. The chambers can be similarly or identically sized in order to result in similar or identical retention times. The chamber volume is determined in part by the amount of solution that is being processed. In general, production processes will utilize larger chambers than do laboratory scale processes. In various embodiments, the volume of one or more chambers can be less than 1 L, less than 500 mL, less than 250 mL, less than 100 mL, less than 50 mL, greater than 10 mL, greater than 20 mL, greater than 50 mL, greater than 100 mL, greater than 500 mL, greater than 1 L, greater than 5 L or greater than 50 liters. The overall volume of the apparatus, totaling the plurality of chambers, can be less than 5 L, less than 2 L, less than 1 L, less than 500 mL or less than 250 mL. In other cases the total volume is greater than 250 mL, greater than 500 mL, greater than 1 L, greater than 5 L or greater than 50 liters.

[0037] In some embodiments chambers can be equipped with structures to promote mixing (turbulence) in the chamber. The structures include baffles that can be, for example, molded or attached to the chamber walls, molded or attached to the liner walls, or attached to a mixing shaft. These mixing structures can be permanent or can be removable from the chambers and can be single use. Baffles may be comprised of inert materials such as metal or polymer. An example of a baffle is a perfluoropolymer sheet including passageways defined therein. The sheet can be mounted, for example, between the two halves of a housing.

[0038] A chamber may be in fluid communication with a chamber upstream, a chamber downstream or both. The fluid communication can be achieved by direct overlap of the chambers as shown in FIG. 1 or by using connectors such as tubing or channels molded or machined intoZFT00005WQU1the apparatus. The fluid communication connectors may be tubes, connectors or channels within the housing that allow fluid communication between chambers. The pathways can include a check valve. In various embodiments, the volume of these pathways may be less than 50 mL, less than 10 mL, less than 5 mL or less than 1 mL. In some embodiments, channels or connectors can be dimensioned to avoid clogging. For example, a channel or connector may have a length of less than 1, less than 1 / 4, less than 1 / 4 or less than 1 / 10 of the mean diameter of the chamber. In some embodiments the channel is inflexible and is not comprised of tubing or other flexible material. Connecting channels can be wide enough that they do not contribute significant back pressure when the upstream solution is pulsed through a chain of chambers.

[0039] One or more of the chambers can be in fluid communication with a volume modulator that can be activated to provide a reduction in chamber volume resulting in a pulse of fluid and crystals that travels downstream through the crystallizing apparatus from chamber to chamber. It can also be retracted to return the chamber to its original volume. The volume modulator can comprise a movable surface that can expand into and retract out of a chamber to alter the volume of the chamber. The volume modulator can comprise, for example, a piston, an inflatable bladder, a diaphragm, a solenoid, a roller or pressurized fluid (e.g., behind a liner). The volume modulator can be controlled by a microprocessor that can be programmed to vary the action of the volume modulator. The parameters that can be controlled include, for example, the amount of volume reduction, the rate of volume reduction, the wait time before retraction of the modulator (increase in volume), the rate of retraction and the amount of retraction. The volume modulator can reduce and / or increase the volume of a chamber by, for instance, greater than 1 %, greater than 2%, greater than 5%, greater than 10%, greater than 20% or greater than 30% of the original volume of the chamber. The volume reduction or increase can occur over a time period of from 0.1 s to 10 s, greater than 0.1 s, greater than 10 s, greater than 30 s, less than 60 s, less than 30 s or less than 10 s. The rate of reduction or increase can also vary during a single stroke. For instance, the initial stroke may start slowly, for example, 1 mL / s and may be ramped up by the end of the stroke to 10 mL / s. Alternatively, the stroke could start quickly and taper off at the end. The volume of fluid that is moved by the action of the volume modulator, in absolute amounts, can be, for example, greater than 1 mL, greater than 5 mL, greater than 10 mL or greater than 50 mL. In other embodiments the volume of a single stroke can be, for example, less than 1 L, less than 500 mL, less than 100 mL, less than 50 mL or less than 10 mL. The rate of flow from one chamber to the next, as a result of movement of the volume modulator can be greater than 1 mL / s, greater than 2ZFT00005WQU1mL / s, greater than 5 mL / s, greater than 10 mL / s, less than 50 mL / s, less than 10 mL / s or less than 1 mL / s.

