WO2004058377A1 - Appareil et procede permettant de former des cristaux/precipites/particules - Google Patents

Appareil et procede permettant de former des cristaux/precipites/particules Download PDF

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Publication number
WO2004058377A1
WO2004058377A1 PCT/US2003/040240 US0340240W WO2004058377A1 WO 2004058377 A1 WO2004058377 A1 WO 2004058377A1 US 0340240 W US0340240 W US 0340240W WO 2004058377 A1 WO2004058377 A1 WO 2004058377A1
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WO
WIPO (PCT)
Prior art keywords
draft tube
vessel
agitator
particles
crystals
Prior art date
Application number
PCT/US2003/040240
Other languages
English (en)
Inventor
Ross Edward Kendall
Sean Mark Dalziel
Arthur W. Etchells
Daniel Albert Green
Stephan Claude De La Veaux
Foster W. Rennie
Original Assignee
E.I. Du Pont De Nemours And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Priority to AU2003293576A priority Critical patent/AU2003293576A1/en
Priority to EP03790524A priority patent/EP1572314A1/fr
Priority to JP2004563683A priority patent/JP2006510484A/ja
Publication of WO2004058377A1 publication Critical patent/WO2004058377A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0004—Crystallisation cooling by heat exchange
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0063—Control or regulation

Definitions

  • This invention relates to an apparatus for use in the production of particles via precipitation or crystallization and the like, methods for forming the crystals/precipitate or other particles, and a method providing for the variation of the scale of the apparatus while substantially maintaining a constant specific power intensity.
  • This apparatus can be configured to crystallize biological products such as proteins and enzymes, small organic molecules such as pharmaceuticals and fine chemicals, as well as inorganic materials such as mineral salts.
  • Draft tube crystallizers are commonly used to produce many different kinds of materials and particles, including but not limited to organic compounds such as adipic acid and pentaerythritol, and inorganic compounds such as gypsum, calcium fluoride and sodium sulfate.
  • organic compounds such as adipic acid and pentaerythritol
  • inorganic compounds such as gypsum, calcium fluoride and sodium sulfate.
  • U.S. Patent No. 1 ,997,277 (Burke) describes an apparatus for forming single nuclei crystals from a solution by evaporative cooling.
  • particles particularly fine particles
  • current precipitation and crystallization techniques do not work reliably to produce crystals having a suitable size and size distribution.
  • large crystals are desired to ease solid/liquid separation and improve powder flow characteristics of the product, in other instances, such as with inhalable pharmaceuticals, fine particles of a narrow size range (e.g. 1 - 5 microns) are desirable.
  • Increasing particle size is a difficult and often unsuccessful challenge for a crystallization process engineer.
  • Much of the methods in the art concern (i) mixing and agitation systems and (ii) classification methods that enable various size fractions within the crystallizer to be recycled, dissolved or enriched.
  • mixing and agitation systems and (ii) classification methods that enable various size fractions within the crystallizer to be recycled, dissolved or enriched.
  • many milling, crushing, or grinding processes are required as a post treatment to reduce the crystallized particles to the desired size and distribution ranges. If the product size could be adequately directly controlled by manipulating the crystallizer rather than a post treatment milling step, the processing would be simpler, more robust, particle surfaces would be clean faced, leading to less dust and improved particle properties (e.g. flow, compaction into tablets, etc.), and improved dispersibility for dry powder inhaled therapeutic products.
  • crystallizers are commonly designed with a fixed geometric proportion between the diameter and height of the vessel, as well as, the diameter and pitch or thickness of the agitator blades. However, in crystallization practice there are many times when this fixed geometric scaling is not desirable.
  • the present invention provides an efficient and scalable apparatus and a process for producing crystals/precipitate or other particles.
  • One advantage provided by the present invention is a high internal pumping (or circulation) rate, while requiring a low specific power input, thus enabling an environment for good mass transfer and minimal breakage/attrition/damage to mechanically sensitive crystals/precipitate or particles.
