JP2006510484A - Apparatus and method for producing crystals / precipitates / particles - Google Patents

Abstract

The present invention relates to an apparatus used for the production of particles, such as by precipitation or crystallization, and a method for producing crystals / precipitates or other particles.

Description

  The present invention modifies equipment used in producing particles, such as by precipitation or crystallization, methods for producing crystals / precipitates or other particles, and equipment scale while keeping specific power intensity substantially constant. Regarding the method. This apparatus can be configured as a crystallizer for not only inorganic substances such as mineral salts but also biological products such as proteins and enzymes, and low molecular organic substances such as pharmaceuticals and fine chemicals.

  To produce many different types of substances and particles, including but not limited to organic compounds such as adipic acid, pentaerythritol, and inorganic compounds such as gypsum, calcium fluoride, sodium sulfate, A draft tube crystallizer is generally used. For example, Patent Document 1 (Burke) describes an apparatus for generating a single nucleus crystal from a solution by evaporative cooling.

  The production of particles, especially microparticles, includes oral, transdermal, injection or inhalation pharmaceuticals, biopharmaceuticals, dietary supplements, diagnostics, agricultural chemicals, pigments, food additives, food formulations, beverages, fine chemicals, cosmetics, It is used in many applications such as electronic materials, inorganic substances and metals. With current precipitation and crystallization techniques, crystals having an appropriate particle size and particle size distribution may not be produced with high reliability. In some cases, large crystals are desired to facilitate solid-liquid separation and improve the powder flow properties of the product, while in other cases, a narrow particle size range (eg, 1 Fine particles (˜5 microns) are desired.

  Increasing the particle size is difficult and often challenging for crystallization process engineers. Many of the methods in this technology allow (i) mixing and stirring systems, and (ii) various particle size fractions in the crystallizer to be recycled, dissolved or concentrated. This is related to the classification method. When it is desired to produce fine particles, a pulverization, crushing or pulverization step is often required as a post-treatment in order to reduce the crystallized particles to a predetermined diameter and distribution width. If the product size can be controlled to the appropriate particle size directly by operation of the crystallizer without relying on the post-treatment grinding step, the process will be simpler and more powerful, the particle surface will be clean, Dust will be reduced, particle properties (eg, flowability, compressibility into tablets, etc.) will be improved, and dispersibility will be improved in dry powder inhalation therapy products.

  Also, in the crystallizer, the relationship between the diameter and the height of the tank is usually designed with a certain geometric ratio as well as the relationship between the diameter and pitch or thickness of the stirrer blade. However, this fixed geometric ratio is often undesirable in crystallization practice.

  It is not optimal that the agitator system of the crystallizer has a fixed geometric ratio. This is because the slurry pumping in the tank and the specific power intensity (SPI), which is the energy sent to the agitator to the slurry, are not proportional to each other, and the pumping speed and the SPI design parameters are changed when the ratio of the apparatus (for example, the diameter of the agitator) is changed. Will change. Thus, it is a challenge for the designer to determine which parameters remain constant, which parameters to change, or which to compromise and change both parameters together. For example, in texts such as Non-Patent Document 1, Non-Patent Document 2 is cited and it is recommended to keep the tip speed constant in laboratory, pilot, and actual crystallizers. However, as the impeller diameter increases, the specific power intensity changes and is more closely related to attrition and secondary nucleation than tip speed.

  The present invention provides an efficient and scaleable apparatus and method for producing crystals / precipitates or other particles. One of the advantages provided by the present invention is that a high internal pumping (or circulation) speed is obtained while having a low specific power input, which results in good mass transfer and mechanically sensitive crystals / precipitation. An environment can be realized that minimizes destruction / wear / damage to the body or particles. As a result, the benefits of the device are particularly significant in mechanically sensitive solid products such as biological products (eg, proteins) and low molecular weight organics such as pharmaceuticals.

  Another advantage of the present invention is that the apparatus is not limited to the use of crystallization, but is not limited to the following: fermentation apparatus, extraction apparatus and liquid / emulsion separation apparatus, heterogeneous catalytic reactor This means that it can be used as a general treatment tank. In these applications, the apparatus is substantially lower in slurry than alternative processing tanks (such as those stirred by a Rushton turbine, fixed pitch impeller, hydrofoil, marine impeller, rotor-stator, etc.). Provides very good mixing and rapid dilution of the feed stream at the power input to.

  Yet another advantage of the present invention is that it can optionally be utilized to provide a fluid containing seed crystals or other particles for co-precipitation, further growth or coating.

  Thus, the present invention provides an apparatus that is a processing vessel for laboratory, pilot or industrial scale crystallization or precipitation processes that allow excellent control over crystal / particle formation. Is provided. Based on the specific parameters discussed herein, the apparatus and method of the present invention can also be used for crystallization compared to current crystallization techniques such as using a draft tube baffle crystallizer. / The size of the crystals / particles produced in the precipitation process can be better controlled.

  Also, commercially available crystallizers are generally hampered by limited performance because their crystal nucleation rates are higher than desired. Techniques dealing with nucleation rates higher than desired have been in practice for a long time and are described in most crystallization texts. Such techniques include, for example, fines destruction, clear liquor advance, and double draw off. Each of these three techniques necessitates separation of a slurry of crystals (eg, for clear liquid, fine and coarse particle fractionation). This separation is usually performed by an external separation device such as an eltriator or cyclone.

  In Fines Destruction, the fine particle fraction of crystals is passed through a system (eg, heat exchanger, diluter) that dissolves them, and the clear liquid is returned to the crystallizer. This is particularly useful in the operation of batch crystallizers, but is also widely practiced in continuous processing. In the case of Clear Liquor Advance, the separation is extreme and the fraction collected in the separator is essentially crystalline, as used in many continuous mineral crystallization / precipitation processes. Not. Double draw off is used in a continuous crystallization process where a representative stream of slurry is removed and sent to a downstream separator, as is the separated fines fraction stream.

In all these cases, the device produces crystals of relatively large diameter, which is preferred per se and also requires a separator (e.g. a downstream required for the crystallizer) (e.g. It is also desirable in that the cost of a centrifuge, filter press, etc. can be reduced. Another advantage of the present invention is that larger crystals / precipitates / particles can be produced than using other crystallizers found in the art, and this allows operation at the limit of production capacity. In the process being used, even if the downstream separation equipment is the same, a higher production capacity is provided by producing crystals with a larger average particle size. Separating the slurry into fine, fine and coarse particle fractions is a process to make this advantage available.

  The potential scope of application of the present invention is wide-ranging, for example, industries that can use the particles produced according to the present invention include pharmaceuticals, dietary supplements, diagnostics, polymer intermediates, agricultural chemicals, pigments, food additives Products, food blends, beverages, cell cultures and products thereof, fine chemicals, cosmetics, electronic materials, inorganic materials, metals, and the like.

US Pat. No. 1,997,277 JW Mullin, "Crystallization", 3rd edition, Butterworth-Heinemann, 1993 A. W. Nienow, “The effect of Aggregation on the Crystal Growth and Nucleation Rate and on Secondary Nucleation”, Journal of Chemical Engineers Association (Transactions Association of Japan). Volume 54, p. 205-207

The present invention
(A) tank,
(B) a crystallization / precipitation apparatus comprising a radial flow stirrer having an optional top and bottom plate and (c) a draft tube,
The draft tube has a plurality of baffles firmly attached thereto, and is arranged in the tank to form a flow path between the draft tube and the tank side wall, and the diameter of the draft tube is the diameter of the tank. Is about 0.7 times the device.

The present invention further provides:
Supplying at least one fluid to the device, the fluid comprising at least one dissolved substance to be crystallized / precipitated;
Agitating the at least one fluid to crystallize / precipitate at least one dissolved material from the at least one fluid to form particles; and at least one fluid and particles from the apparatus of the present invention. The present invention relates to a method for crystallizing / precipitating particles, comprising the step of discharging.