[0040] In some embodiments, the apparatus can include means for preventing or reducing backflow from a downstream chamber back to an upstream chamber. These means for preventing backflow can ensure that flow between chambers occurs only in one direction. These means for preventing backflow can include check valves such as gates, valves, constrictors. Means for preventing backflow can assure that both liquid and solids travel in the direction intended thus eliminating back mixing and improving plug flow characteristics. Such a check valve can be achieved in different ways. A passive check valve is one that reacts passively to a change in flow direction. An active check valve is one that is activated externally, such as by a microprocessor or a mechanical interface. In one embodiment, a disk of flexible plastic is mounted on the shaft of the impellers. The disk has diameter larger that the diameter of the gap between the chambers and rests on the surface of the downstream chamber. Upon generation of the volume change responsible for the forward movement of the slurry, the disk is flexed or lifted upward opposing minimal or zero resistance to flow. Once the pulse is over, the disk provides a stop to flow that would like to return back, due to gravity for example, because of its contact with the chamber and a fluid-tight seal between the disk and the shaft. Disks can be anchored or slidably anchored to the shaft with simple restraining devices such as rings connected to the shaft. In such a way the disk cannot slide over the shaft, can only flap up and down to provide flow passage or to prevent it. In another embodiment, a disk or cone or other valving structure is attached to the mixing rod and the entire mixing rod can shift to either open or close the passageways between chambers. Other means to provide flow in a single direction can be arranged such as rigid elements that can slide in a controlled way onto the shaft. Unidirectional flow can be achieved also with elastomeric check valves, and these may or may not be mounted on a shaft. As an example, elastomeric check valves can be used in a device that does not have a shaft because mixing is achieved by a means that does not rely on rotating elements.

[0041] FIG. 1 illustrates a piston 180 as an example of a volume modulator. Piston 180 can move laterally to decrease or increase the volume of chamber 110. Similarly, piston 182 can be moved to decrease and increase the volume of terminal chamber 140. Activation of piston 180 results in a pulse of liquid and solids / crystals moving upwardly (as shown) through chambers 120, 130 and 140. As piston 180 is retracted, solution, e.g., supersaturated solution or reagent, can be fed through port 114 to make up the increasing volume that results from the retraction of piston 180.In this manner, back flow through the system can be avoided. Activation of piston 182 results in a pulse of fluid that includes solids / crystals through outlet 170, at which point solids / crystals can be collected. An absence of headspace in chambers 110, 120, 130 and optionally 140 means that any decrease in volume only pushes fluid up and out of the chamber 140. Piston 180 can include a cutaway portion to allow for impeller clearance when the piston is moved into the chamber.

[0042] Chambers may be equipped with one or more ports that provide fluid communication with solution, antisolvent, solvents or reagents for example. Antisolvents are one or more fluids that promote precipitation due to very low solubility of the target compound in the fluid. The antisolvent is generally miscible in the solution, but the target compound is only sparingly soluble in the antisolvent. Each chamber can be associated with zero, one, two, three or more ports. Ports may be dedicated to one type of fluid or may be used for two or more different fluids. For example, port 114 can be used to feed either solution or antisolvent to chamber 110 while port 124 can be used exclusively for solution and port 126 is used exclusively for antisolvent. Ports 114, 124, 134, 144 and 126 may include valves and can be in fluid communication with a solution or antisolvent reservoir. Fluid ports may be controlled and plumbed individually or can be plumbed in parallel with a solution source, an antisolvent source or an additive source. Fluid ports may include oneway valves to preclude backflow during an increase in pressure, such as during a pulse.

[0043] In some precipitation procedures, and in particular in crystallization procedures, a solution reaches supersaturation prior to crystallization of product. In a linear system, this supersaturation can be achieved in a first chamber, a final chamber or in any chamber or chambers within the linear chain. For example, supersaturation can be achieved by cooling an nthchamber(s) or by injecting antisolvent into an nthchamber(s). In other embodiments, components either in solutions, suspensions, or mixtures are reacted to produce a product that is not soluble and therefore precipitates (in some cases crystallizes) as a result of the reaction. This precipitation or crystallization can be independent of changing parameters such as temperature or antisolvent addition.

