KR20050088383A - Apparatus and method for forming crystals/precipitate/particles - Google Patents

Abstract

This invention relates to an apparatus for use in the production of particles via precipitation or crystallization and the like and methods for forming the crystals/precipitate or other particles.

Description

Apparatus and method for forming crystals / precipitations / particles {APPARATUS AND METHOD FOR FORMING CRYSTALS / PRECIPITATE / PARTICLES}

The present invention relates to an apparatus for use in the production of particles by precipitation or crystallization, and to a method for providing a scale change of the apparatus while maintaining a substantially constant intrinsic power strength. Such devices can be formed to crystallize small organic molecules such as biological products such as proteins and enzymes, pharmaceuticals and fine chemicals, and inorganic materials such as inorganic salts.

Draft tube crystallizers are generally used to produce organic compounds such as adipic acid and pentaerythritol, and many other kinds of materials and particles, including but not limited to inorganic compounds such as gypsum, calcium fluoride, sodium sulfate, and the like. Used. For example, US Pat. No. 1,997,277 (Burke) describes a mechanism for forming single nuclear crystals from solution by evaporative cooling.

The production of particles, especially fine particles, can be used in oral, subcutaneous, infusion or inhalation pharmaceuticals, biopharmaceuticals, nutraceuticals, diagnostic agents, agrochemicals, pigments, food ingredients, food formulations, beverages, fine chemicals, cosmetics, It is used in many applications such as electronic materials, inorganic materials and metals. In some instances, current precipitation and crystallization techniques do not reliably produce crystals with the appropriate size and size distribution. In some instances, large crystals are desirable to facilitate solid / liquid separation and to improve the powder flow characteristics of the product. In other examples, such as inhalable pharmaceuticals, fine particles in a narrow size range (eg, 1-5 microns) are preferred.

Increasing particle size is a difficult and sometimes unsuccessful challenge for crystallization process technicians. Most methods in the art relate to sorting methods that enable (i) mixing and stirring systems and (ii) various size ratios to be regenerated, dissolved and enriched in the crystallization apparatus. In a preferred example of producing fine particles, sometimes a milling, compacting or grinding process is necessary as a post treatment to reduce the crystallized particles to the desired size and distribution range. If the product size is appropriately adjusted directly by adjusting the crystallization apparatus, not the post-processing milling step, the process is simpler, more robust, the surface of the particles is cleaner, less dusty and particulate properties (eg flow, purification). Consolidation, etc.), and the dispersibility of the therapeutic product inhaled as dry powder will be improved.

In addition, the crystallization apparatus is usually designed such that the diameter and height of the vessel and the geometric ratio between the diameter and pitch or thickness of the stirring blades are constant. However, there are many cases where this constant geometric scaling is undesirable in actual crystallization.

The constant geometric scale of the stirring system in the crystallization device is not optimized because the specific power intensity (SPI) of the slurry pumping action in the vessel and the stirring transfer energy to the slurry is not scaled proportionally to each other, Changing the scale of the unit (eg stirring diameter) changes the pumping speed and SPI design parameters. The designer's puzzle, therefore, is to decide which parameters will be constant, which parameters will be variable, or trade-offs to make both parameters variable. See, eg, A. W. Nienow, "The Effect of Agitation on the Crystal Growth and Nucleation Rates and on Secondary Nucleation", Transactions of the Institution of Chemical Engineers, 54, pp. Crystallization, Third Edition, by J. W. Mullin, Butterworth-Heinemann, 1993, citing 205-207, recommends keeping the tip speed constant in laboratories, pilots, and highest capacity crystallization equipment. However, for larger diameter vanes, this varies the natural power strength, which is more related to friction and secondary nucleation speeds than tip speeds.

The present invention provides an efficient and dose-variable instrument and method for making crystal / precipitate or other particles. One advantage provided by the present invention is a high internal pumping (or circulation) rate, which requires low intrinsic power input, which results in a good mass transfer environment and minimal breakage / to mechanically sensitive crystals / precipitations or particles. Enables friction / damage. As a result, the apparatus is particularly advantageous for mechanically sensitive solid products, such as small organic molecules such as biological products (eg proteins) and pharmaceuticals.

In addition, another advantage of the present invention is that the apparatus is not only used for crystallization, but also as a general process vessel for applications including, but not limited to, fermenters, extractors and liquid / emulsion separators, reactors for heterogeneous catalysis processes, and the like. Can also be used. In these applications, the instrument also provides inherent power input to a slurry that is substantially lower than other process vessels (such as Rushton turbines, fixed pitch vanes, hydrofoils, submarine vanes, roto-stators, etc.). Provides very good mixing and rapid dilution of the infusion stream.

Another advantage of the present invention is that the present application may optionally be used to enable infusion of a fluid comprising seed crystals or other particles for co-precipitation, further growth, or coating.

Therefore, the present invention provides an apparatus that is a process vessel and a configuration for a laboratory scale, pilot scale or industrial scale crystallization or precipitation process that allows for improved control over the formation of crystals / particles. Based on the particular parameters discussed herein, the apparatus and methods according to the invention also determine the size of the crystals / particles formed during the crystallization / precipitation process, for example in the art of crystallization, such as draft tube bulkhead type crystallization apparatus. Better control than what is currently done.

In addition, commercial crystallization apparatus are typically higher than the desired rate of crystal nucleation in performance, which is limited or disturbing. Techniques for dealing with faster than desired nucleation rates have been tested for many years and are described in most crystallography textbooks. These techniques include microdestruction; Pure liquid advancing and double withdrawal, and the like. Each of these three techniques requires the crystal slurry to be sorted (for example as pure liquid, fine and coarse fractions). This sorting is usually accomplished through external sorting devices such as suspension separation devices and cyclones.

In the case of microfracture, fine fractions of crystals pass through a system that dissolves them (eg, heat exchanger, dilution apparatus) and pure liquid is recovered to the crystallization apparatus. This is particularly useful for batch crystallization operations, but is also widely used in continuous processes. In the case of pure liquid advancing, fractionation reaches extremes, where fractions collected from the fractionator are essentially crystalless and are used in several successive inorganic crystallization / precipitation processes. Double evacuation is used in a continuous crystallization process, in which the fractionated stream of fine fractions, as well as representative slurry streams, are removed and sent to downstream separation equipment.

In all these cases, larger production crystal sizes arise from the apparatus, which are inherently desirable and also require less investment in the separation apparatus required downstream of the crystallization apparatus (eg centrifuges, filter presses, etc.). Make it possible. Another advantage of the present invention is that larger crystals / precipitates / particles can be made than with other crystallization apparatus found in the art, and therefore, for processes approaching manufacturing speed limits, larger average crystal size Higher manufacturing rates may be possible for the same downstream separation device through the manufacture of. The classification of the slurry into pure, fine and coarse fractions is a step which makes it possible to exploit this advantage.

The potential uses of the present invention are very wide, for example, industries that can utilize the particles produced by the present invention include pharmaceuticals, nutraceuticals, diagnostic agents, polymer intermediates, agrochemicals, pigments, food ingredients, food formulations, Beverages, cell cultures and their products, fine chemicals, cosmetics, electronic materials, minerals and metals, and the like.

Summary of the Invention

The present invention

(a) a container;

(b) a radial flow stirrer optionally having a top plate and a base plate; And

(c) a vent pipe having a plurality of bulkheads securely attached and disposed in the container to form a conduit between the vent pipe and the side wall of the container and having a diameter of about 0.7 times the diameter of the container

It relates to a crystallization / precipitation apparatus comprising a.

The present invention also provides

Supplying one or more fluids to the device, the fluid comprising one or more dissolved substances to be crystallized / precipitated;

Stirring the one or more fluids to cause one or more dissolved materials to crystallize / precipitate from the one or more fluids into particles; And

Causing one or more fluids and particles to exit the instrument of the present invention

It relates to a method for crystallizing / precipitating particles comprising a.