The present invention relates to an apparatus for producing crystals / precipitates or other particles and a method of using said apparatus. In general, the present invention is used to produce crystals / precipitates / particles of various sizes, depending on the compound being crystallized. Usually, however, crystals / precipitates or other particles range from about 0.5 to about 3000 microns, but in the present invention, the crystal / precipitate / particle diameter can be controlled so that it is smaller or more Large particle sizes are also contemplated. Thus, the present invention enables the production of narrower particle size distributions or finer crystals with narrower particle size distributions than those normally supplied by other crystallizers in the art, Allows the production of larger crystals.

  Since the present invention discloses a method of changing the scale of the present invention while maintaining a substantially constant specific power intensity, the present invention further provides for processing tanks of different scales (eg, for laboratory scales). Production scale) provides the ability to produce crystals with the same particle size and particle size distribution.

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

  The apparatus of the present invention can use many types of fluids as feed / reactants, such as solvents, liquids, slurries, suspensions, liquefied gases, supercritical fluids, subcritical fluids, etc. However, it is not limited to these.

  The present invention relates to any precipitated or crystallized particles such as pharmaceuticals, biopharmaceuticals, nutritional supplements, diagnostics, agricultural chemicals, pigments, food additives, food formulations, beverages, fine chemicals, cosmetics, electronic materials, inorganics and metals. Can also be used in the manufacture of Crystallized / precipitated particles in other industrial fields can be produced using techniques that are readily modified by those skilled in the art from the general techniques described herein.

  In general, crystallizer agitation is potentially conflicting with, for example, (1) good mixing and uniform particle suspension, and (2) particle damage and minimization of secondary crystal nucleation. There is a request. Good mixing for the initial dispersion of the feed stream is usually obtained by a large volumetric flow rate from the stirrer and a turbulent zone. Uniform particle suspensions are usually obtained by relatively high fluid velocities, especially at upward flow. However, setting such conditions is problematic because it usually creates conditions that damage the particles and form secondary nuclei. The present invention provides an apparatus and method for technically mitigating such problems.

  As used herein, the term "shear zone" refers to all zones subject to the shear force of the present invention, such as the zone between the impeller blade tip and baffle, the opening in the bottom plate and the sweep of the stirrer. Includes payment volume area.

  As used herein, the term “shearing force” encompasses all mixing / dispersing, mechanical forces that occur within the apparatus of the present invention, and in the swept volume region of the stirrer. These include, but are not limited to, the slight shear rates that occur, stretching forces, turbulence, cavitation and surface impact.

  As used herein, the terms “crystallization” and / or “precipitation” are intended to include any method of generating particles from a fluid and are classical solvent / antisolvent crystallization / precipitation. , Temperature dependent crystallization / precipitation, “salting out” crystallization / precipitation, pH dependent reaction, “cooling drive” crystallization / precipitation, crystallization / precipitation based on chemical and / or physical reaction Although precipitation etc. are included, it is not specifically limited to these.

  As used herein, the term “biological agent” refers to any therapeutically obtained from a biological resource or chemically synthesized equivalent to a product obtained from a biological resource. It also includes compounds, such as proteins, peptides, vaccines, nucleic acids, immunoglobulins, polysaccharides, cell products, plant extracts, animal extracts, recombinant proteins, enzymes, or combinations thereof.

The present invention generally includes:
(A) tank,
(B) optionally comprising a stirrer having a top plate and a bottom plate, and (c) a draft tube,
The draft tube has a plurality of baffles firmly fixed thereto, is disposed in the tank to form a channel between the draft tube and the side wall of the tank, and the diameter of the draft tube is equal to the diameter of the tank. An apparatus is provided that is approximately 0.7 times.

  Since the present invention can be scaled to various scales, the dimensions of the device (30) of the present invention will generally vary (eg, a diameter from about 1 cm to more than about 15 meters). Thus, the dimensions are varied to accommodate the scaled version of the present invention. This type of equipment can be designed for small volume production (eg 0.0005 kg / h), through various scale tanks, and for production of about 300,000 kilograms of crystalline product per hour on a dry weight basis. As such, the scale of the present invention can vary greatly.

  The vessel (1) of the present invention may be of any shape conventionally used in the crystallization / precipitation or particle production art. However, the vessel is preferably a closed cylindrical shell having a side wall (2) and at least one port (11) into which a nozzle, supply pipe or the like can be inserted.

  The vessel is made of any material that can withstand various forces generated by the present invention, such as glass fiber, steel, preferably stainless steel, more preferably carbon steel, PVC, glass, etc. Also good. The tank of the present invention is preferably stainless steel.

  The tank can be inserted or fitted with at least one pipe and / or nozzle for the introduction and / or discharge of vapor and / or liquid and / or for extracting product from the tank, and / or It has at least one port (11), preferably a plurality of ports, so that it can be cleaned and / or sterilized (in the field) as part of the hygiene requirements of the process. At least one port, and thus at least one inlet pipe, line nozzle, etc. may be located at any location in the vessel.

  The tank may also be provided with a centering support (8) that is fixed to the side wall of the tank and the draft tube and contributes to the stability and support of the draft tube.

  A second baffle (9) may optionally be attached to the side wall of the vessel in order to change the direction of the feed / reactant flow it contains and to generate a downward flow substantially towards the interior of the draft tube. Good.

  The dimensions of the tank vary depending on the scale of use. Those skilled in the art will recognize and understand the necessary adjustments that must be made to the bath when scaling the device in light of the disclosure herein.

As shown in FIG. 7, another embodiment of the present invention presents a tank with a peripheral sedimentation zone (10), which is a clear solution and / or fine crystals / Separation of the precipitate / particle fraction is possible. The peripheral sedimentation area (10) may surround the tank to form a continuous peripheral area, or may surround only a part of the tank, and You may install in the arbitrary positions lower than a liquid level. The peripheral sedimentation zone (10) is usually filled with slurry but is not exposed to the range of agitation seen in the rest of the vessel and is therefore shielded from the circulation of the slurry in the vessel. As a result, the peripheral precipitation area (10
) Provides an area where crystals precipitate from the slurry. In general, large crystals precipitate faster than small crystals. As a result, a portion of the slurry may be withdrawn from the top of the surrounding precipitation area (ie, through the withdrawal port shown in FIG. 7), thereby separating the clear liquid or particulate fraction. Thus, the size of the crystal is determined internally, avoiding the high cost, operating and space requirements of external separation equipment such as, for example, an elitorator and cyclone.

  Those skilled in the art will recognize and understand that, in light of the disclosure herein, the size, eg width and depth, of the surrounding sedimentation area must be changed. Depending on the specific parameters of the crystal / precipitate or other particles, the particle size and particle size distribution, the type of fluid used to produce the crystals / precipitate or other particles, and the operating conditions of the vessel, Such adjustments can be made.

  The agitator (13) of the present invention provides mixing of feed streams, rapid dilution of the concentrated feed into the tank body, suspension of crystals / precipitate / particles in slurry, and fluid circulation throughout the apparatus. provide. These properties are important for stable operation and consistent crystal / precipitate / particle formation. In general, the stirrer (13) of the present invention may be of any configuration as long as it can provide the necessary liquid circulation, the radial flow impeller provided at the top or bottom (or both) of the draft tube, and the draft tube. Examples include, but are not limited to, an axial flow propeller or a marine propeller, a double propeller, and a multi-propeller provided in the intermediate portion. The stirrer of the present invention is preferably a radial flow stirrer, more preferably a radial flow impeller having at least one blade, a bottom plate, and optionally a top plate. A typical commercially available crystallizer uses an axial impeller and generally has a very high ratio due to its higher rotational speed per minute than that of the present invention and its use with small agitator dimensions. Used with power intensity.