  • the benefits of this apparatus are especially so for mechanically sensitive solid products such as biological products (e.g. proteins) and small organic molecules such as pharmaceuticals.
  • the apparatus may also be used as a general process vessel, not only for crystallization applications, but also for applications including, but not limited to, its use as a fermentor, extractor and liquid/emulsion separator, reactor for heterogeneously catalyzed processes and the like.
  • this apparatus provides very good mixing and rapid dilution of a feed stream(s), with substantially lower specific power input to the slurry than alternative process vessels (such as those agitated by Rushto ⁇ turbines, fixed pitch impellers, hydrofoils, marine type impellers, rotor-stator, and the like).
  • Still another advantage of the present invention is that it may be optionally utilized to enable feeding a fluid containing seed crystals or other particles for co-precipitation, further growth or coating.
  • the invention provides an apparatus that is a process vessel and configuration for a lab scale, pilot scale or industrial scale crystallization or precipitation process that enables improved control over the formation of crystals/particles.
  • the apparatus and process according to the present invention are also better able to control the size of the crystals/particles formed during the crystallization/precipitation process than is presently done in the crystallization art, for example utilizing the draft tube baffled type crystallizer.
  • commercial crystallizers are commonly limited or hindered in their performance by higher than desired rates of crystal nucleation. Techniques to deal with higher than desired nucleation rates have been in practice for many years and are described in most crystallization texts.
  • Such techniques include fines destruction; clear liquor advance and double draw off.
  • Each of these three techniques require the slurry of crystals to be classified (e.g. into clear liquor, fine and coarse fractions). This classification is commonly achieved via external classification devices, such as elutriators and cyclones.
  • the fine fraction of crystals are passed through a system that leads to their dissolution (e.g., a heat exchanger, diluter) and the clear liquor is returned to the crystallizer.
  • a system that leads to their dissolution (e.g., a heat exchanger, diluter) and the clear liquor is returned to the crystallizer.
  • This is particularly useful for batch crystallizer operation, but also widely practiced in continuous processes.
  • the classification is at the extreme, where the fraction collected from the classification device is essentially free of crystals, as is used in a number of continuous mineral crystallization/precipitation processes. Double draw off is used in continuous crystallization processes, where a representative stream of the slurry is removed, and sent to the separation device downstream, as well as a classified stream of the fines fraction.
  • a larger product crystal size is generated from the equipment, which can be desirable in itself, as well as enabling less investment in the separation equipment required downstream of the crystallizer (e.g., centrifuge, filter press, etc.).
  • Another advantage of the present invention is that it can enable larger crystals/precipitate/particles to be made than when utilizing other crystallizers found in the art, and thus, for a process that is at its production rate limit, a higher production rate may be possible for the same downstream separation equipment via the production of a larger mean crystal size.
  • the classification of the slurry into clear, fine and coarse fractions is the enabling step to harness this advantage.
  • Potential applications of the present invention are very broad, for example, industries able to utilize the particles generated by the present invention include pharmaceuticals, nutraceuticals, diagnostics, polymer intermediates, agrochemicals, pigments, food ingredients, food formulations, beverages, cell cultures and their products, fine chemicals, cosmetics, electronic materials, inorganic minerals and metals.
  • the present invention relates to a crystallization/precipitation apparatus comprising: (a) a vessel; (b) a radial flow agitator having an optional top plate and a base plate; and (c) a draft tube, having a plurality of baffles rigidly attached thereto, arranged within the vessel forming a channel between the draft tube and a sidewall of the vessel, wherein the draft tube has a diameter that is about 0.7 times the size of a diameter of the vessel.
  • the present invention further relates to a method for crystallizing/precipitating particles comprising the steps of:
  • Figure 1 represents a lateral cross-sectional view of an embodiment of the present invention.
  • Figure 2 represents a top view of an impeller according to the present invention.
  • Figure 3 represents a side view of an impeller according to the present invention.
  • Figure 4 represents a bottom view of an embodiment of an impeller according to the present invention.