1 shows a cross-sectional side view of one embodiment of the present invention.

Figure 2 shows a top view of the wing wheel according to the present invention.

Figure 3 shows a side view of the wing wheel according to the present invention.

4 shows a bottom view of one embodiment of a wing wheel according to the present invention.

5 shows a side view of one embodiment of a wing wheel according to the present invention.

6 shows a side view of another embodiment of a vent pipe according to the invention.

Figure 7 shows a side cross-sectional view of another embodiment of the present invention.

8 is a side cross-sectional view of another embodiment of the present invention.

9 shows a system incorporating the present invention.

10 illustrates a system incorporating the present invention.

The present invention relates to an apparatus for forming crystals / precipitates or other particles and a method of using the apparatus. In general, the present invention can be used to produce crystals / precipitates / particles of various particles depending on the compound to be crystallized. Typically, however, crystal / precipitation or other particles are in the range of about 0.5 microns to 3000 microns, but due to their ability to control crystal / precipitation / particle size, smaller or larger particle sizes are also contemplated by the present invention. Can be. Therefore, the present invention enables the production of larger crystals and the production of finer crystals of narrower size distribution or narrower size distribution than is generally emitted by other crystallization apparatus in the art.

The present invention also provides the ability to make crystals of the same size and size range in different capacity process vessels (e.g., laboratory capacity versus prefabricated capacity), while the present invention substantially maintains a constant intrinsic power strength. This is because the method of varying the dose of.

The instruments of the present invention can be used in a batch or continuous configuration.

The apparatus of the present invention can be used with a variety of fluids that act as feeds / reactants, including but not limited to solvents, liquids, slurries, suspensions, liquefied gases, supercritical fluids, subcritical fluids, and the like.

The present invention is directed to any precipitation or crystallization, including pharmaceuticals, biopharmaceuticals, nutraceuticals, diagnostic agents, agrochemicals, pigments, food ingredients, food formulations, beverages, fine chemicals, cosmetics, electronic materials, minerals and metals, and the like. It can be used for the production of particles. Crystals / precipitated particles of other industrial fields can be prepared easily by those skilled in the art of general techniques such as those described herein.

In general, potentially conflicting demands on crystallization apparatus agitation, such as (1) good mixing and uniform particle suspension; And (2) minimizing particle damage and secondary crystal nucleation. Good mixing is generally provided by high volumetric flow rates from the stirrer and disturbance zones in the initial dispersion of any feed streams. Homogeneous particle suspension is generally provided by fluid velocity at relatively high, especially upstream. However, generating these conditions can be problematic, as this usually also involves the formation of conditions that damage the particles and cause secondary nucleation. The present invention provides both apparatus and methods that alleviate these problems in the art.

As used herein, the term “shear region” includes all regions within the invention that relate to shear forces, such as, for example, the area between the top and septum of the vane blade, the base plate opening, and the stirrer-stirrer volume.

As used herein, the term "shear force" refers to mixing caused by the apparatus of the present invention, including but not limited to nominal shear rates, elongation forces, disturbances, cavitations, and collisions of surfaces occurring in agitator-stirrer volumes. Covers both dissipation and mechanical forces.

As used herein, the terms “crystallization” and / or “precipitation” refer to typical solvent / antisolvent crystallization / precipitations; Temperature dependent crystallization / precipitation; “Salt” crystallization / precipitation; pH dependent crystallization / precipitation; "Cold forced" crystallization / precipitation; Crystallization / precipitation based on chemical and / or physical reactions; And any method of preparing particles from a fluid, including but not limited to, and the like.

As used herein, a "biological agent" refers to a biological source or the like, for example, proteins, peptides, vaccines, nucleic acids, immunoglobulins, polysaccharides, cell products, plant extracts, animal extracts, recombinant proteins, enzymes and combinations thereof, and the like. And therapeutic compounds derived from equivalent chemically synthesized products.

The present invention generally;

(a) a container;

(b) an agitator optionally having a top plate and a base plate; And

(c) a vent pipe having a plurality of bulkheads securely attached and disposed in the container to form a conduit between the vent pipe and the side wall of the container and having a diameter of about 0.7 times the diameter of the container

It provides a mechanism comprising a.

In general, the dimensions of the instrument 30 of the present invention vary (eg from about 1 cm to about 15 meters or more) because the present invention can be dosed to various sizes. Therefore, the dimensions will change to comply with the capacitive version of the present invention. The dosages of the present invention are substantially varied such that such device configurations can be designed for low manufacturability (eg 0.0005 kg / h) through various container sizes, up to about 300,000 kg / h crystalline products on a dry weight basis.

The vessel 1 of the present invention may be in any form commonly used in crystallization / precipitation or particle formation techniques. Preferably, however, the container is a closed cylindrical contour having a side wall 2 and one or more holes II into which injection holes, feed tubes and the like can be inserted.

The container may be composed of any material capable of withstanding the forces formed by the present invention, for example glass fiber, steel, preferably stainless steel, more preferably carbon steel, PVC, glass and the like. Preferably, the container of the present invention is stainless steel.

The container has one or more holes 11, preferably a plurality of holes, to introduce and / or remove vapors and / or liquids, and / or to withdraw the product from the container and / or to clean as part of the process hygiene requirements. And / or the insertion or attachment of one or more tubes and / or nozzles that allow sterilization (in place). One or more holes and consequently one or more inlet tubes, line nozzles, or the like may be located anywhere on the vessel.

The container may also optionally have a central support 8 attached to the container side wall and the vent pipe, which provides stability and support of the vent pipe.

The second septum 9 can optionally be attached to the vessel sidewall to help redirect the contained feed / reactant to substantially flow downward toward the interior portion of the vent.

Vessel dimensions vary depending on the volume used. Those skilled in the art will recognize and understand the necessary adjustments that should be made to the vessel in the capacity of the instrument in light of the disclosure herein.

As shown in FIG. 7, another embodiment of the present invention provides a container having a peripheral settling region 10 that allows for fractionation of pure liquid and / or fine crystal / sedimentation / particle fractions without the need for an external sorting device. do. Peripheral settling vessel 10 may enclose the vessel to form a continuous peripheral area, or may enclose only a portion of the vessel and be positioned at any point along the vessel height below the liquid level. The surrounding settling zone 10 is generally filled with a slurry, but is not dependent on the degree of agitation seen in the rest of the vessel and therefore is protected from circulation of the slurry in the vessel. In this way, the surrounding settling region 10 provides a region where crystals can settle out of the slurry. In general, larger crystals settle faster than smaller crystals. As a result, a portion of the slurry may escape at the top of the surrounding settling zone (ie, via the removal hole depicted in FIG. 7), thereby allowing fractionation of the pure liquid or fine fraction. Therefore, the crystal size can be determined internally, which makes it possible to avoid the high cost, drive and space requirements of external classifiers such as, for example, suspension separators and cyclones.

Those skilled in the art will recognize and understand that the dimensions of the surrounding sedimentation area, such as width and depth, should be varied in light of the disclosure herein, and the type, size and size distribution, crystal / particle or other particle of the crystal / precipitate or other particles to be obtained. Adjustments may be made to specific parameters such as the type of fluid used and the operating conditions of the vessel.

The stirrer 13 of the present invention provides for mixing of the feed stream, rapid dilution with the vessel contents of the concentrated feed, suspension of crystals / precipitates / particles in the slurry and circulation of the fluid throughout the apparatus. This property is important for robust driving and constant crystallization / sedimentation / particle formation. In general, the stirrer 13 of the present invention is a radial flow vane located at either (or both) of the upper or lower part of the vent pipe, an axial flow propeller or submersible propeller in the middle part of the vent pipe, a double propeller or a multi propeller. It may be any configuration capable of providing the required liquid circulation, including but not limited to. Preferably, the stirrer of the present invention is a radial flow stirrer, more preferably a radial flow stirrer having at least one blade, base plate and optional top plate. Typical commercial crystallization apparatus generally use axial flow vanes that are used at higher rpm and smaller stirrer diameters resulting in much higher intrinsic power strengths than shown here.