  The stirrer may be formed of any material as long as it can withstand various forces generated in the present invention, such as glass fiber, steel, preferably stainless steel, PVC, titanium, and glass. The stirrer of the present invention is preferably stainless steel or titanium.

  Radial flow impellers include, for example, the number of blades, blade dimensions, blade attack angle, and the number of revolutions per minute that an operator can operate to control the turbulent mixing and shear properties to which the crystal is exposed. Has several aspects. By indirectly controlling the degree of turbulence attenuation in this way, it is possible to mix and dilute high-concentration feed streams, suspend crystals, entrain bubbles, and form crystal precipitation zones such as surrounding precipitation zones. become.

  In addition, the dimensions of the blade, the number of revolutions per minute and the degree of separation affect not only the turbulence created by the impeller, but also the magnitude of the turbulence (usually indicated by epsilon from the disappearance of turbulent energy). give. Smaller and faster impellers form higher energy turbulence at higher frequencies (and smaller scales) than large impellers of the same power level, but the turbulence disappears more quickly. This is especially true in crystallizers because the solid content increases and the turbulent velocity spectrum disappears in the high frequency region.

  The radial impeller of the present invention can include several configurations to include at least one blade, optionally provided top and bottom plates. However, the impeller preferably comprises the configuration shown in FIGS.

The at least one blade of the impeller may have any shape as long as it provides an appropriate diameter impeller and provides the pumping speed necessary to circulate fluid throughout the device. However, typically the blade height is about 1/6 (1/6) of the stirrer diameter. The width of the at least one blade varies with the angle of the blade, however, it is usually determined to be equal to the agitator diameter divided by the amount of (8 × blade angle cos). For example, using a 10 foot (120 inch) diameter stirrer, if the blade angle of at least one blade is 55 degrees, the blade height is about 120 inches × 1/6, or 20 inches, and the width is 120 / (8 × cos 55), that is, (8 × 0.574), that is, about 26 inches.

  In general, the blades may have any angle that allows the necessary circulation of fluid throughout the device. However, the blade angle of the present invention is typically in the range of about 45 degrees to about 65 degrees. Preferably, the blade angle is about 55 degrees.

  As long as the impeller blade is in a separate flow (which occurs when the attack angle is as low as 6-10 degrees), the blade lift (eg, the force applied to the blade in the radial direction when pumping fluid from the impeller) is Blade drag (force applied to the blade in the direction of blade movement) depends on the attack angle, substantially independent of the angle. The separation flow is related to the blade lift and blade drag forces independent of each other, as in this case where the blade lift is constant and the drag force is related to the effective area of the blade. The energy from the blade drag is almost completely converted to turbulence. Thus, by controlling the blade angle, it is possible to control the amount of energy toward turbulence and mixing. The flow rate is controlled by the energy of turbulent flow depending on the rotational speed of the impeller, the blade angle and the rotational speed.

  The number of revolutions per minute (RPM) of the agitator varies depending on the scale of the apparatus of the present invention. However, in general, the maximum allowable RPM decreases as the size of the device increases.

  The optional impeller top plate (14) is generally provided over the distance of the individual blades such that the width is substantially the same as the length of the blade and is generally annular. Since the flow must move along the upper plate (14) leading to a strong turbulent region with a negative pressure and a strong separation flow just below the plate, the presence of the upper plate (14) strongly influences the flow. In this turbulent flow region, turbulent flow disappears extremely violently and occurs only in a small portion with respect to the entire cross section, but is not efficient in terms of energy. Removing the plate or enlarging the inner diameter, which is essentially a disc (rather than an annulus), could increase the efficiency of the impeller.

  As shown in FIG. 3, the agitator bottom plate (15) is substantially a unitary structure located at the bottom of at least one blade of the agitator and having a hole capable of receiving a drive shaft.

Alternatively, the bottom plate (15) further comprises at least one opening (16), preferably a plurality of, in order to function it rather than as a point source of feed and / or reactants to be introduced and dispensed into the vessel. May be included. In the radial flow stirrer shown in FIG. 3, the feed / reactant addition from the non-point source is preferably done by feeding the feed / reactant from under the bottom plate (15) of the stirrer. Good dilution / dispersion of the feed / reactant is made by addition from below the stirrer, but the bottom plate of the stirrer has a radius that is larger than the radius of the draft tube and less than the internal radius of the vessel. As a result, the feed and / or reactants can flow through these openings (16) and can spread radially through the rapid mixing zone as it passes through the stirrer blade. In that case, it is preferred that at least one sweeper blade (17), preferably a plurality of sweeper blades, is used to assist in the distribution of the feed and / or reactants. As shown in FIGS. 4 and 5, a plurality of sweeper blades (17) are typically mounted on the underside of the bottom plate (15) and extend along the vertical and / or horizontal axis of the bottom plate (15) and are perpendicular to each other. However, the length is usually the same as or shorter than the diameter of the bottom plate. The height of the sweeper blade is preferably tapered as it extends away from the drive shaft (for example, the height of the sweeper blade is 1.75 at the end adjacent to the drive shaft, opposite Can be about 1.25 at the side edge).

  Non-point source addition of feed / reactant has been used commercially in the past, with devices where the radius of the stirrer bottom plate is equal to the radius of the draft tube. ing. This enlargement does not affect the internal circulation made by the stirrer (13). This enlargement reduces the high feed / reactant ratio that bypasses the feed flow through the openings in the agitator bottom plate (15). The greater the radius of the stirrer bottom plate (15), the less feed / reactant will pass through the gap between the stirrer (13) and the inner wall of the apparatus tank.

  Usually, point sources such as sparger pipes are often used in commercially available crystallizers, but this type of supply equipment is used around the outlet when the supplied liquid is diluted and dispersed throughout the crystallizer tank. Has a serious disadvantage of forming a strong supersaturated region and consequently forming a strongly supersaturated water column.

  The opening (16) in the bottom plate (15) may be any shape and / or size, including but not limited to grooves, circles, triangles or squares or a combination thereof. This ensures that the fluid passes through the shear region, so that a homogeneous mixing takes place. The size and shape of the opening (16) does not affect the size or shape of the crystals produced by the present invention, but does affect the fluid flow pattern in the device and thus affects the generation of shear forces. . The crystal size can be manipulated by varying the fluid flow chemistry, the impeller speed, the flow rates of the various feed streams and their relative flow rates.

  In general, the agitator (13) of the present invention has a wide range of diameters, for example from about 10 cm to about 550 cm, and depends on the equipment scale used. The preferred stirrer, impeller, has a diameter (measured from the tip of one blade to the tip of the other blade) ranging from about 0.4 to about 0.75 times the diameter of the vessel used. Those skilled in the art, in light of the disclosure herein, can determine that the size of the stirrer (13) can be changed in response to changes in the equipment scale, and that such dimensions can be changed as described below. Although defined by law, you will recognize and understand how to change such dimensions.

In general, the volumetric flow generated by the agitator of the present invention (ie, the pumping speed, which is the volume of slurry delivered per unit time), and therefore the linear speed (eg, the average linear speed covers the agitator pumping speed). Divided by the cross-sectional area) is proportional to the diameter of the agitator (13). For example, an agitator having a diameter of about 10 feet typically produces a volumetric flow rate of about 112,800 gpm and a linear velocity of about 3.2 ft / sec at about 30 rpm. Similarly, the specific power input is also proportional to the cube of the stirrer angular velocity. Thus, the stirrer (13) having a relatively large diameter rotates relatively slowly at the same volumetric flow rate. Therefore, increasing the diameter of the agitator (13) can minimize the specific power intensity for a given volumetric flow rate and average linear velocity. This is described in December 2001 by Butterworth-Heinemann, edited by AS Myersson, “Booklister of the CrystallizationMidson” Suspension Flow "by D.A. Green (D
. A. Green). However, this is also limited because it can generally increase undesirable secondary nucleation (due to crystal attrition) and the tip of the stirrer blade cannot be brought very close to the vessel wall.