[0044] In many embodiments, temperature control of one or more chambers can promote precipitation or reaction. For instance, one, two, three or more of the chambers can include cooling. In other embodiments, the entire apparatus can be cooled or heated. Temperature regulation can be implemented through the use of coolant pathways that pass in proximity to the chamber being regulated. For example, a passageway can surround a chamber, and as shown in FIG. 1 at 184a, 184b, 184c and 184d, a passageway can spiral around a chamber to provideefficient temperature regulation. In the embodiment shown, the passageway is not in fluid communication with the chamber and heat transfer occurs between passageway 184 and chamber 120 through a portion of the housing material 102. The apparatus can have an external heating or cooling source that can provide heated or cooled fluid to passageway 184. A temperature sensor in the chamber can provide constant temperature readings to assure real time control of the temperature. Temperature can be raised or lowered to a fixed level or can be ramped up or down as the precipitation process progresses. In other embodiments, cooling or heating can be provided by the introduction of cooled or heated solution or antisolvent directly to one or more chambers. Temperature can be different in each of the chambers to achieve temperature gradients beneficial to the precipitation. For example, multiple chambers with plug flow characteristics allow for tighter residence time distribution which reduces the variability in the crystal size and shape.PROCESS

[0045] FIG. 4 provides a flow chart illustrating one embodiment of a process for continuous precipitation. The actions described may be optional, duplicated or performed in a different order in other embodiments. The apparatus of FIG. 1 can be referred to in reference to the following process embodiment.

[0046] To prepare the apparatus of FIG. 1, housing 102 is assembled by placing complementary halves together and bolting them closed to provide a fluid-tight seal. Feed lines and cooling lines are attached, and any mechanical connections, such as impeller drives, are made. If one or more liners are to be used, the liners can be installed prior to closing and sealing the apparatus.

[0047] The first chamber 110 is evacuated of air by filling it with solution via port 114. The solution can be, for example, a supersaturated solution of the compound to be crystallized. After chamber 110 has been filled, the solution continues to fill subsequent chambers 120, 130 and 140. In some cases, there can be a time delay in filling subsequent chambers so that, for example, the solution experiences a specific residence time in each chamber before advancing to the subsequent chamber.

[0048] Process promoters such as agitation, antisolvent addition and temperature control (cooling) may be initiated at any time during the process. For instance, impellers can be operated throughout the entire process. Antisolvent addition can take place, for instance, intermittently in one or more chambers, continuously in one or more chambers, or at different times and rates by specific chamber.

[0049] Agitation can be used to promote mixing and turbulent flow for improved precipitation. Agitators include, for example, mixers, impellers, blenders, fluid jets and stirring bars. Although the apparatus can also be shaken or vibrated, the absence of headspace and a gas phase in a chamber makes mixing through shaking less effective than direct mechanical agitation. Agitators can be controlled independently or in unison and can be adjusted during precipitation. Similarly, any baffles that may be used can be controlled or positioned independently.

[0050] Antisolvent addition can take place in one or more chambers or can be mixed with the solution prior to entry into the first or any other chamber. Antisolvent ports can be plumbed to sources of antisolvent, and the antisolvent can be fed via a pump that is controlled by a microprocessor. Antisolvent flow can be initiated, increased, decreased or ceased depending on instructions from the microprocessor. The microprocessor can monitor various parameters of the solution being crystallized. For example, temperature, turbidity, particle count, flow rates and particle size can be monitored, and the flow of antisolvent can be adjusted in response to, or in anticipation of, changes to one or more of these parameters.

[0051] As shown in FIG. 1, individual chambers can be temperature controlled so that the chambers cool or heat the contained solution to above or below ambient temperature. For example, the solution in one or more chambers can be cooled to more than 5, more than 10, more than 15 or more than 20 degrees C below ambient. In other embodiments, the solution can be heated to more than 5, more than 10, more than 15 or more than 20 degrees C above ambient. In addition to cooling the chamber housing, the solution itself can be chilled or heated prior to feeding to a specific chamber. Antisolvent can also be heated or cooled prior to being fed into one or more chambers.