The stirrer may be composed of any material capable of withstanding the forces formed by the present invention, for example glass fiber, steel, preferably stainless steel, PVC, titanium, glass and the like. Preferably, the stirrer of the present invention is stainless steel or titanium.

Radial floating wheels can be manipulated in various ways, for example by the number of blades, blade size, blade attack angle, and revolutions per minute, in order for the driver to manipulate the nature of the disturbing mixing and the shear force to which the crystals are exposed. Have Therefore, indirect control of the degree of disturbance damping allows for the completion of crystal precipitation zones such as mixing and dilution of concentrated feed streams, suspension of crystals, incorporation of bubbles and end settling zones.

In addition, blade size, rpm, and degree of separation affect not only the disturbances injected into the fluid by the vane wheels, but also the capacity of the disturbances (via the disturbance energy loss, commonly called epsilon). Smaller, higher speed vanes at the same power level as larger vanes produce stronger disturbances at higher frequencies (and smaller capacities), but these disturbances decay faster. This is particularly the case for crystallizers, since the high solids content leads to greater losses at higher frequencies in the disturbance rate spectrum.

Radial flow vanes of the present invention may include a variety of configurations, which include one or more blades, an optional top plate and a base plate. Preferably, however, the vanes include the configurations shown in FIGS. 2, 3, 4 and 5.

One or more blades of the vane wheel may be of any type as long as it provides the necessary diameter of vane wheels and the necessary pumping speed for the circulation of the fluid throughout the instrument. Typically, however, the height of the blade is about one sixth (1/6) of the stirrer diameter. The width of one or more blades varies depending on the angle of the blade, but is typically determined to be equal to the diameter of the stirrer divided by (cos of 8x blade angle). For example, if one or more blades use an agitator having a diameter of 10 feet (120 inches) with a blade angle of 55 degrees, the blade height is about 120 inches by 1/6, or 20 inches, and the width is 120 / (8x cos 55) or (8x0.574), or about 26 inches.

In general, the blades can have any angle that can provide the required circulation of fluid throughout the instrument. However, the blade angle of the present invention is typically about 45 degrees to about 65 degrees. Preferably, the angle of the blade is about 55 degrees.

As long as the blades are in separate flow (occurring at attack angles at low angles of 6-10 degrees), the lift of the blades (the radial force exerted on the blades, eg pumps against the wing wheels) The fluid being applied) is essentially independent of the angle of the blade, but the attraction of the blade (the force exerted in the direction of the blade's movement) depends on the angle of attack. Separate flows are related to the lift of the blades and the attraction of the blades, which are independent of each other, in which case if the lift of the blades is constant, the attraction is related to the effective area of the blade. The energy from the attraction of the day is almost completely transformed into disturbances. Therefore, by adjusting the angle of the blade, it is possible to control the amount of energy that changes with disturbance and mixing. The flow rate is controlled by the rpm of the vane wheel, the disturbance energy by the blade angle and rpm.

The revolutions per minute (RPM) of the stirrer will vary depending on the capacity of the apparatus of the present invention. In general, however, as the size of the instrument increases, the maximum allowable RPM decreases.

The optional top plate 14 of the vane generally extends over the distance of the individual blades so that the width thereof is substantially the same as the length of the blades and is generally annular in configuration. The presence of the top plate 14 has a profound effect on the flow because the flow must return the top plate 14 to form a highly disturbing region with a highly separated flow underneath the plate with negative pressure. This disturbance zone has a very high disturbance dissipation and occurs only over a small portion of the overall cross section, but is not energy efficient. Removal of the plate, or increasing the inner diameter of the plate to the extent that it becomes a virtually full disk (not ring), will improve the efficiency of the wheel.

The stirrer base plate 15 is a substantially full structure, positioned under one or more stirrer blades, as shown in FIG. 3, with holes for receiving the propulsion shaft.

Alternatively, the base plate 15 may also include one or more openings 16, preferably a plurality of openings, such that the base plate can serve as a non-point source through which feed and / or reactants are introduced and dispensed in the vessel. Preferably, in the radial flow stirrer shown in Figure 3, the non-point source feed / reactant addition is achieved by introducing the feed / reactant below the base plate 15 of the stirrer. Dilution / dispersion of the feed / reactant is provided by use under stirring addition, where the stirrer base plate has a radius up to the inner radius of the vessel, which is larger than the radius of the vent pipe, so that the feed and / or the reactant has this opening. Flowing through (16), it can spread radially through the fast mixing zone as it passes through the blade of the stirrer. The above whisk blade 17, preferably a plurality of whisk blades, is used to help distribute the feed and / or reactants, as shown in Figures 4 and 5, typically a plurality of whisk blades 17 Located below the base plate 15 and extending in the axial direction along the longitudinal and transverse axes of the base plate 15 perpendicular to each other, and may be any length, but generally less than or equal to the base plate diameter. Preferably, the height of the whisk blade becomes smaller as it extends away from the propulsion shaft (e.g., the one closest to the propulsion shaft has a height of 1.75 and the opposite end has a height of about 1.25). have).

Non-point source feed / reactant addition has been used in commercial practice where the stirrer base plate has the same radius as the vent tube radius, but in the present invention further increases the radius of the stirrer base plate 15. This elongation does not affect the internal circulation achieved by the stirrer 13. Elongation bypasses the feed flow through the opening in stirrer base plate 15 to reduce the fraction of high feed / reactant. The larger the radius of the stirrer base plate 15, the fewer feeds / reactants passing through the gap between the stirrer 13 and the inner wall of the instrument vessel.

Typically, a point source, such as a blowoff tube, is usually used in commercial crystallization apparatus, but this type of industrial apparatus has a high supersaturation zone near the outlet and the resulting liquid is diluted and dispersed in the crystallizer vessel. There is a serious disadvantage of having a high supersaturated plume when

The openings 16 of the base plate 15 may be of any shape and / or size, including but not limited to slots, circles, triangles or squares or mixtures thereof. This ensures that the fluid passes through the shear zone to allow for intimate mixing with the fluid. The size and / or shape of the openings 16 does not affect the size or shape of the production crystals according to the present invention, but due to their influence on the flow pattern of the fluid in their apparatus, they affect the generation of shear forces. Gives. The size of the crystals can be adjusted by varying the chemistry of the fluid stream, vane rpm, the flow rates of the various inlet streams and their relative flow rates with respect to each other.

In general, the stirrer 13 of the present invention may have a wide range of diameters, for example, from about 10 cm to about 550 cm, depending on the capacity of the appliance used. Preferred stirrers, vanes may have a diameter of about 0.4 to 0.7 times the diameter of the vessel used (measured from the end of one blade to the end of the other blade). Those skilled in the art, in light of those disclosed herein, may determine that the measurement of the stirrer 13 may vary as the instrument's capacity changes, and such changes will be defined by the capacity diversification methods provided below, You will recognize and understand how to achieve it.