  The agitator (13) is coupled to a drive shaft (18) that is rotatably mounted. The drive shaft (18) is generally coupled to a motor or driving force that can rotate the agitator (13) at a speed that allows the solution or slurry to be crystallized to be well mixed and suspended. The rotatably mounted drive shaft (18), whether it is a solid shaft, or conversely, functions as a single or multiple inlet pipe and forces fluid into the sweeper volume (19) of the agitator. Therefore, it may be hollow. Similarly, the stirrer itself may be hollow, in which case at least one fluid stream is fed through the stirrer and along the stirrer, eg at least one blade and / or along the tip of the blade, at one or several points. Dispersed at points.

  The draft tube (23) of the present invention is generally used to circulate the fluid surrounding it, thereby providing a homogeneous mixing of the feed / reactant, consistent with the formation of crystals / precipitate / particles. This gives a different distribution. More specifically, the draft tube (23) forms a flow path (24) between the outer portion of the draft tube wall (25) and the inner portion of the cylindrical shell (26) of the vessel. After entering the sweeping volume (19) of the radial flow stirrer, the fluid rises substantially toward the upper end of the draft tube by the baffle. Thereafter, the fluid flows into the flow path (24), moves in the length direction of the draft tube (23), and is finally pulled back toward the impeller until it flows out from the upper end of the tube. In special batch applications where the vessel volume is not fully used or the level at which the slurry is filled increases or decreases throughout the batch operation, the draft tube (23) of the present invention further comprises , Including at least one window (27), preferably a plurality of windows, provided along the height direction of the draft tube. This allows for forced circulation of the slurry upward on the outside of the draft tube and downward on the inside of the draft tube.

  Further, generally, the flow toward the center of the device is separated at the upper end of the draft tube (23), so the flow along the inside of the upper portion of the draft tube is an upward flow, so that it is only about 70 at the upper end. % Draft tube is actually used, which reduces the effective area of the draft tube (23). However, the window (27) of the present invention allows the use of draft tubes at a greater rate.

The draft tube (23) is a cylindrical body arranged concentrically in the tank and has a diameter of about 0.7 times the diameter of the tank. The use of the draft tube is superior to the draft tube of the conventional crystallizer because the diameter of the draft tube makes the inner and outer volumes of the draft tube equal geometrically. The draft tube is a tapered cylindrical body, and the tapered draft tube has an upper end diameter (28) and a lower end diameter (29), and the upper end diameter is larger than the lower end diameter. preferable. The draft tube may be linearly or non-linearly tapered, or may be a combination of a cone base and a right cylindrical body. Alternatively, the draft tube may be a substantially right cylinder with a flared upper end and a shape like the end of a horn or trumpet, thus having a larger diameter than the lower end. This shape is determined by the settling rate of crystals / precipitates / particles in the slurry, and such determination could be made by one skilled in the art. When the slurry flow rises outside the draft tube, the slurry flow is accelerated if it has a tapered shape. Generally, it is desirable that the slurry rising speed outside the draft tube is equal to the slurry falling speed inside the draft tube. This results in equal slurry flow rates upward and downward on both sides of the draft tube. If the feed / reactant is the same speed inside and outside the draft tube, further shear forces are avoided during acceleration and deceleration. For crystals that are large or dense compared to the specific gravity of the fluid, outside the draft tube, the crystals rise at a slower rate than the fluid containing it (due to gravity). This leads to crystal accumulation or catastrophic blockage outside the draft tube. For some crystallized materials, a tapered draft tube is superior to a cylindrical diameter draft tube because it accelerates the slurry against gravity outside the draft tube, thereby overcoming settling and accumulation phenomena. . A guideline for sizing the tapered draft tube is to keep the volume of the external and internal areas on either side of the tank draft tube essentially the same.

  The draft tube (23) further acts so that the liquid flow is a vertical flow towards the upper end of the draft tube and prevents liquid vortices from being generated in the circular motion of the stirrer. More preferably, the baffle (12) is included. The baffle (12) has a strong influence on the degree of vortices maintained in the tank and the disappearance speed of the turbulent flow in the annular part, and affects the material distribution inside the baffle.

  The draft tube (23) may be formed of any material as long as it can withstand various forces generated in the present invention, such as glass fiber, steel, preferably stainless steel, PVC, and glass. . The draft tube of the present invention is preferably stainless steel.

  Another embodiment includes a hollow draft tube with holes between the walls of the draft tube. The holes can be used for several purposes, for example, for the purpose of introducing feed / reactants into the device and / or as a means of heat transfer for heating or cooling the device and contents. However, the present invention is not particularly limited thereto. Thus, the draft tube can be used as a heat exchanger.

  In yet another embodiment, it includes a draft tube having a peripheral sedimentation region, the region being substantially the same shape as the peripheral sedimentation region found in the vessel. The peripheral sedimentation zone may be outside the draft tube or in the hole of the hollow draft tube. However, since the size of the draft tube is smaller than that of the tank, differences in size, diameter, height, etc. must be weighed.

  To achieve a truly uniform particle distribution in the tank (1) and the draft tube (23), in the upflow, the particles settle in the opposite direction of the average fluid direction, whereas in the downflow, the settling velocity and average Since the fluid velocity of each is in the same direction, it is necessary to make the fluid velocity higher in the upward flow region than in the downward flow region. This suppresses particle damage and secondary nucleation and avoids catastrophic particle accumulation outside the draft tube. However, the ratio of the average rate of upflow and downflow will vary depending on the properties of the suspension, flow conditions and type of feed / reactant used to produce crystals / precipitate / particles. Therefore, a general ratio cannot be presented and is optimized according to the respective process conditions. In general, however, the linear velocity of the slurry is in the range of about 0.1 to about 1.8 meters per second, and preferably about 0.9 meters per second. A high ascent rate also facilitates slurry / liquid mixing in the recirculation zone. This region is easy to separate, especially when the suspension level is very high beyond the top of the draft tube. In extreme cases, a liquid layer with few particles is formed on top of the circulating suspension. This problem can be reduced by increasing the ascent rate of the suspension. The fast fluid momentum exiting the flow path outside the draft tube will bring the fluid higher into the area above the draft tube and promote mixing in this area.

  In order to minimize secondary nucleation and facilitate rapid de-encrusting, the components in the tank such as a stirrer (13) and draft tube (23) are not particularly limited. As with, a permanent or heat removable coating may be applied to a portion of the interior of the bath.

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

  As with any part in the tank, such as a stirrer blade, the collision of crystals with a hard surface such as a steel wall of the tank will also accelerate the secondary nucleation rate, so in the present invention We are examining enough. Soft coating the interior and moving parts is particularly advantageous for biological products, as it prevents crystal breakage upon impact. Thus, the secondary nucleation rate is suppressed and a relatively large crystal size is achieved. Applying a soft coating to the interior and moving parts of the device of the invention is particularly useful when biological products are involved.

  In yet another embodiment of the present invention, further consideration is given to the use of a second baffle (9), optionally attached to the side wall of the tank, to reduce the large recirculation area (described above) at the upper end of the draft tube (23). Yes. The second baffle (9) can be used by modifying the draft tube so that a gentle turn is made when the liquid turns from upward to downward flow at the upper end of the draft tube. Recirculation is caused by the momentum of the liquid turning 180 degrees from the upflow to the downflow at the upper end of the draft tube. The flow of the liquid cannot be suddenly changed by 180 degrees instantaneously, particularly in the upward flow portion where the change is most severe at a position close to the draft tube. Thus, when the flow turns, it leaves the draft tube at the top and does not follow the inside of the draft tube, but instead, inside the weak recirculation zone that is in close proximity to the inside of the draft tube, Form. As a result, the downward flow is compressed and becomes a high-velocity nucleus. Tapering the top of the draft tube reduces both the size and speed of this area. This also provides a means to increase the local velocity of the upward flow toward the region above the draft tube, and as described above, has the advantage of promoting mixing in this region.