[0052] To pulse the solution and entrained crystals to a downstream chamber, volume modulator 180 can be actuated. As shown in the embodiment of FIG. 1, the volume modulator is a piston that can be controlled manually or by a microprocessor. When the piston is moved to the right (as shown in FIG. 1) the volume of chamber 110 is reduced and that amount of volume reduction causes an equal volume of solution to be pulsed to the next chamber. The same amount of fluid is pulsed from the second to the third, the third to the fourth, etc., and, if the apparatus is at capacity, an equivalent volume of solution and crystals is dispensed from the final chamber. This pulse of fluid through the system can provide for movement of crystals that would not occur with a constant flow rate through the system. The pulse can also promote turbulent flow, prevent settling of crystals, and remove crystals that may otherwise adhere to the wall of the chamber. As the pistonis retracted, the increase in volume can be made up by the flow of solution through port 114. Unlike piston 180, piston 182 does not induce a pulse throughout the apparatus but only pulses fluid out of terminal chamber in which it is in mechanical communication. This terminal chamber pulse can push solution and crystals through outlet 170 but has little or no effect on the upstream flow that is feeding the terminal chamber because of the lack of headspace in the upstream chambers. As piston 182 is retracted, a headspace can develop or enlarge in the terminal chamber, or the volume can be filled by the feed from the upstream chamber. In cases where a check valve is employed, the volume is filled from the upstream chamber.

[0053] After crystals have been delivered via outlet 170, the crystals can be isolated, washed and further treated if desired. Crystal isolation can be, for example, via filtration, centrifugation or solvent evaporation. Washing of crystals can be performed using methods known to those of skill in the art.TEMPERATURE CONTROL

[0054] The devices described herein can provide a piecewise linear temperature gradient across the crystallization device. In one aspect the solid cross section of the device (across the direction of the gradient) is changed in order to control heat flux between different portions of the device. This provides a precise, linear temperature gradient across the device without a need to control temperature anywhere except at the extremities of the device.

[0055] With this advanced and careful temperature control, the device can be used to perform chemical processes such as cooling crystallizations — where a hot, supersaturated solution is progressively cooled, decreasing the solubility of the solute and inducing crystallization — without needing to control the temperature of each crystallization chamber with its own heat exchanger. By setting the temperature of the extremities of the device to an equal value, a constant and uniform temperature profile can be obtained.

[0056] By removing material in the cross section (transfer section) between the crystallization chambers, a choking effect with regards to heat transfer is effected and results in larger temperature gradients between chambers compared to across a given chamber.

[0057] This effect is confirmed when approximating the heat transfer in the choked and nonchoked regions by using Fourier’s Law for ID heat transfer in a 2D body as described below, and in reference to FIG. 5.

[0058] q = -k^

[0059] Q = f q dw = ~k^-w

[0060] By the conservation of energy assuming all walls are adiabatic,

[0061] X1T — T

[0062] Q2= -k^^w2x2

[0063] Q3x2

[0064] Q = Q2+ Q3

[0065] For a centered cut so that

[0066] w2— w3,

[0067] then

[0068] Q2= Q3

[0069] and therefore

[0070] Q = 2Q2

[0071] —kTA T1w1— —2kT1 T2W2.X1x2

[0072] Let

[0073] a = —,13W2x2

[0074] then

[0075] 7^ - ^ = ^(T1- T2),

[0076] and

[0077] T2= -T^

[0078] by symmetry.

[0079] Solving for T±yieldsTA+—T2

[0080] 7\ = -1+—a

[0081] By minimizing the ratio

[0082]

[0083] by maximizing the ratio between wrand w2and / or minimizing the ratio between x and x2, the following temperature difference inequality

[0084] TA- Ti < Ti - T2

[0085] will hold true, resulting in a larger temperature drop between crystallization chambers than across a given chamber.