In general, the volumetric flow rate (or pumping rate, volume of slurry pumped per unit time) generated by the agitator of the present invention and the resulting linear velocity (e.g., average linear velocity is the stirrer pumping velocity divided by the cross section of the region of interest). Is determined according to the diameter of the stirrer 13. For example, a stirrer with a diameter of about 10 feet typically has a volume flow rate of about 112,800 gpm and a linear speed of about 3.2 ft / sec at about 30 rpm. Similarly, the natural power input is determined using the cube of stirrer angular velocity. Therefore, having a relatively large diameter makes it possible to rotate the stirrer 13 relatively slowly at the same volume flow rate. As a result, increasing the diameter of the stirrer 13 is to minimize the intrinsic power strength at a given volume flow rate and average linear velocity. This is described in D. A. Green in "Crystallizer Mixing: Understanding and Modeling Crystallizer Mixing and Suspension Flow" in Handbook of Industrial Crystallization, A. S. Myerson, ed. Butterworth-Heinemann, 12/01. However, there is a limitation here, that the tip of the blade of the stirrer is not able to approach the adjacent position of the vessel wall too close, which can increase secondary nucleation (by crystalline friction), which is generally undesirable. Because.

The stirrer 13 is connected with the propulsion shaft 18 installed to be rotatable. The propulsion shaft 18 is in turn connected with a propulsion force which, in turn, can rotate at a speed sufficient to adequately mix and suspend a solution or slurry to be crystallized with a motor or stirrer. The rotatable propulsion shaft 18 may be a full shaft or, conversely, hollow to act as one or multiple inner tubes that deposit fluid in the stirrer-stirrer volume 19. Similarly, the stirrer itself is also hollow, so that one or more fluid streams are fed through the stirrer, where it can be dispersed at one or several points, for example one or more blades and / or blade ends.

The vent tube 23 of the present invention is generally used to guide the circulation of the fluid surrounding it, thereby providing intimate mixing of the feed / reactant which leads to the formation and uniform distribution of crystals / precipitates / particles. More particularly, the vent tube 23 provides a channel 24 between the outer portion of the vent wall 25 of the vessel and the cylindrical inner tube 26. After entering the stir volume of the radial flow stirrer, the fluid is guided substantially upward by the septum towards the top of the vent. The fluid then flows into the channel 24 and finally moves back towards the vanes by moving along the length of the vent tube 23 until it pours over the top of the tube. Optionally, and as a special use in batch applications, where the vessel volume is not used to the fullest or the slurry filling level increases or decreases throughout the batch, the vent pipe 23 of the present invention is provided with one or more windows located along the height of the vent pipe. (27), preferably further includes a plurality of windows. This allows for forced circulation of the slurry upwards on the outside of the vent and downwards on the inside of the vent.

In addition, since the flow towards the center of the instrument to the upper part of the vent pipe 23 is generally separated, the flow along the inside of the upper part of the vent pipe is directed upward, so that only about 70% of the vent pipe in the upper part is actually used. This reduces the effective area of the vent pipe 23. However, the window 27 of the present invention allows the use of a higher percentage of the vent.

Preferably, the vent pipe 23 is a cylinder arranged centrally in the container, where the vent pipe has a diameter of about 0.7 times the diameter of the container. The use of this vent has advantages over conventional crystallizer vents because, geometrically, it is a diameter that enables the same volume inside and outside the vent. Preferably, the vent pipe is a taper cylinder, wherein the taper tube has an upper diameter 28 and a lower diameter 29, the upper diameter being greater than the lower diameter. The vent may be linear or non-linear, or tapered in the form of a frustum or cone and a straight cylinder. Alternatively, the vent may be a substantially straight cylindrical with a diameter larger than that of the bottom of the cylinder, with the top of the trumpet or trumpet bulging out. The composition is determined by the rate of precipitation of the crystals / precipitations / particles in the slurry, which determinations can be made by those skilled in the art. The taper construction promotes slurry flow while lifting the exterior of the vent. In general, the slurry rising out of the vent can be at the same rate as the slurry falling into the vent. This involves the same slurry flow rates up and down the vent. The same speed of the internal and external feed / reactant of the vent pipe prevents the generation of additional shear forces during acceleration and deceleration. In an example of a larger and dense crystal compared to flow intrinsic gravity, the crystal will grow at a slower rate than the fluid containing the crystal outside the vent (by gravity). This can cause deposition and tragic fluxgage of crystals outside the vent. For some materials to be crystallized, the taper vent is an additional improvement beyond the vent of a cylindrical vessel diameter, because it forces acceleration of the slurry against gravity and thereby overcomes precipitation and deposition out of the vent. A guideline for determining the dimensions of the tapered vent is to keep the volume essentially the same on both the outer and inner regions of the vessel of the vent.

More preferably, the vent tube 23 further comprises a partition 12 which directs the liquid flow vertically toward the top of the vent tube and prevents the liquid from swirling and circulating by the stirrer. The partition 12 has a strong effect on the degree of swirl held in the vessel, the rate of disturbance loss in the rings, and affects the distribution of material in the partition.

The vent tube 23 may be made of any material capable of withstanding the forces formed by the present invention, for example glass fiber, steel, preferably stainless steel, PVC, glass, and the like. Preferably, the vent pipe of the present invention is stainless steel.

Yet another embodiment includes a hollow vent that has a cavity between the vent walls. This cavity can be used for a variety of purposes, including but not limited to, introduction of feed / reactants into the apparatus and / or heat transfer methods for heating or cooling the apparatus and its contents, and the like.

Another embodiment includes a vent pipe having a terminal settling zone, which has the same configuration as the terminal settling zone that can be found in the vessel. The terminal settling region can be found outside of the vent or in the cavity of the hollow vent. However, dimensional differences for differences in size, diameter, height, etc., due to the smaller size of the vents compared to the container, should be considered.

In order to achieve precisely uniform particle distribution in the vessel 1 and the vent pipe 23, a higher velocity is required in the upstream direction than in the downstream region, in which the particles settle in the opposite direction of the average flow direction, but downstream This is because both the sedimentation rate and the average flow rate are in the same direction. This causes particle damage and secondary nucleation and avoids catastrophic particle deposition outside the vent. However, the average velocity ratio upstream to downstream varies depending on the nature of the suspension, the flow conditions and the type of feed / reactant used to form the crystals / precipitates / particles. Therefore, general ratios cannot be mentioned and are optimized for every set of process conditions. Generally, however, the linear velocity of the slurry ranges from about 0.1 to about 1.8 meters per second, preferably about 0.9 meters per second. Higher upstream rates also improve the slurry / liquid mixing in the recycle zone. This area is easy to isolate, especially if the level of suspension becomes too high above the top of the vent. In an extreme example, a liquid layer with few particles may be formed over the circulating suspension. This problem can be reduced using higher upstream suspension rates. Faster fluid thrust leaving the channel outside the vent pipe directs the fluid to a higher area above the vent pipe and improves mixing in this area.

Optionally, the vessel may contain any internal component, including but not limited to, agitator 13, vent 23, etc., coated with a permanent or heat removable coating to minimize secondary nucleation and aid in rapid shell removal. And internal portions.

Suitable soft coating agents include, but are not limited to, polyethylene, poly (tetrafluoroethylene), polypropylene, neoprene, latex, rubber, and the like.

Flexible coatings are envisioned by the present invention because collisions to hard surfaces such as crystals, steel walls of vessels, and any parts therein, such as blades of agitators, are the major contributors to the rate of secondary nucleation. . Flexible coatings on internal and moving parts reduce the disruption of crystals upon impact and have particular advantages for biological products. Therefore, the secondary nucleation rate can be reduced and larger crystal size can be achieved. The use of flexible coatings in the interior and flow parts of the apparatus of the present invention is particularly useful in connection with biological products.

Another embodiment of the present invention envisions the use of an optional second partition 9 attached to the side wall of the container to reduce the large recirculation area at the top (mentioned above) in the vent. The vent can be adjusted to use the second septum 9 in the liquid direction to make a smoother transition, since the septum makes a transition from upstream to downstream at the top of the vent. Recirculation is the result of the propulsion of the liquid making a 180 degree turn from upstream to downstream at the top of the canister. The flow of liquid cannot immediately produce a sharp 180 degree turn, especially in the most intense upstream portion where the change is immediately at a location near the vent. As a result, the flow diverts and separates from the vent at the top without following it inside the vent, but instead forms a downstream center inside the weakly recirculated region in and near the vent. This compresses the downstream to the high speed center. The tapered top of the vent reduces both size and speed of this region. This is also a means of locally increasing the upstream velocity to the region above the vent, which has the advantage of improved mixing of this region as mentioned above.