  Generally, the device (30) is operated with fluid (feed material / reactant) introduced from at least one port (11) and / or at least one feed / reactant pipe. The fluid is introduced into the tank (1), preferably very close to the stirrer (13) and supplied to the stirrer. The fluid rotates rapidly in the sweep-off volume (19) by the rotation of the stirrer. The centrifugal force generated by the rotating stirrer pushes the fluid radially toward the side wall (2) of the tank (1) and further beyond the baffle (12). As fluid approaches the vessel sidewall and / or baffle, their flow is redirected axially and upwardly due to the presence of the baffle and draft tube. A flow path that passes from the at least one port through the sweep volume and over the baffle and outwards to the outside of the draft tube provides good mixing of the feed stream. Furthermore, a large circulating flow rate increases the dilution rate by the tank contents body of the supply flow. The feed / reactant stream is further mixed when the single mixture changes direction of flow from the top to the bottom of the draft tube and then down the interior of the draft tube. As a result, newly produced crystals / precipitates or other particles are discharged from the vessel and grow to the desired size before being recovered for separation or subsequent processing.

Depending on the chemistry of the feed / reactant and its supersaturated solution, crystal formation and growth proceeds so that various mechanisms include conventional mechanisms known in the crystal / precipitation / particle generation art. Examples of such a technique include, but are not limited to, the methods shown below. It will be apparent to those skilled in the art that the size of the crystals obtained by the method of the present invention can be controlled by adjusting the process parameters. For example, increasing the crystallizer rpm often results in finer particles, and adjusting the rate of addition and / or agitation will change the degree of supersaturation and mixing, thereby changing the size of the particles. Can be changed. A person skilled in the art will be able to determine the optimum parameters for a particular situation by carrying out routine experiments.

  In the present invention, the solvent is selected according to the solubility of the substance to be crystallized / precipitated. A solution that is substantially saturated or supersaturated is preferably formed when the feed / reactant fluid streams fed through the respective pipes are mixed. Similar to anti-solvent crystallization / precipitation techniques known to those skilled in the art, at least one fluid is usually a solvent containing the substance to be precipitated. When more than one feed stream is included, the at least one entrained second fluid is an antisolvent, reactant, precipitant, pH adjuster, neutralizer, dissolved salt or buffer, cooling or heating fluid , Pressurized gas.

  When adding a second feed to induce crystallization, the choice of a specific feed stream and a second feed stream (eg, anti-solvent) is determined by considering the solubility characteristics of the compound being precipitated. Can be easily performed by those skilled in the art. For example, the anti-solvent is, for example, an anti-solvent that dissolves in water and is compatible with the appropriate water (eg, acetone, isopropanol, dimethyl sulfoxide, etc., or mixtures thereof), for example, using 20 wt% methanol and 80 wt% ethanol It can be set as the water-soluble substance which precipitates by doing. Examples of antisolvents further include low water soluble substances that are soluble in organic solvents such as petroleum light distillates or ethyl acetate and precipitated with, for example, dimethyl ether or cyclohexane.

Examples of reactive precipitation / crystallization include materials that dissolve in water at high pH and precipitate in acidic water at lower pH. An example of another reaction is an abrupt reaction of two inorganic ions initially dissolved in separate aqueous solutions. Examples of such reactive precipitation or crystallization are due to the formation of mineral salts (eg fluorescent substances such as Al (OH) ₃ or Ca ₅ (PO ₄ ) ₃ OH, or CaF ₂ ), or changes in pH. Crystallization / precipitation of a compound that forms a solid phase (for example, crystallization occurs when the pH of a protein solution is adjusted to the equipotential point of the protein with an acid or base. For example, the solubility in water is low at low pH. Low, but at high pH, there are various forms such as high solubility in water, including carboxylic acid-containing compounds such as ibuprofen.

  Examples of salting out precipitation / crystallization include proteins or peptides that dissolve in a buffered aqueous solution and precipitate or crystallize, for example, by homogeneous mixing with a salt solution (such as sodium chloride or ammonium sulfate) dissolved in water. Substances.

  Examples of crystallization / precipitation by cooling include substances that dissolve in a solvent and crystallize / precipitate upon rapid cooling, in which case the second liquid stream is e.g. water, ethylene glycol or ammonia. Refrigerant.

The operating temperature is one of the parameters that affects the solubility of the material and thus the process yield. For many materials, the yield can be maximized by operating at low temperatures. However, if the antisolvent is selected carefully, high yields can be obtained even if the process is operated at room temperature. However, maximizing the yield of this process is not an important aspect of the process of the present invention. The present invention simply requires a temperature at which crystallization occurs. The temperature at which crystallization occurs is determined from solubility data, and in some cases, solubility data can be obtained from, for example, Handbook of Chemistry and Physics, 73rd Edition, CRC Press publication, or scientific journal tables .

  When the present invention is utilized as part of a continuous process, the solvent and antisolvent feed rates from the pipe may be controlled in any known manner, such as a pump. However, the present invention is not limited to this. In general, one skilled in the art will recognize and understand how to limit the flow rate to a typical crystallizer. Such a method includes the use of a flow rate adjusting valve, but is not particularly limited thereto. Therefore, these same methods are also applicable to the present invention. Solvent and antisolvent feed rates are limited only by the equipment that controls them. The fluid is supplied at a flow rate equal to the outlet flow rate. That is, the sum of the solvent and antisolvent inlet flow rates is equal to the slurry flow rate leaving the process. When using two or more feed / reactant streams, the ratio of the two or more inlet streams, as is well known to those skilled in the art, is determined by the substance phase diagram. Any value can be used. If one or more fluids are slurries / suspensions, crystal / precipitate seeding can occur, in which case the crystals / precipitates purified by this process will be crystallized / precipitated. Crystallization / precipitation occurs on the same material as the one to do or on a different material suspended in at least one fluid stream supplied to the vessel, for example.

  At the outlet of the apparatus of the present invention, precipitated / crystallized particles are removed from the fluid mixture (eg, filtration, centrifugation, etc.). The precipitated compound may optionally be dried by conventional methods generally known to those skilled in the art. Examples of such methods include tray drying, oven drying, flash drying, and air drying, but are not particularly limited thereto. Optionally, prior to the drying step, the crystallized or precipitated particles may be separated from the fluid mixture using solid-liquid separation techniques commonly known to those skilled in the art, such as filtration, sedimentation, centrifugation, and the like.

  Furthermore, the present invention can be used to produce various small, high surface area particles that can be used as liquid carrier particles or seeds for crystallization or precipitation. The crystals / precipitates produced by the methods of the present invention may also be coated with moisture-proofing agents, taste masking agents, or other additives that often improve the quality of the crystalline pharmaceutical, either simultaneously or in subsequent steps. Can do. Similarly, other drugs (such as excipients, surfactants, polymers, etc.) may be blended to provide the active substance crystals / particles as substances in suitable dosage forms (eg, tablets, capsules, etc.). Can do. Thus, in the method of the present invention, in addition to the substance, a surfactant, an emulsifier, and a stabilizer can be introduced into the shear region as separate fluid streams to stabilize the precipitation dispersion.

  The apparatus of the present invention can also be used for processes other than crystal / precipitate or particle production, including (i) use of the tank as a fermenter, and (ii) during fermentation. Examples include, but are not limited to, the use of an annular sedimentation zone for liquid / liquid extraction, and (iii) use for a heterogeneous catalytic reaction in a tank.

  The tank (1) can also be used as a fermentation tank for cell culture.