[0086]

[0087] Experimental Results: Simulation 1: Taking these considerations into account, initial simulations were run on a pseudo 2-chamber system without considering the void volume of the crystallization chambers. The temperature of the top surface (TA) was held constant at 25°C, the temperature of the bottom surface (TB) was held constant at 15°C. All walls were considered to be adiabatic, and the height of the gap was equal to the height of the solid material — equal to half the height of an entire crystallization chamber. A thermal image is provided in FIG. 6. These results confirmed that the temperature difference between the middle of a chamber and the height where the cutout (cavity) begins (TA—was less than the temperature difference between the height where the cutout begins and the middle of the gap T1— T2'). Next, the effect of widening the gap (increasing a) and shortening the gap (increasing ft) \rac investigated. FIG. 7 provides a thermal image showing temperatures with a wider gap (smaller cross section of material) compared to that of FIG. 6. FIG. 8 provides a thermal image showing a shorter gap (same cross section) compared to that of FIG. 6. These simulations confirmed that the temperature difference between portions separated by a gap is increased by increasing a at a given chamber and cutout height and decreased by increasing / ? at a constant cutout width.

[0088] In another experiment, a 3 -chamber spherical system (FIG. 9) was designed and simulated with and without the presence of liquid flowing through the system. For these simulations, the temperature of the top face was held constant at 35°C, the temperature of the bottom face was held constant at 5°C, all external walls and faces were considered to be adiabatic, the height of the gap (5.6 mm) was equal to 20% of the chamber height of 28mm, the width of the device was 58mm, and the width of the cutout was 56mm. Thermal images showing different viewing angles are provided in FIGS. 10A-10C (empty chambers) and 11A-11C (full chambers). For comparison, FIGS. 12A-12C provide the same data on chambers (empty) that do not include a cutout at all. No material was removed from the space between the chambers. FIGS. 10A-10C and 11A-11C show a much sharper temperature gradient in the cutout section than in the chamber areas and show a nearly constant temperature throughout a given chamber. In contrast, the chambers of FIGS. 12A-12C show a relatively consistent gradient throughout the entire device and a temperature gradient within each chamber. This means that the temperature within a chamber is much more consistentwith the cutout embodiment than with the non-cutout version. These simulations show that adequate temperature segmentation between chambers should be achievable.

[0089]

[0090] Using the design described above, heat transfer rates were investigated to compare the heat flux between chambers through the metal to the heat flux between chambers due to the movement of fluid. This would ensure a steady state could be reached.

[0091] When considering the liquid, the following flux equation was used:

[0092] Q — mCpT — vpCpT

[0093] where m and v are the mass and volumetric flow rates, p is the density of the fluid, Cpis the specific heat of the fluid, and AT is the temperature difference between the two fluids. Assuming the fluid to be water, using a AT of 7K as determined by the simulations, and a “worst case” flow rate of 8 mL / min (1.333* 1 O'7m3s'1, 10 minute residence time), the heat flux between chambers due to the liquid was calculated to be

[0094] Q = (1.333 * 10~7* (997^) * (4180^) * (7K) = 7.23 W

[0095] Comparatively, the heat flux through the metal can again be approximated using Fourier’s Law for ID heat transferdT

[0096] Q = kA- dT

[0097] where k is the thermal conductivity of the metal, A is the cross sectional area, and — canbe approximated asTbotto™Tt01where Tbottom and Ttopare the temperatures at the bottom and top of subsequent chambers and L is the height of the gap. Assuming the metal to be aluminum, using the value of 7K for AT assuming the liquid and the chamber are the same temperature, a cross sectional area of 1.024* 10-4m2as given by the CAD software (SolidWorks), and a gap height of 6.1*10'3m, the heat flux through the metal between chambers due to the heat exchangers was calculated to be

[10098] 1QY= (273—) * (1.024 * 10~4m2) * ( - ) = 32.1 WV m WJ\6.1*10-3m /

[0099] This indicates that the heat flux due to the heat exchangers should be significantly greater than the heat flux from the liquid and steady state should be achievable.