  • Figure 5 represents a side view of an embodiment of an impeller according to the present invention.
  • Figure 6 represents a side view of an alternative embodiment of the draft tube according to the present invention.
  • Figure 7 represents a lateral cross-sectional view of an alternative embodiment of the present invention.
  • Figure 8 represents a lateral cross-sectional view of an alternative embodiment of the present invention.
  • Figure 9 represents a system incorporating the present invention.
  • Figure 10 represents a system incorporating the present invention.
  • the present invention relates to an apparatus and a process using said apparatus for forming crystals/precipitate or other particles.
  • the present invention can be utilized to generate crystals precipitate/particles of various sizes, depending upon the compound to be crystallized.
  • the crystals/precipitate or other particles are in the range of about 0.5 micron to about 3000 microns, however smaller or larger particle sizes are also contemplated by the present invention due to its ability to control crystal/precipitate/particle size.
  • the present invention allows for the production of larger crystals as well as for a narrower size distribution or finer crystals of narrower size distribution than is typically delivered by other crystallizers in the art.
  • the present invention further provides the ability to make crystals of the same size and size distribution at different scales of the process vessel (e.g. lab scale versus production scale) because it sets forth a method for varying the scale of the present invention, while substantially maintaining a constant specific power intensity.
  • process vessel e.g. lab scale versus production scale
  • the apparatus of the present invention may be utilized in either batch or continuous configurations.
  • the apparatus of the present invention may be utilized with a wide diversity of fluids to act as feed/reactant(s) including, but not limited to, solvents, liquids, slurries, suspensions, liquefied gases, supercritical fluids, subcritical fluids and the like.
  • the present invention may be utilized for the production of any precipitated or crystallized particles, including pharmaceuticals, biopharmaceuticals, nutraceuticals, diagnostic agents, agrochemicals, pigments, food ingredients, food formulations, beverages, fine chemicals, cosmetics, electronic materials, inorganic minerals and metals.
  • the crystalline/precipitated particles for other industry segments can be produced using the same general techniques described herein as easily modified by those skilled in the art.
  • crystallizer agitation for example (1) good mixing and uniform particle suspension; and (2) the minimization of particle damage and secondary crystal nucleation.
  • Good mixing is typically provided by high volumetric flow rates from an agitator and a turbulent zone for the initial dispersion of any feed streams.
  • Uniform particle suspension is typically provided by relatively high fluid velocities, particularly in upflow.
  • the generation of these conditions may be problematic, because it usually entails creating conditions that will also damage particles and cause secondary nucleation.
  • the present invention provides both an apparatus and method to alleviate these problems within the art.
  • the term "shear zone” shall include all areas within the present invention that are subject to shear force, for example, the area between the tip of an impeller blade and the baffle, the base plate apertures, and the agitator-swept volume.
  • shear force shall encompass all of the mixing/dispersion, mechanical forces produced in the apparatus of the invention including, but not limited to, the nominal shear rate generated in the agitator-swept volume, elongation forces, turbulence, cavitation, and impingement of the surfaces.
  • crystallization and/or “precipitation” include any methodology of producing particles from fluids; including, but not limited to, classical solvent/antisolvent crystallization/precipitation; temperature dependent crystallization/precipitation; “salting out” crystallization/precipitation; pH dependent reactions; “cooling driven” crystallization/precipitation; crystallization/precipitation based upon chemical and/or physical reactions; etc.
  • biopharmaceutical includes any therapeutic compound being derived from a biological source or chemically synthesized to be equivalent to a product from a biological source, for example, a protein, a peptide, a vaccine, a nucleic acid, an immunoglobulin, a polysaccharide, cell product, a plant extract, an animal extract, a recombinant protein an enzyme or combinations thereof.
  • the present invention generally provides an apparatus comprising: (a) a vessel; (b) an agitator having an optional top plate and a base plate; and
  • a draft tube having a plurality of baffles rigidly attached thereto, arranged within the vessel to form a channel between the draft tube and a sidewall of the vessel, wherein the draft tube has a diameter that is about 0.7 times the size of a diameter of the vessel.