  Removal of the product in situ from the fermentor of this design can be done by using the peripheral precipitation zone (10) with minimal agitation. This is possible when used in liquid / liquid extraction mode. The lower density liquid is gradually concentrated toward the top of the surrounding precipitation area.

When this tank (1) is used as a fermentation tank, mechanically sensitive microorganisms can be suspended without being exposed to high shearing force due to the minimum power input characteristics of the stirrer (13). For example, linear yeast is used for cell culture, but it is destroyed by a stirrer that is usually used in the cell culture method.

  In the case of fermentation products that actually become toxic to cells or inhibit production when the cell product exceeds a certain threshold concentration, to avoid this condition, use an immiscible extraction solvent. In-situ removal of the product is performed using the emulsion in the bath. Since the emulsion can be introduced into the fermentor from many possible locations, it circulates inside the vessel (1) with cells, products and media. However, the feed / reactant stream is preferably introduced from an upflow sparger located below the bottom plate of the stirrer and / or close to the stirrer in the draft tube. Toxic (or other) products are distributed in the extraction solvent. In order to remove the fermentation product without stopping the fermentation, the extraction solvent can be continuously concentrated and extracted using the peripheral precipitation zone (10). In this region, an extraction solvent such as an organic liquid (this specific gravity is smaller than the specific gravity of the cell culture medium) rises in the annular portion and increases in concentration toward the top. The concentrated or combined dispersion is continuously withdrawn from the fermentor through an extraction nozzle at the top of the peripheral sedimentation zone (10). This material is sent to a stripping process to separate the product from the extraction solvent. The regenerated extraction solvent is returned to the emulsification step and then returned to the fermentation tank.

  The present invention can also be used for heterogeneous catalysis because good mass transfer is possible by high-speed internal circulation. Furthermore, wear of the catalyst particles can be suppressed by a low specific power input as compared with the conventional stirred tank reactor. While this advantage has general utility for heterogeneous catalysis, immobilized enzymes and cross-linked enzyme crystals (CLEC®), a registered trademark of Altus Corporation, are mechanically sensitive. It is a homogeneous catalyst and benefits greatly from its low specific power intensity.

  Biological products include natural, synthetic or semi-synthetic (eg, peptides, proteins, enzymes, nucleotides, etc.) that have been demonstrated to crystallize in large tanks (eg, glucose Isomerase enzyme). Biological products have also been demonstrated to precipitate in an amorphous or semi-crystalline state (eg, soy protein isolates). In such precipitation, the physical properties of the biological product precipitation process follow many crystallization process operating principles, such as the benefits of good particle suspension and the lowest possible specific power intensity. . Biological products usually crystallize as particles that are more sensitive to mechanical damage than small molecules, salts or minerals. Therefore, the gentle stirring characteristics of the crystallization tank have a particularly great utility for crystallization of biological products. One reason for this is that crystal breakage is minimized, resulting in significantly reduced secondary nucleation, resulting in a large average crystal size and a narrow particle size distribution. Impurities are mainly present in the mother liquor and adhere to the crystal surface, so large crystals tend to be more pure than small crystals. Large crystals have a small surface area per unit volume. Larger crystal sizes also facilitate down-flow solid / liquid separation.

  Crystallization of biological products is usually done by salting out techniques or pH adjustment. In the case of these crystallizations, the concentrated salting-out solution or the acid / base introduction means greatly affects the nucleation rate and the formation of crystals / precipitates. The feed / reactant non-point source technology used in this technology tank is much larger for biological product crystallization than the more common sparger type feed / reactant feed pipes Have advantages. In this method, very fine precipitates are not generated around the introduction point, and larger and better crystal grains are generated.

Although not a requirement for processing, as with many pharmaceutical crystallization processes, biological products are best suited for batch operation. In this case, unless the crystallization is induced by a thermal operation, the liquid level in the tank rises with the lapse of time of the crystallization operation. In a tank with a draft tube, this leads to a liquid / slurry flow path that recirculates back to the stirrer over the upper end of the draft tube because the liquid level is low at the beginning of batch operation. The problem of the circulation of the liquid that it does not form occurs. To overcome this limitation, the draft tube should be windowed to ensure a liquid / slurry flow path from the outside of the draft tube to the inside of the draft tube when the liquid / slurry surface is lower than the draft tube. Can do. This allows slurry / liquid circulation even in batch operation periods where the liquid level is lower than the draft tube height.

  Examples of biological products include foods and food additives. Water-soluble and water-insoluble foods and food additives that can be crystallized or 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, thickeners, emulsifiers, stabilizers, antibacterial agents, antioxidants, polypeptides, small organic therapeutic agents, cofactors, nucleotides, oligonucleotides, RNA sequences, DNA sequences, vaccines, immunoglobulins, monoclonal or other antibodies, viruses, gene therapy vectors, carbohydrates, polysaccharides, oligosaccharides, disaccharides, monosaccharides, colorants, other pigments and mixtures thereof However, it is not particularly limited to these.

  Examples of substances that can be crystallized / precipitated by the apparatus of the present invention include, but are not limited to, biopharmaceuticals as defined above and chemical compounds such as crop protection chemicals. The present invention makes it possible to prepare finer or coarser chemical crystals than those normally produced by mass crystallization (about 50 microns), and therefore the present invention requires the need for a grinding step / grinding step. It is possible to increase the solubility of chemicals that are hardly soluble in water without the cost / contamination of the grinding process, or without introducing a solubility promoter such as cyclodextrin or surfactant.

  Pharmaceutical or biopharmaceutical substances include pulmonary delivery mechanisms, parenteral delivery mechanisms, transdermal delivery mechanisms, oral delivery mechanisms, ophthalmic delivery mechanisms, anal or vaginal delivery mechanisms, otic delivery mechanisms, nasal delivery mechanisms and Some are delivered by an implant delivery mechanism.

  The pharmaceuticals produced by the present invention further include water-soluble and water-insoluble pharmaceuticals such as anabolic steroids, stimulants, analgesics, anesthetics, antacids, antiarrhythmic drugs, antiasthmatic drugs, antibiotics, Caries, anticoagulant, anticholinergic, anticonvulsant, antidepressant, antidiabetic, antidiarrheal, antiemetic, antiepileptic, antifungal, anthelmintic, hemorrhoid, antihistamine, antihormonal, Antihypertensive, Antihypertensive, Anti-inflammatory, Antimuscarinic, Antifungal, Antineoplastic, Antiobesity, Antiplaque, Antiprotozoal, Antipsychotic, Antiseptic, Antispasmodic, Antithrombotic Drugs, antitussives, antivirals, anxiolytics, astringents, beta-adrenergic receptor blockers, bile acids, breath fresheners, bronchospasmodics, bronchodilators, calcium channel blockers, cardiac glycosides, contraceptives, adrenal glands Cortical sterol Decongestants, decongestants, diagnostic agents, digestives, diuretics, dopamine agonists, electrolytes, emetics, expectorants, hemostatic agents, hormones, hormone replacement therapy agents, hypnotics, hypoglycemic agents, immunosuppressants, Treatment for sexual dysfunction, laxatives, lipid regulators, mucolytic agents, muscle relaxants, nonsteroidal anti-inflammatory agents, dietary supplements, analgesics, parasympathomimetic drugs, parasympathomimetic drugs, prostaglandins, mental Stimulants, psychotropic drugs, sedatives, sex steroids, antispasmodics, steroids, stimulants, sulfonamides, sympathomimetic blockade, sympathomimetics, sympathomimetics, thyroid hormone-like agonists, thyroid hormones Examples include suppressive drugs, vasodilators, vitamins, xanthines, and mixtures thereof. However, the present invention is not limited to these.