[0100]

[0101] A 10-stage prototype with 9 interstage cutouts was built to experimentally test the results of these calculations and simulations. Initially, the temperature segmentation was measuredon an empty device with the temperature of the bottom surface heater set to 50°C and the temperature of the top surface chiller set to 0°C. The device and transfer lines were not insulated resulting in the temperature of the bottom chamber being 43.5°C and the temperature of the top chamber being 7.7°C. With these conditions, an average temperature difference of ~4°C between chambers was expected. The experimental average temperature drop between chambers was 3.98 ± 0.22°C with a linear correlation of R2= 0.9995. After steady state was achieved, the temperature of the bottom heater was increased to 70°C resulting in a bottom chamber temperature of 60.7°C and increasing the temperature of the top chamber to 9.4°C. With these conditions, an average temperature difference of ~5.7°C between chambers was expected. The experimental average temperature drop between chambers was actually 5.71 ± 0.42°C with a linear correlation of R2= 0.9988. Results are shown over time for each chamber in FIG. 13. A comparison of the temperature at steady state for each chamber at a bottom surface temperature of 50°C and a bottom surface temperature of 70°C is provided in FIG. 14.

[0102]

[0103] In another experiment, room temperature (~21°C) water was flowed into the device at a 30 minute residence time (2.917 mL / min) with each chamber having a stirring speed of 1000 RPM to allow for proper mixing of the liquid. The temperature of the bottom heater was set to 50°C and the temperature of the top chiller set to 0°C. The temperature of both the metal chamber and the liquid were measured and the device and transfer lines were again left uninsulated. Results are illustrated in FIGS. 15 and 16. The temperature of the bottom chamber was measured to be ~44°C and the temperature of the top chamber was measured to be 9.4°C. With these conditions, an average temperature difference of ~3.8°C between chambers was expected. The experimental average temperature drop between chambers was measured as 3.87 ± 0.32°C with a linear correlation of R2= 0.9987 for the metal chambers and 3.82 ± 0.43°C with a linear correlation of R2= 0.9984 for the liquid. The temperature difference between the metal and liquid for a given chamber was calculated to be 0.15 ± 0.08°C, within the error of the thermocouples used. After steady state was achieved, the flow rate was increased to 8.75 mL / min (10 min RT) resulting in a bottom chamber temperature of ~43°C and increasing the temperature of the top chamber to ~11.5°C. With these conditions, an average temperature difference of ~3.6°C between chambers was expected. The experimental average temperature drop between chambers was measured as 3.56 ± 0.84°C with a linear correlation of R2= 0.9805 for the metal chambers and 3.39 ± 1.06°C with a linear correlation of R2= 0.9860 for the liquid. The temperature difference between themetal and liquid for a given chamber was calculated to be 0.41 ± 0.27°C, primarily caused by the large temperature difference between the metal and liquid in the bottom chamber due to the liquid being flown into the device at room temperature.

[0104]

[0105] Although these simulations and experiments were performed by limiting temperature control to the temperature of the top and bottom faces and using a uniform cutout between chambers to create a uniform temperature jump between chambers, conditions could be altered to allow for multiple piecewise linear temperature regions to be achieved. 1) This could be achieved by varying the size of the cutout between chambers to allow for more or less of a temperature drop between chambers as discussed above or 2) by adding additional heat exchangers between one or more intermediate chambers to fix the temperature of multiple locations throughout the device. For an N chamber system, up to M intermediate heat exchangers — where M < N-l — could be added in addition to the 2 extremity heat exchangers to create M+l independent piecewise linear temperature regions. 3) A combination of 1) and 2) could be utilized.

[0106] The embodiment shown in FIG. 9, the cavities cut out of the apparatus are a rectangular box and are internal to the apparatus. However, in other embodiments, the cavities and be different shapes and can be positioned differently. For example, FIG. 17A illustrates embodiments of externally and internally formed cavities. For example, cavity 210 is an external cavity with a curved surface. Cavity 212 is an externally formed cavity (cutout) with planar surfaces. Cavity 214 is an internal cavity with planar surfaces, similar to the cavity shown in FIG. 9. Cavities can be empty space, but in some embodiments can be filled or partially filled with a material exhibiting low heat transfer, for instance, a material that exhibits less than 50% of the thermal conductivity of the base material. For example, cavities can be filled with an expanded polymer, glass fibers or aerogel. Cavities can include complementary inserts that can be inserted and removed from cavities to increase and decrease heat flux, should such an increase or decrease be desired. Inserts can be partial or total, and multiple inserts can be used in a single cavity.