In general, the device 30 operates by having fluid (feed / reactant) introduced into the device through one or more holes 11 and / or one or more feed / mixture tubes. The fluid is deposited inside the vessel 1, preferably in close proximity to the stirrer and fed to the stirrer. The fluid is rapidly rotated inside the stirrer-stirrer volume 19 by the rotation of the stirrer. The centrifugal force generated by the sharp stirrer circulates the fluid in the radial direction towards the side wall 2 of the container 1 and eventually passes through the partition 12. When the fluid reaches the container side wall and / or the partition wall, their flow is guided in the axial direction and upward direction by the presence of the partition wall and the vent pipe. This passage, which passes through the septum through the stirrer-stirrer volume from one or more holes and extends out of the vent, leads to good mixing of the flow stream. In addition, high circulation flow rates allow for high dilution rates of the feed stream and the vessel contents. The feed / mixture stream is further mixed as the current single mixture diverts the flow direction from the top to the bottom of the vent pipe and then down through the internal portion of the vent pipe. Subsequently, newly formed crystals / precipitates or other particles are grown to the desired size and collected during isolation or subsequent processing before exiting the vessel.

The chemistry of the feed / reactant and consequent supersaturation directs the formation and growth of crystals, the various mechanisms of which are known by conventional mechanisms known as crystal / precipitation / particle formation techniques, including but not limited to the methods described below. Include. It will be apparent to one skilled in the art that the size of the crystals obtained by the method of the present invention can be adjusted by adjusting the process parameters. For example, an increase in rpm of the crystallizer often results in finer particles, and adjustment of the addition and / or stirring speed will change the particle size by changing the supersaturation and the degree of mixing. One skilled in the art can use routine experimental techniques to determine the parameters that are most optimized for each individual situation.

In the present invention, the choice of solvent depends on the solubility of the material to be crystallized / precipitated. Preferably, substantially saturated or supersaturated solution is obtained by mixing the feed / reactant flow stream fed through each tube. As with the antisolvent crystallization / precipitation techniques known to those skilled in the art, one or more fluids are generally solvents comprising the material to be precipitated. Where more than one feed stream is involved, the one or more associated second fluids are antisolvents, reactants, precipitates, pH converting agents, neutralizing agents, dissolved salts or buffers, cooling or heating fluids and compressed gases.

In the case of a second feed addition to induce crystallization, the selection of a particular feed stream and a second feed stream (eg antisolvent) can be readily made by one skilled in the art taking into account the solubility properties of the precipitated compound. For example, the antisolvent can be, for example, a water soluble substance that is soluble in water, and suitable water-miscible antisolvents (eg, acetone, isopropanol, dimethyl sulfoxide, etc., or mixtures thereof), for example Precipitates using 20% by weight methanol, 80% by weight ethanol and the like. Examples of additional antisolvents may include, for example, less water soluble materials that can be dissolved in light oil or ethyl acetate and precipitate for example in diethyl ether or cyclohexane.

Examples of reactive precipitation / crystals may include materials that are soluble in water at high pH and precipitate in acidified water at low pH. Additional reactive examples include a rapid reaction between two inorganic ions, initially dissolved in a separate aqueous solution. One example of such reactive precipitation or crystallization is a solid that depends on the formation of inorganic salts (e.g., optoelectronic materials such as Al (OH) ₃ or Ca ₅ (PO ₄ ) ₃ OH, or CaF ₂ , etc.) or changes in pH. Phase-forming compounds (e.g., by adjusting the pH of the protein solution towards the isoelectric point of the protein with acid or base to cause precipitation; in addition, one example is less soluble in water at low pH but much better at higher pH). And crystalline / precipitated carboxylic acids, including compounds such as soluble ibuprofen.

Examples of salt precipitation / crystallization may include substances such as proteins or peptides that are dissolved in a buffered aqueous solution and are precipitated or determined by mixing with a solution of, for example, water-soluble salts (such as sodium chloride or ammonium sulfate).

Examples of cold forced crystallization / precipitation may include materials that are soluble in solvent and crystallized / precipitated by impact cooling, where the second liquid stream may be a refrigerated solvent such as, for example, water, ethylene glycol or ammonia.

The operating temperature is one parameter that can affect the solubility of the material and thus the process yield. For many materials, yield can be maximized by operation at low temperatures. However, careful selection of antisolvents allows for increased yields at room temperature operation of the process. However, maximizing the yield of this process is not an essential aspect of the method of the present invention. The present invention merely requires that the temperature be adequate so that crystallization can take place. Temperature the crystallization takes place is determined from solubility data, in some instances, the solubility data is available in tables found in the literature [Handbook of Chemistry and Physics, 73 ^rd edition, CRC Press] or scientific literature.

When the present invention is used as part of a continuous process, the rate of addition of solvents and antisolvents through the tubes can be controlled by any known method, including non-limiting examples of the tubes. In general, those skilled in the art will recognize and understand methods that can limit the flow rate to a typical crystallization apparatus, including but not limited to the use of control valves and the like. Therefore, this same method is applicable to the present invention. Solvent and antisolvent addition rates are limited only by the equipment used to control them. The fluid is added at the same rate as the outflow, ie the sum of the injection flow rates of the solvent and the antisolvent is equal to the rate of the slurry exiting the process. If two or more feed / reactant streams are used, the rate of the two or more feed streams may be any value determined by the phase diagram of the material well known to those skilled in the art. If one or more fluids are slurries / suspensions, seeding of crystals / precipitates can be induced, where the crystals / precipitates by this process are one or more fluid streams supplied to the vessel, for example a material such as crystallized / precipitated It may be crystallized / precipitated over other materials suspended in.

In exiting the apparatus of the present invention, the precipitated / crystallized particles may be removed from the fluid mixture (eg, by filtration, centrifugation, etc.). Optionally, the precipitated compound may be dried by conventional methods generally known to those skilled in the art. Examples of such methods include, but are not limited to, dish-drying, oven-drying, heat-drying, and air-drying. Optionally, prior to the drying step, the drying and precipitated particles may be separated from the combined fluid mixture using solid / liquid separation techniques commonly known to those skilled in the art, such as, for example, filtration, precipitation, centrifugation.

In addition, the present invention can be used to prepare any of a variety of small high surface area particles that can be used as carrier particles for liquids or as seeds for crystals or precipitates. The crystals / precipitates formed by the methods of the present invention are also, in many cases, simultaneously or subsequently coated with a moisture barrier, taste masking agents, or other additives that enhance the character of the crystallized agent. Similarly, crystals / particles of the active substance can be formulated with other agents (excipients, surfactants, polymers, etc.) to provide the substance in the appropriate dosage form (eg, tablets, capsules, etc.). Therefore, in the process of the present invention, in addition to the material, surfactants, emulsions and stabilizers can be introduced into the shear zone as another fluid stream to stabilize the precipitated dispersion.

The apparatus of the present invention also includes (i) the use of the vessel as a fermenter, (ii) the use of a cyclic precipitation zone for liquid / liquid extraction during fermentation, and (iii) the use of the vessel for non-uniform catalytic reactions. However, the present invention may be used in processes other than crystal / precipitation or particle formation, but not limited thereto.

The vessel 1 can also be used as a fermentor for cell culture purposes.

In situ removal of the product from a fermentor of this design can be achieved using the minimally stirred terminal settling zone 10 described above. This would be possible using a liquid / liquid extraction method. Lower density liquids are gradually concentrated towards the top of the terminal settling region.