  As shown in FIGS. 8 and / or 9, the present invention also contemplates performing an ultrafiltration process (or other cross-flow filtration device) in a closed loop with a biological product crystallizer. ing. Supersaturation can be caused by concentration at the interface of the ultrafiltration membrane. This is a clear advantage over salting out and reaction crystallization because the higher supersaturation distribution extends over the entire membrane, not just the feed / reactant introduction. In addition, the membrane process is used in series with the crystallizer, so that the volume of the raw fluid can be reduced compared to a diluted method that uses a salting-out method for crystallization. For biological products of macromolecules such as peptides, enzymes, proteins and polysaccharides that may be rejected by the pore size of the ultrafiltration membrane, placing the membrane processes in series for concentration is a continuous cycle. This is a useful combination of a crystallizer and a film process. If a milling system is used before the membrane device, the flux will be maximized. If a pulverizer is not used, a cross-flow ultrafiltration device is preferred to minimize the adhesion of crystals to the membrane surface. Membrane processes that are placed in series with the crystallizer and show similar utility can also be achieved with microfiltration, nanofiltration and reverse osmosis membranes. The utility of such a configuration is not limited to biological molecules.

  The on-site cleaning (CIP) and / or on-site sterilization (SIP) properties of the batch crystallizer are additional properties that can be used in the present invention to meet the demands made for food or therapeutic agent processing. . The food grade crystallization process likewise requires CIP and SIP capabilities. Also provided in the system is a nozzle and piping that automatically introduces cleaning fluid and sterilizing fluid when a batch operation is complete.

  Crystallization / precipitation techniques in the biotechnology and food industries have been rapidly used to crystallize biological products. This gentle agitation system, non-point source material / reactant introduction system, and membrane concentrating process in series give significant advantages in operability over currently used stirred tank crystallizers. It is. The introduction of CIP and SIP systems is one requirement to meet sanitary production standards.

  The invention further relates to a method for changing the device scale of the invention. It is very important to control the specific power intensity of the device. Specific power intensity (SPI) often affects the properties of crystals and, for example, the flowability of the powder product. It is known that particle damage and secondary nucleation vary depending on the specific power intensity, that is, the value of the power supplied to the stirrer divided by the mass of the stirrer swept volume. A crystallizer loop that uses a pump and a separate shear zone to vary the two factors independently is described in Chemical Engineering Science, 2001, volume 56, p. 2459-2473 in “Influence of differential scalars of mixing crystallisation” by Marika Torbacke and Ake Rasmusson.

  This demonstrates the need to control both factors, as is done in the present invention, and further points to a lack of knowledge in the industry regarding how to control both factors of a single stirrer. .

  Thus, the present invention provides a stirrer design method that provides the necessary pumping flow rate and specific power intensity for any scale.

  In order to further describe and explain the method of the present invention, the following definitions are provided.

As used herein, “stirrer pumping flow” is used to suspend crystals uniformly and to dilute areas of supersaturated product and allow them over the desired total crystallization volume. In order to mix as uniformly as possible, it is defined by a mathematical formula that shows the circulation flow around the required draft tube. The stirrer pumping flow rate is shown in Perry's Chemical Engineer's Handbook, 7th edition (formula 18-2) issued in 1997 by McGraw-Hill, NY. I.
IQ = NQ ^* D ^{3 *} N
Here, Q is the stirrer discharge flow rate (for example, M ³ / sec), NQ is the discharge coefficient (no dimension), D is the stirrer diameter (for example, meter), and N is the rotation speed (for example, the number of rotations per second). is there.

As used herein, “specific power intensity” (SPI) is the mixing provided by the stirrer during each rotation to the slurry through the stirrer as the slurry travels the path around the draft tube path. Indicates the degree of strength (which is quite different from the average value for tanks often used in the mixing literature). Mathematically, the SPI is a value obtained by dividing the power input to the stirrer by the mass of the slurry in the swirling volume of the stirrer. Therefore, it is represented by Formula II.
II SPI = Agitator power / (Agitator volume ^* Rho)
Where the stirrer power (eg, watts) is the input from the stirrer to the slurry, as shown in Equation IV below, and the denominator is the mass in the sweeper volume of the stirrer (in this case, cubic meters in kilograms per cubic meter) (Unit is simply kilogram). Rho is the density of the slurry (eg, kilograms per cubic meter).

“Stirrer volume” is the area of the stirrer multiplied by its height and is represented by formula III (by elementary geometry). Therefore, the mass of the sweep-off volume is III The mass of the agitator volume = π ^* D ^{2 *} H ^* Rho / 4
It is. Here, H is the vertical height (for example, meter) of the stirrer.

“Stirrer power” is given by Equation IV in Perry's Handbook (as described above, Equation 18-3).
IV P = Np ^* N ^{3 *} D ^{5 *} Rho
Where Np is the power number (dimensionless), N is the stirring speed (eg, revolutions per second), D is the agitator diameter (eg, meters), and Rho is the density of the slurry (eg, kilograms per cubic meter). .

Substituting Formulas III and IV into Formula II, the SPI is
SPI = Np ^* D ^{5 *} N ^{3 *} Rho / (π ^* D ^{2 *} H ^* Rho / 4)
And, when simplified, V SPI = K ^* D ^{3 *} N ³ / H
It becomes. Here, K = 4 ^* Np / π.

  In general, the pumping flow rate and specific power intensity (SPI) values are not proportional to each other, so as the dimensions of the equipment change, these important agitator design parameters change, resulting in which parameters remain constant, Deciding which parameters to change or whether to adjust and change both parameters together is a problem for the designer. The pumping flow rate (Equation I) is directly proportional to the rotational speed, but the specific power intensity (Equation V) is proportional to the cube of the rotational speed, so it cannot be geometrically scaled up or down. The proportionality cannot be kept the same.

Therefore, in the present invention, since the discharge coefficient NQ and the power number (Np) are both proportional to the height of the stirrer, these two important variables can be changed by changing the height of the stirrer (H in the equation). It provides a way to control. Thus, for a given stirrer diameter, the SPI remains constant for stirrers of different heights (because the reject mass varies linearly with respect to height), while the pumping flow rate is high It changes linearly. This allows control of both pumping flow rate and SPI when attempting to scale up or down the crystallizer.

In a draft tube crystallizer having a preselected diameter (D), stirrer speed (N), power number (Np) and specific power intensity (SPI), the value of H is calculated by A method for determining height (H) is provided.
H = K ^* D ^{2 *} N ³ / SPI, where K = 4 ^* Np / π.

  For illustration purposes, for example, an 8 inch diameter, 2.5 gallon pilot device will run a pilot test program to confirm the effect of the difference in purity of the feed material and simulate a 12 foot diameter actual crystallizer. Let's try. If the 8 inch crystallizer was scaled based on circulation rate (and hence blade tip speed), the following results would be obtained:

  Since this method gives an extremely high SPI compared to the actual device, it is more likely to produce finer crystals than a commercial scale device. Thus, the inherent high SPI of small scale devices increases the degree of crystal attrition, and therefore the average crystal size distribution is smaller.

  However, if the method of the present invention is used, the circulation rate is kept constant as in the comparative example, but the SPI is lowered. Thus, this stirrer design procedure discloses a means for operating devices of various scales in the same manner as possible. With a pilot stirrer that is twice as high, the following results are obtained:

Thus, the SPI has dropped to 1/8. If desired, this 8-in device could be used at half speed. However, if it is desired to lower the SPI further (perhaps the crystals are very brittle needles, for example), the stirrer will be 3 times higher and run at the original 1/3 speed. It will be as follows.

  For a stirrer that is 3.1 inches tall, the SPI is lower than that of a commercial scale device, a device that is equivalent to a commercial scale device with the same flow rate and SPI, if the height is slightly reduced and the speed increased proportionally. The design has been made.