[0107] As described above, the reduction in cross-sectional area in a plane that is normal to the flow path through the apparatus is most beneficial to a reduction in flux. The size of the cavity can be described as the percentage of cross-sectional area of the material that has been removed to create the cavity. In various embodiments, the amount of material missing or removed can be more than 10%, more than 20%, more than 50%, more than 75% or more than 90% of the original cross-sectional area. The cavity can be symmetrical around the flow path but need not be. The sizeof a cavity can also be described in terms of the cross-sectional area of the apparatus material (e.g., metal) at the cavity compared to the cross-sectional area of the apparatus material at the chamber itself. For example, FIG. 17B is a cross-sectional plane taken at line 220 at the midpoint between two adjacent chambers. Passageway 234 is defined by solid metal portion 230. External cavity portion 232a is void and is empty space. FIG. 17C is a cross-sectional plane taken at line 222 at the midpoint of a chamber. No additional cavity (cutout) has been made and solid metal portion 230 defines chamber 120. FIG. 17D is a cross-sectional plane taken at line 224 in FIG. 17A. Internal cavity 232b is surrounded by solid metal portion 230 (housing). Passageway 234 passes up through the middle of cavity 232b. As can be seen from comparing FIGS. 17B, C and D, the amount of solid material (230) in cross-section is much greater at the midpoint of the chamber as shown in FIG. 17C than it is between chambers as shown in FIGS. 17B and D. As shown, the ratio of the area of solid material 230 in FIG. 17D is about 20% of the area of solid material 230 in FIG.17C. In other embodiments, the area of the plane at the midpoint between two chambers can be less than 90%, less than 75%, less than 50%, less than 20% or less than 10% of the area of the plane at the midpoint of an adjacent chamber.

[0108] Using the designs described herein, temperature gradients in chambers can be consistent throughout the chamber. This can be accomplished with a single source of heat and a single cooling source. Typically, the source of heat and the source of cooling are positioned at opposite ends of the device. In some embodiments, the source of cooling or heating can be room temperature with no heat exchanger required. Under operation, the temperature change across a transfer region can be greater than the temperature change across the length of a chamber. For example, the change in temperature along the interior of the device, in a vertical direction as oriented in FIG. 17A, can be 2X, 3X, 5X, 10X, 50X or 100X greater, per unit length, in the transfer region compared to a chamber. For example, a 5 mm vertical portion in the transfer region may decrease in temperature by 5°C from the bottom of the portion to the top of the portion, while in the same device, a 5 mm vertical portion of the chamber may decrease in temperature by less than 0.1 °C. Thus, in this example, there is a 50X difference in temperature change for the transfer region compared to the chamber.

[0109] The embodiments described herein eliminate the need for intermittent heat exchangers in the device. In some instances however, it may be beneficial to use multiple heat exchangers throughout the body of the device to alternate between cooling and heating in sequential chambers. In a crystallization procedure, following a temperature drop between chambers, a majority of theZFT00005WQU1increase in solid material will occur through growth on existing crystals. However, either through the breakage of larger crystals into smaller ones or the creation of new crystals, some small crystals will also be formed. By slightly increasing the temperature in the following chamber, this can increase the solubility and allows the finer crystals to redissolve into solution and creates final crystals with a tighter particle size distribution. In addition to solely alternating between colder and hotter chambers, many combinations of the alternating cold / hot chambers and linearly cooling chambers may be used, and examples are provided in FIGS. 18A-18D. These temperature profiles include, for example: alternating hot and cold (FIG. 18 A), a linear cooling region followed by an alternating cold / hot region (FIG. 18B), an alternating cold / hot region followed by a linear cooling region (FIG. 18C), and a linear cooling region followed by an alternating cold / hot region followed by another linear cooling region (FIG. 18D).

[0110] The foregoing description of example embodiments has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the present disclosure to the precise forms disclosed. Many modifications and variations are possible in light of this disclosure. It is intended that the scope of the present disclosure be limited not by this detailed description, but rather by the claims appended hereto. Future-filed applications claiming priority to this application may claim the disclosed subject matter in a different manner and generally may include any set of one or more limitations as variously disclosed or otherwise demonstrated herein.