In using the vessel 1 as a fermentor, the minimum power input of the stirrer 13 allows mechanically sensitive microorganisms to be suspended without exposure to high shear forces. For example, fungal yeast can be used for cell culture, which is all broken up by other methods by agitators commonly used in cell culture.

For fermentation products in which the cell product is substantially toxic to the cell if the cell product exceeds a threshold concentration or causes product inhibition, in situ removal of the product may be achieved by using an extraction solvent in the form of an emulsion that cannot be mixed in the vessel. It can be used to overcome this limitation. Emulsions may be introduced into the fermentor at several possible locations whereby the emulsions circulate through the vessel 1 together with the cells, products and medium. Preferably, however, the feed / reactant stream is introduced into an upstream sparger at close proximity to the stirrer below the stirrer base plate and / or inside the vent. Toxic (or other) products will be fractionated into the extraction solvent. In order to recover the fermentation product without terminating the fermentation, the extraction solvent can be continuously concentrated and removed using the terminal settling zone 10. In this region, an extraction solvent such as an organic liquid (specific gravity is lower than the cell culture medium) is raised in the ring region and gradually concentrated upwards. The concentrated and coalesced dispersion may be continuously removed from the fermentor through a removal nozzle at the top of the terminal settling zone 10. This material can be sent to a removal process to separate the product from the extraction solvent. The regenerated extraction solvent can be returned to the emulsification step and then returned to the fermentor vessel.

The present invention can also be used for heterogeneous catalysis because high speed internal circulation allows good mass transfer. In addition, low intrinsic power input enables lower friction of catalyst particles than conventional stirred tank reactors. While these advantages have general utility for non-uniform catalysts, fixed enzymes and crosslinked catalyst crystals (CLEC ^R ) (registered trademark of Alters, Inc.) are mechanically sensitive that benefit from the reduced intrinsic power strength characteristics of the instrument. It is a heterogeneous catalyst.

Biological products are natural, synthetic, or semi-synthetic (eg peptides, proteins, enzymes, nucleotides, etc.) and have been demonstrated to crystallize in bulk containers (eg glucose isomerase). Biological products have also been demonstrated to precipitate in non-crystalline or semi-crystalline state (eg soy protein isolate). In the case of such precipitation, the physical characteristics of the precipitation process of the biological product follow some of the process operating principles of crystallization, such as the benefits of good suspension of the particles and in fact the inherent power strengths as low as possible. Biological products generally crystallize into particles that are more susceptible to mechanical damage than smaller molecules, salts or minerals. The gentle stirring characteristics of the vessel of the present crystallization device therefore have particular utility in the crystallization of biological products. The reason for this is that crystal breakage is minimized, which results in significantly lower secondary nucleation and thereby larger average crystal size and narrower size distribution. Larger crystals tend to be purer than smaller crystals because impurities are found mainly in the mother liquor that adheres to the surface of the crystal. Larger crystals have a smaller surface area per unit volume. Larger crystal sizes also make it easier to achieve downstream solid / liquid separation.

Crystallization of biological products is usually accomplished using salting out techniques or pH adjusting methods. In this example of crystallization, the method of introducing the concentrated salt solution or acid / base has a major influence on the rate of nucleation and formation of crystals / precipitations. The nonpoint source feed / reactant technique used in the vessel provides significant advantages over more conventional sparger type feed / reactant introduction tubes for crystallizing biological products. This approach can avoid the formation of very fine precipitates around the entry point, resulting in the formation of larger and better crystal grains.

While not a requirement for processing, biological products, like many pharmaceutical crystallization methods, are most suitable for batch drive. In this example, the liquid level in the vessel increases over time of the crystallization batch, except when crystals are introduced by thermal techniques. For containers with vents, this presents a problem of liquid circulation at the beginning of the batch, since the low liquid height prevents the liquid / slurry passage above the vents from being recycled down towards the stirrer. To overcome this limitation, when the liquid / slurry level is less than the ventilating height, an open window is placed in the ventilating opening to allow passage of the liquid / slurry from the outside of the ventilating into the ventilating tube. This enables recycling of the slurry / liquid during the batch reaction time when the liquid level is below the vent height.

Biological products include, for example, food or food ingredients. Water-soluble and water-insoluble foods and food ingredients that can be crystallized and precipitated include carbohydrates, polysaccharides, oligosaccharides, disaccharides, monosaccharides, proteins, peptides, amino acids, lipids, fatty acids, phytochemicals, vitamins, minerals, salts, food colors, enzymes , Sweeteners, anti-caking agents, antioxidants, polypeptides, oleomolecule therapeutics, cofactors, nucleotides, oligonucleotides, RNA sequences, DNA sequences, vaccines, immunoglobulins, monoclonal or other antibodies, viruses, gene therapy vectors, carbohydrates, Polysaccharides, oligosaccharides, disaccharides, monosaccharides, colorants and other pigments, and mixtures thereof.

Still other materials that may be crystallized / precipitated in the apparatus of the present invention include, but are not limited to, pharmaceutical compounds such as biopharmaceuticals as defined above, such as grain protection drugs. The present invention provides the ability to make finer or coarser drug crystals than are normally produced by bulk crystallization (about 50 microns), and therefore the present invention provides the necessity / It will be possible to have higher dispersion rates without the need for cost / contamination and the introduction of solubility enhancers such as cyclodextrins or surfactants.

Pharmaceutical or biopharmaceutical substances are delivered through pulmonary delivery mechanisms, parenteral delivery mechanisms, transdermal delivery mechanisms, oral delivery mechanisms, intraocular delivery mechanisms, suppository or vaginal delivery mechanisms, intra-internal delivery mechanisms, intranasal delivery mechanisms and implantable delivery mechanisms. May be ones.

Still other pharmaceutical substances that can be made by the present invention include water-soluble and water-insoluble pharmaceuticals, anabolic steroids, tonics, analgesics, anesthetics, antacids, antiarrhythmics, anti-asthma, antibiotics, anti-caries, anticoagulants, antiparkinson Anticonvulsants, antidepressants, antidiabetics, antidiabetics, anti-nausea agents, antiepileptic agents, antifungal agents, antiparasitic agents, anti-hemorrhoids, antihistamines, anti-hormones, antihypertensives, antihypertensives, anti-inflammatory, anti-muscarinic, antifungal Antitumor agent, anti-obesity agent, anti tartar agent, antigenic probiotic agent, antipsychotic agent, antiseptic agent, antifungal agent, antithrombotic agent, antitussive agent, antiviral agent, anxiolytic agent, astringent drug, beta-adrenergic receptor blocker, Bile acids, mouthwashes, tracheal spasms, bronchodilators, calcium channel blockers, cardiac glycosides, birth control pills, corticosteroids, anti-inflammatory agents, diagnostic agents, digestive stimulants, diuretics, dopamine agonists, Electrolytes, vomiting agents, expectorants, hemostatic agents, hormones, hormone replacement therapies, hypnotics, hypoglycemic agents, immunosuppressants, erectile dysfunctions, laxatives, lipid control agents, mucolytic agents, muscle relaxants, non-steroidal anti-inflammatory agents, nutraceuticals, pain Emollients, parasympathetic inhibitors, parasympathetic drugs, prostaglandins, psychostimulants, psychotropics, sedatives, sex steroids, antispasmodic, steroids, stimulants, sulfonamides, sympathomimetic agents, sympathomimetic agents, sympathetic stimulants, thyroid Similar agents, but not limited to, thyroid functioning drugs, vasodilators, vitamins, xanthines and mixtures thereof.