Example 1-Sweeper Blade Test This example shows that the use of the apparatus of the present invention results in better circulation and suspension of crystals than can be obtained using another crystallizer in the field. Is. A 25 inch diameter radial agitator with a 36 inch diameter crystallizer, a clear bath, a 25 inch diameter non-tapered (straight) draft tube, and a variable speed drive as a power source. The agitator was located at the bottom and was driven using a variable speed DC drive. As shown in FIG. 4, four 10.5 inch long sweeper blades were mounted under the bottom plate. They were tapered in height, 1.75 inches at the drive shaft end and 1.25 inches at the opposite end. The particles used in the test were 150 to 200 micron sand particles, the specific gravity was 2.9 g / cm ³ , and 1% by weight based on the fluid water. The measurement results are shown in Table 1 below.

  Extrapolating the results, the control device required about 122 RPM to suspend all sand particles, while the device using the sweeper blade had only about 100 RPM. The RPM difference of 22 seems insignificant, but in the light of the fact that the power is proportional to the cube of RPM, the control device suspended sand particles in water and floated from the bottom of the tank. Therefore, 73% extra power (1.2 ^ 3/1) is required from the device using the sweeper blade.

Example 2-Gypsum Synthesis Process A 3 wt% weak sulfuric acid stream 40 gpm from ion exchange resin regeneration is neutralized with a 20 wt% lime slurry to produce a synthetic or chemical gypsum as shown in the following reaction. did.
H ₂ SO ₄ + Ca (OH) ₂ → CaSO ₄ : 2H ₂ O

A 10 liter, draft tube pilot crystallizer having a diameter of 5.5 inches was used at about 200 rpm and SPI about 8 W / kg. The crystals obtained were needle-like and relatively fine (wt% average diameter less than 100 microns (by Coulter Counter ^™ )). When a double draw-off treatment was performed and the residence time was doubled (by double the concentration), the crystals were concentrated and a dramatic increase in the crystal diameter was observed. Thereafter, a Burke type apparatus having a tank diameter of 10 ft with an additional precipitation region at the top was used. Commercial aircraft results were consistent with all predictions from pilot tests. The average diameter by CC of the produced crystals was greater than 400 microns (weight percent basis).

It is a cross-sectional view of one embodiment of the present invention. It is a top view of the impeller by this invention. It is a side view of the impeller by this invention. It is a bottom view of one embodiment of an impeller according to the present invention. It is a side view of one Embodiment of the impeller by this invention. FIG. 6 is a side view of another embodiment of a draft tube according to the present invention. It is a cross-sectional view of another embodiment of the present invention. It is a cross-sectional view of another embodiment of the present invention. 1 illustrates a system incorporating the present invention. 1 illustrates a system incorporating the present invention.

Claims (27)

(A) tank,
(B) a radial flow stirrer having a top plate and a bottom plate, optionally provided;
And (c) a crystallization / precipitation apparatus comprising a draft tube,
The draft tube has a plurality of baffles firmly attached thereto, and is arranged in the tank to form a flow path between the draft tube and the tank side wall, and the diameter of the draft tube is the diameter of the tank. Is about 0.7 times the device.   The apparatus according to claim 1, wherein the tank is made of a material selected from the group consisting of steel, glass, glass fiber, and PVC.   The apparatus of claim 1, wherein the vessel further comprises a peripheral precipitation region.   The apparatus of claim 1, wherein the vessel further comprises at least one second baffle attached to the side wall of the vessel above the draft tube.   The apparatus of claim 1, wherein the vessel further comprises a centering support.   The apparatus of claim 1, wherein the agitator is a radial flow impeller.   The apparatus according to claim 1, wherein the agitator is made of a material selected from the group consisting of steel, glass fiber, titanium, glass, and PVC.   The apparatus of claim 1, wherein the bottom plate further comprises at least one opening.   The apparatus of claim 1, wherein the bottom plate further comprises at least one sweeper blade.   The apparatus of claim 1, wherein the bottom plate has a radius equal to or greater than the diameter of the draft tube.   The apparatus of claim 1, wherein the draft tube is a cylindrical body.   The apparatus of claim 1, wherein the draft tube is tapered.   The apparatus of claim 1 wherein the draft tube is hollow.   The apparatus of claim 13, wherein the hollow draft tube further comprises a peripheral sedimentation region.   14. An apparatus according to claim 13, wherein the hollow draft tube comprises a heat exchanger.   The apparatus of claim 1, wherein the draft tube further comprises a peripheral sedimentation region.   The apparatus of claim 1, wherein the draft tube further comprises at least one window.   The apparatus of claim 1, wherein the draft tube is made of a material selected from the group consisting of steel, glass fiber, glass and PVC.   The apparatus according to claim 1, wherein at least one of the inside of the tank, the stirrer, the draft tube and the plurality of baffles firmly attached thereto is coated with a suitable soft coating.   20. The device of claim 19, wherein a suitable soft coating is selected from the group consisting of polyethylene, poly (tetrafluoroethylene), polypropylene, neoprene, latex and rubber.   A fermenter comprising the apparatus according to claim 1.   A heterogeneous catalytic reactor comprising the apparatus according to claim 1. A method of crystallizing / precipitating particles,
Supplying at least one fluid to the apparatus of claim 1, wherein the fluid comprises at least one dissolved material to be crystallized / precipitated;
The step of stirring the at least one fluid, crystallizing / precipitating at least one dissolved material from the at least one fluid to produce particles, and at least one fluid and particles. A method comprising the step of discharging from the apparatus.   24. The method of claim 23, wherein the at least one dissolved substance is selected from the group consisting of biological products, pharmaceutical substances and biopharmaceutical substances.   25. A method according to claim 24, wherein the biological product is a natural product, a synthetic product or a semi-synthetic product.   Biological products may be proteins, enzymes, peptides, polypeptides, amino acids, small organic therapeutics, cofactors, nucleotides, oligonucleotides, RNA sequences, DNA sequences, vaccines, immunoglobulins, monoclonal or other antibodies, Viruses, gene therapy vectors, carbohydrates, polysaccharides, oligosaccharides, disaccharides, monosaccharides, lipids, fatty acids, phytochemicals, vitamins, minerals, salts, colorants and other pigments, sweeteners, anti-caking agents, thickening 26. The method of claim 25, selected from the group consisting of agents, emulsifiers, stabilizers, antibacterial agents, antioxidants and mixtures thereof. Drug substance is anabolic steroid, stimulant, analgesic, anesthetic, antacid, antiarrhythmic, antiasthmatic, antibiotic, anticaries, anticoagulant, anticholinergic, anticonvulsant, antidepressant Antidiabetic, antidiarrheal, antiemetic, antiepileptic, antifungal, antiparasitic, hemorrhoid, antihistamine, antihormonal, antihypertensive, antihypertensive, antiinflammatory, antimuscarinic, anti Mold, anti-neoplastic, anti-obesity, anti-plaque, antiprotozoal, antipsychotic, antiseptic, antispasmodic, antithrombotic, antitussive, antiviral, anxiolytic, astringent, Beta-adrenergic receptor blockers, bile acids, breath fresheners, bronchospasmodics, bronchodilators, calcium channel blockers, cardiac glycosides, contraceptives, adrenal cortex Teroids, decongestants, diagnostics, digestives, diuretics, dopamine agonists, electrolytes, emetics, expectorants, hemostatics, hormones, hormone replacement therapy drugs, hypnotics, hypoglycemic drugs, immunosuppressants, Treatment for sexual dysfunction, laxatives, lipid regulators, mucolytic agents, muscle relaxants, non-steroidal anti-inflammatory agents, dietary supplements, analgesics, parasympathomimetic drugs, parasympathomimetic drugs, prostaglandins, mental Stimulants, psychotropic drugs, sedatives, sex steroids, antispasmodics, steroids, stimulants, sulfonamides, sympathomimetic blockade, sympathomimetics, sympathomimetics, thyroid hormone-like agonists, thyroid hormones Suppressive drugs, vasodilators, vitamins, xanthines, and mixtures thereof The method of claim 24 which is selected from Li Cheng group.

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