Claims

ZFT00005WQU1What is claimed is:

1. A continuous chemical processing apparatus comprising:a housing defining a linear plurality of chambers in fluid communication with each other; a fluid transfer region in the housing, the fluid transfer region connecting adjacent chambers and providing a pathway for fluid transfer from a first chamber to an adjacent second chamber; anda cavity in the fluid transfer region of the housing, the cavity isolated from the pathway for fluid transfer;wherein a cross-section of the housing across the transfer region includes less area than does a cross-section of the housing across a midpoint of an adjacent chamber.

2. The continuous chemical processing apparatus of claim 1 wherein the fluid transfer region defines a channel connecting adjacent chambers.

3. The continuous chemical processing apparatus of any of the previous claims wherein the fluid transfer chamber comprises an intersection of two adjacent chambers.

4. The continuous chemical processing apparatus of any of the previous claims wherein heat is transferred more efficiently through a housing section including the chambers than through a housing section including the transfer region.

5. The continuous chemical processing apparatus of any of the previous claims wherein the cross-sectional area across the transfer region is less than half the cross-sectional area across the adjacent chamber.

6. The continuous chemical processing apparatus of any of the previous claims comprising a plurality of agitators, each of the plurality of agitators disposed in one of the plurality of chambers.

7. The continuous chemical processing apparatus of any of the previous claims, at least one of the plurality of chambers including a volume modulator wherein the volume modulator is configured and arranged to change the volume of the chamber.

8. The continuous chemical processing apparatus of any of the previous claims comprising at least 3 chambers, at least 5 chambers, at least 10 chambers or at least 20 chambers.

9. The continuous chemical processing apparatus of any of the previous claims wherein one or more of the chambers are substantially spherical.ZFT00005WQU110. The apparatus of any of the previous claims wherein serial chambers are fluidly connected by a passageway connecting one chamber to a next chamber or via direct overlap of the chambers.

11. The apparatus of any of the previous claims wherein the volume of at least one of the chambers, or each of the chambers, is less than 100 L, less than 10 L, less than 1 L, less than 500 mL, less than 250 mL, less than 100 mL, less than 50 mL, less than 25 mL, greater than 1 mL, greater than 5 mL, greater than 10 mL, greater than 50 mL, greater than 100 mL, greater than 500 mL, greater than 1 L, greater than 5 L or greater than 10 L.

12. The apparatus of any of the previous claims comprising a volume modulator configured and arranged to change either the first volume, the second volume, or both.

13. The apparatus of claim 18 wherein the volume modulator changes a first volume or a second volume in a first chamber, a final chamber or an intermediate chamber.

14. The apparatus of any of the preceding claims comprising a heat exchanger in thermal communication with one or more chambers.

15. A method of segmenting temperature in at least n chambers of a chemical processor having a plurality of serially connected chambers in fluid communication with each other, the chambers having a length and a width, the method comprising:heating or cooling a first end of the chemical processor to provide a temperature differential T between the first end and a second end of the chemical processor, T being greater than 5°C; andflowing a fluid from the first end to the second end through the plurality of connected chambers, the connected chambers being physically and fluidly connected by a series of fluid transfer regions, wherein the temperature difference at steady state between an nthchamber and an (n+1)thchamber is T / n + / - 5%, + / - 10%, or + / - 20%.

16. The method of claim 15 wherein n is at least 5.

17. The method of claim 15 wherein there are no heaters or coolers acting between the first and second ends.

18. The method of claim 15 wherein there are a plurality of heaters or coolers associated with at least two of the plurality of serially connected chambers.

19. The method of claim 18 wherein there is a heater or cooler associated with each of the plurality of serially connected chambers.

20. The method of claim 15 wherein the cross-sectional area of a fluid transfer region is less than ½ the cross-sectional area of a chamber.

21. The method of claim 15 wherein heat flux through a transfer region is less than ½ the heat flux through a chamber.

22. The method of claim 15 wherein the transfer regions are comprised of the same material as the chambers.

23. The method of claim 15 wherein fluid is flowed at a rate equal to or greater than 0.05 chamber volumes per minute.

24. The method of claim 15 wherein adjacent chambers are separated by less than ½ of the chamber length.

25. The method of claim 15 wherein the chambers are essentially spherical.

26. The method of claim 15 wherein the volume of at least one of the plurality of chambers can be modulated.

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