As shown in Figures 8 and / or 9, the present invention also contemplates the use of ultrafiltration drives (or other cross-flow filtration devices) in closed loops equipped with biological product crystallization devices. Supersaturation is induced by concentration at the surface of the ultrafiltration drive membrane. This has a unique advantage over salting out or reactive crystallization, since higher supersaturation is better distributed across the membrane area than the feed / reactant introduction area. In addition, the use of a membrane process in series with the crystallization apparatus makes it possible to use a smaller volume batch than the thinner selection in which salts are used to induce crystallization. For macromolecular biological products, each containing peptides, enzymes, proteins, polysaccharides, and the like, which do not pass through the pore size of the ultrafiltration membrane, the serial use of the membrane process for concentration results in a membrane and crystallization apparatus that undergo continuous recycling. Provide a useful combination of processes. If a fine particle breaking system is used before the membrane device, the flow rate will be maximum. If no fine particle destruction device is used, a cross flow ultrafiltration device would be desirable to minimize contamination of the crystals on the membrane surface. Similar utility of the membrane process in series with the crystallization apparatus can be achieved in the case of microfiltration, nanofiltration and reverse osmosis membranes. The usefulness of this configuration is not limited to biological molecules.

Proper clean in place (CIP) and / or proper sterilize in place (SIP) features of the batch crystallization device are additional features that may be used in the present invention to meet processing requirements for food and therapeutic products. Food grade crystallization processes similarly require CIP and SIP capabilities. Injectors and lines are also provided herein for this system for the automatic introduction of fluid cleanliness and sterilization of the fluid at the completion of the deployment.

Crystallization of biological products is the use of crystallization / precipitation techniques that are rapidly emerging in the biotechnology and food industries. The gentle agitation system, the non-point feed / reactant introduction system, and the serial use of the membrane concentration here provide a key operational advantage over the crystallizers of the stirred tank type currently used. The inherent power intensity control of the instrument is crucial. Specific power intensity (SPI) often controls the crystal properties, such as the flowability of powdered products. Particle damage and secondary nucleation are known to be dependent on the intrinsic power strength, i.e., the value of the power supplied to the stirrer as the mass in the stirrer volume. Crystallization device loops using pumped and separated shear zones to vary the two factors independently are described in Influence of different scales of mixing in reaction crystallization :, by Marika Torbacke and Ake Rasmuson, Chemical Engineering Science, 56 (2001). 2459-2473.

While this illustrates the need for adjustment of both factors, it also shows a lack of understanding in the industry how to adjust both factors in a single stirrer, such as is done in the present invention.

Therefore, the present invention provides a method of designing an agitator that provides the required pumping speed and inherent power strength at any capacity.

The following definitions are set forth to further describe and define the methods of the present invention.

As used herein, “stirrer pumping rate” is a mathematical formula that helps describe the required circulating flow around the vent to uniformly suspend the crystals, dilute the supersaturated production area, and mix them as uniformly as possible throughout the desired crystal volume. Can be defined using an expression. Stirrer pumping rates are given as shown in Equation I in Perry's Chemical Engineer's Handbook, Seventh Edition, McGraw-Hill, NY, 1997 (equation 18-2).

Q = NQ * D ³ * N

Where Q is the stirrer release rate (e.g. M ³ / sec), NQ is the release coefficient (unitless), D is the stirrer diameter (e.g. meter), and N is the rotational speed (e.g. revolutions per second) .

As used herein, the "intrinsic power strength" (SPI) is a measure of the mixing that is given to the slurry passing through the stirrer by the stirrer during each revolution as it passes through the duct (in contrast to the average value of the vessel often used in the mixing literature). Describe the strength. Mathematically, SPI is defined as the value of the power input of a stirrer as the mass of slurry in the stirrer volume of the stirrer. Therefore, this can be expressed in the form of Equation II.

SPI = Agitator Power / (Agitator Volume * Rho)

Where the stirrer power (e.g. watts) is the input from the stirrer to the slurry given in Equation IV below, and the denominator is the mass in the stirrer volume of the stirrer (in this case divided by the unit of cubic meters divided by kilograms per cubic meter, or simply Kilograms). Rho is the slurry density (eg, kilograms per cubic meter).

The "stirrer volume" is the area of the stirrer multiplied by its height (by simple geometry) and is represented by equation III. Therefore, the mass of the agitation volume is

Mass in stirrer volume = π * D ² * H * Rho / 4

Where H is the vertical height (eg, meter) of the stirrer.

The “stirrer power” is given in the form of equation IV in Perry's Handbook (Equation 18-3 cited above).

P = Np * N ³ * D ⁵ * Rho

Where Np is the number of powers (unitless), N is the rotational speed (e.g., revolutions per second), D is the stirrer diameter (e.g., meters), and Rho is the slurry density (e.g., kilograms per cubic meter) to be.

When Equations III and IV are substituted by Equation II, SPI is

SPI = Np * D ⁵ * N ³ * Rho / (π * D ² * H * Rho / 4)

Represented by

SPI = K * D ³ * N ³ / H

It is simplified to, where K = 4 * Np / π.

In general, pumping speed and specific power intensity (SPI) values are not proportional to each other, so changing unit capacity changes these important stirrer design parameters, and the designer's mystery keeps certain parameters constant and The decision is to decide which parameters to vary, or trade off to vary both parameters. The pumping speed (Equation I) is directly proportional to the rotational speed, whereas the intrinsic power strength (Equation V) is proportional to the cube of the rotational speed, so geometrically scales up or down and keeps both proportionally the same. Can not.

Therefore, the present invention provides a method of adjusting these two main variables by the action of changing the stirrer height (H in the equation), in which both the emission coefficient NQ and the power Np are proportional to the height for this stirrer. Because it is determined. Therefore, for a given stirrer diameter, the SPI remains constant for stirrers of different heights (as the mass being replaced also varies linearly with height), the pumping speed varies linearly with height. Thereby, as the crystallization apparatus is scaled up or down, it is possible to adjust both the pumping speed and the SPI.

In the vent crystallization apparatus stirrer having a preselected diameter (D), stirrer rotational speed (N), power number (Np) and intrinsic power strength (SPI), the method of determining the height (H) of the stirrer is given by the following equation. By calculating the H value that follows.

H = K * D ² * N ³ / SPI

Where K = 4 * Np / π.

For purposes of illustration, suppose there is a plant crystallization device with a diameter of 12 feet designed in a pilot test program using, for example, an 8 inch diameter, 2.5 gallon pilot device to verify the effect of different feed purity. If an 8-inch crystallization device is calculated at the circulation speed (and thus the blade tip speed), the following results will be produced.

Crystallization device Agitator diameter Stirrer height in Rotation speed 1 / min Circulation Speed ft / sec SPIW / Kg 12 ft 8.4 ft 18.9 22 2.8 3.5 8 in 5.5 in 1.03 403 2.8 64

Since this method exhibits very high SPI compared to factory devices, it tends to produce finer crystals than commercial size devices. Therefore, inherently high SPI in small capacity devices exhibits higher crystal friction and, hence, smaller average crystal size distribution.

However, in using the method according to the invention, the circulation rate can be kept constant as in the comparative example shown above, but the SPI is lowered. This stirrer design procedure therefore discloses a means of making devices of various capacity sizes to carry out as close as possible to each other. For a pilot stirrer with twice the height, the following results are obtained.

Device Agitator diameter Stirrer height in Rotation speed 1 / min Circulation Speed ft / sec SPIW / Kg 12 ft 4 ft 18.9 22 2.8 3.5 8 in 5.5 in 2.06 202 2.8 8.0

Thus, the SPI has fallen to one eighth. If desired, this 8-in device can be used at half speed. However, if it is desirable to further lower the SPI (perhaps, for example, this crystal is a very fragile needle), running a pilot stirrer three times the height at 1/3 of the original speed gives the following results.

Device Agitator diameter Stirrer height in Rotation speed 1 / min Circulation Speed ft / sec SPIW / Kg 12 ft 8.4 ft 18.9 22 2.8 3.5 8 in 5.5 in 3.1 134 2.8 2.4

Agitators with a height of 3.1-inch provide lower SPI than commercial size devices, with a small reduction in height and a proportional increase in speed, which is identical to commercial size devices with the same flow and SPI design. Will result in

Example 1-Whisk Blade Experiment

This example shows that the use of the apparatus of the present invention results in better circulation and crystal suspension than is seen with other crystallization apparatus in the art. The crystallization apparatus has a 36 inch diameter, 25 inch diameter clean vessel, a tapered (straight) vent and a 25 inch diameter radial flow stirrer using a variable speed propeller as the power source. The stirrer was propelled from the bottom using a variable speed DC propeller. As shown in Figure 4, four 10.5 inch long whisk blades were attached downwards towards the bottom plate. Their tapered heights were 1.75 inches at the propelling shaft end and 1.25 inches at the opposite end. The particles used in the experiment were a fluid solution, water of 150 to 200 microns, specific gravity of 2.9 g / cm ³ , sand particles of 1% by weight. The measurement results are shown in Table 1 below.

RPM % Suspended solids (control) % Suspended solids (using whisk blade) 40 60 70 50 70 80 60 80 90 80 90 95 100 92 99

Extrapolating these results, it can be expected that about 122 RPM is required for suspending all sand particles for the control instrument but only about 100 RPM is required for the instrument using the whisk blade. The difference in 22 RPM may seem small, but in light of the fact that the power is proportional to the cube of RPM, the sand particles are suspended in water and removed from the bottom of the vessel. It needs more power.

Example 2 Synthetic Gypsum Process

A 3 wt%, 40 gpm, weak sulfuric acid stream from ion exchange resin regeneration was neutralized using a 20 wt% lime slurry to produce a synthetic or chemical gypsum represented by the following scheme.

H ₂ SO ₄ + Ca (OH) _2- > CaSO ₄ : 2H ₂ O

A 10 liter vent pipe pilot crystallization device was used, where the vent pipe had a diameter of 5.5 inches at about 200 rpm and provided an SPI of about 8 W / Kg. The resulting crystals were needle-shaped and relatively fine (average diameter less than 100 microns, weight percent (by Coulter Counter®). The double withdrawal procedure doubles residence time (double concentration). Crystals were used to concentrate the crystals, which resulted in a dramatic increase in crystal size Subsequently, a Burke type device of 10 ft vessel diameter was used with the addition of a settling zone on top. The average diameter of the crystals produced by was greater than 400 microns (based on weight percent).

Background of the Invention

Claims (27)

(a) a container; (b) a radial flow stirrer optionally having a top plate and a base plate; And (c) a vent pipe having a plurality of bulkheads securely attached and disposed in the container to form a conduit between the vent pipe and the side wall of the container and having a diameter of about 0.7 times the diameter of the container Crystallization / precipitation apparatus comprising a. The appliance of claim 1 wherein the vessel is comprised of a material selected from the group comprising steel, glass, fiberglass, and PVC. The apparatus of claim 1 wherein the vessel further comprises a terminal settling region. 2. The appliance of claim 1 wherein the vessel further comprises at least one second partition wall attached to the vessel sidewall over the vent. The apparatus of claim 1 wherein the vessel further comprises a central support. The apparatus of claim 1 wherein the stirrer is a radial flow vane. The appliance of claim 1 wherein the stirrer is comprised of a material selected from the group comprising steel, fiberglass, titanium, glass, and PVC. The instrument of claim 1 wherein the base plate further comprises one or more openings. The instrument of claim 1 wherein the base plate further comprises one or more whisk blades. The instrument of claim 1 wherein the base plate has a radius greater than or equal to the diameter of the vent pipe. The instrument of claim 1 wherein the vent pipe is cylindrical. 2. The appliance of claim 1 wherein the vent pipe is tapered. 2. The appliance of claim 1 wherein the vent pipe is hollow. 14. The appliance of claim 13 wherein the hollow vent further comprises a terminal settling region. The apparatus of claim 13, wherein the hollow vent further includes a heat exchanger. The instrument of claim 1 wherein the vent pipe further comprises a terminal settling region. The appliance of claim 1 wherein the vent further comprises one or more windows. The appliance of claim 1 wherein the vent pipe is comprised of a material selected from the group comprising steel, fiberglass, glass, and PVC. 2. The appliance of claim 1 wherein at least one interior portion of the vessel, stirrer, vent and multiple bulkheads firmly attached thereto are coated with a suitable soft coating. 20. The apparatus of claim 19, wherein the suitable soft coating agent is selected from the group comprising polyethylene, poly (tetrafluoroethylene), polypropylene, neoprene, latex, and rubber. A fermentor comprising the apparatus of claim 1. A non-uniform catalytic reaction vessel comprising the apparatus of claim 1. Supplying one or more fluids to the device of claim 1 comprising one or more dissolved materials for which the fluid is crystallized / precipitated; Stirring the one or more fluids to cause one or more dissolved materials to crystallize / precipitate from the one or more fluids into particles; And Causing one or more fluids and particles to exit the instrument of claim 1 Comprising, crystallizing / precipitating the particles. The method of claim 23, wherein the one or more dissolved substances is selected from the group comprising biological products, pharmaceutical substances, and biopharmaceutical substances. The method of claim 24, wherein the biological product is natural, synthetic, or semi-synthetic. The method of claim 25, wherein the biological product is a protein, enzyme, peptide, polypeptide, amino acid, oleomolecule therapeutic agent, cofactor, nucleotide, oligonucleotide, RNA sequence, DNA sequence, vaccine, immunoglobulin, monoclonal or other antibody, virus , Gene therapy vectors, carbohydrates, polysaccharides, oligosaccharides, disaccharides, monosaccharides, lipids, fatty acids, phytochemicals, vitamins, minerals, salts, food colorings and other pigments, sweeteners, anticaking agents, thickeners, emulsions, stabilizers, anti -Microbial agents, antioxidants and mixtures thereof. 25. The method of claim 24, wherein the pharmaceutical agent is an anabolic steroid, tonic, analgesic, anesthetic, antacid, antiarrhythmic, antiasthmatic, antibiotic, anticarious, anticoagulant, antiparkinson, anticonvulsant, antidepressant, antidiabetic, antidiabetic , Anti-emetic agent, antiepileptic, antifungal, antiparasitic, anti-hemorrhoidal, antihistamine, anti-hormonal, antihypertensive, antihypertensive, anti-inflammatory, anti-muscarinic, antifungal, anti-tumor, anti-obesity, anti Tartar, Antibiotic, Antipsychotic, Antiseptic, Antifungal, Antithrombotic, Antitussive, Antiviral, Anxiolytic, Astringent, Beta-adrenergic receptor blocker, Bile acid, Mouthwash, Tracheal spasms, Bronchial Dilators, calcium channel blockers, cardiac glycosides, birth control pills, corticosteroids, anti-inflammatory drugs, diagnostic agents, digestive stimulants, diuretics, dopamine agonists, electrolytes, nausea, expectorants, hemostatic agents, hormones, hormone replacement Drugs, hypnotics, hypoglycemic agents, immunosuppressants, erectile dysfunctions, laxatives, lipid modulators, mucolytic agents, muscle relaxants, non-steroidal anti-inflammatory agents, nutraceuticals, pain relief agents, parasympathetic agents, parasympathetic agents, prostaglandins , Psychotropics, psychotropics, sedatives, sex steroids, antispasmodic, steroids, stimulants, sulfonamides, sympathomimetic agents, sympathomimetic drugs, sympathomimetic agents, thyroid-like drugs, thyroid functioning drugs, vasodilators, vitamins , Xanthine and mixtures thereof.