  • the dimensions of the apparatus (30) of the present invention vary (e.g. a diameter of about 1cm to more than about 15 meters) because the invention can be scaled to a variety of sizes. Thus, the dimensions will change to accommodate the scaled versions of the present invention.
  • the scale of the present invention may change substantially such that this style of apparatus may be designed for small production rates (e.g.
  • the vessel (1) of the present invention may be of any shape conventionally utilized in the crystallization/precipitation or particle formation art.
  • the vessel is a closed cylindrical shell having a side wall (2), and at least one port (11) through which nozzles, feed pipes and the like may be inserted.
  • the vessel may be constructed of any material capable of withstanding the forces created by the present invention, such as, for example, fiberglass, steel, preferably stainless steel, more preferably carbon steel, PVC, glass and the like.
  • the vessel of the present invention is stainless steel.
  • the vessel has at least one port (11), preferably a plurality of ports, to allow for the insertion or attachment of at least one pipe and/or nozzle, for the introduction and/or removal of vapors and/or liquids and/or the draw-off of product from the vessel and/or to permit cleaning and/or sterilization (in-place) as part of processing hygiene requirements.
  • the at least one port, and consequently the at least one inlet pipe, line nozzle or the like, may be positioned anywhere on the vessel.
  • the vessel may also optionally have centering supports (8) attached to the vessel side wall and the draft tube to provide stability and support for the draft tube.
  • Secondary baffles (9) may optionally be attached to the vessel side wall to aid in re-directing the contained feed/reactant(s) to have a substantially downward flow towards the interior portion of the draft tube.
  • the vessel dimensions vary according to the scale utilized. Those persons skilled in the art, in light of the disclosures herein, will recognize and understand the necessary adjustments that must be made to the vessel when scaling the apparatus.
  • another embodiment of the present invention provides for a vessel having a peripheral settling zone (10), which enables the classification of clear liquor and/or a fine crystal/precipitate/particle fraction without the need for an external classification device.
  • the peripheral settling zone (10) may wrap around the vessel to form a continuous peripheral zone, or may wrap around only a portion of the vessel and may be located at any point along the height of the vessel that is below the level of the liquid.
  • the peripheral settling zone (10) typically fills with slurry, but is not subject to the extent of agitation that is seen in the rest of the vessel, and thus, is shielded from the circulation of the slurry in the vessel.
  • the peripheral settling zone (10) provides an area in which crystals may settle out of the slurry. In general the larger crystals will settle faster than the smaller crystals.
  • the crystal size may be determined internally, which allows for the avoidance of high cost, operation and space requirements of an external classifier, such as, for example, an elutriator, cyclone, and the like.
  • peripheral settling zone such as width and depth
  • the dimensions of the peripheral settling zone must be varied, and can make such adjustments according to the specific parameters of the types of crystals/precipitate or other particle being sought, the size and size distribution, the type of fluid being utilized form the crystals/precipitate or other particle and the operational conditions of the vessel.
  • the agitator (13) of the present invention provides for mixing of the feed stream(s), rapid dilution of the concentrated feed(s) in with the bulk of the vessel contents, suspension of the crystals/precipitate/particles in the slurry and for circulation of the fluid(s) throughout the apparatus. These attributes are important for robust operation and consistent crystal/precipitate/particle formation.
  • the agitator (13) in the present invention may be of any configuration capable of providing the necessary liquid circulation including, but not limited to, a radial flow impeller located at either the top or bottom (or both) of the draft tube, an axial flow propeller or a marine propeller in the mid-section of the draft tube, a double propeller or multiple propeller.
  • the agitator of the present invention is a radial flow agitator, more preferably a radial flow impeller having at least one blade, a base plate and an optional top plate.
  • Typical commercial crystallizers utilize axial flow impellers which, in general, are used at higher revolutions per minute and smaller agitator diameters, thus resulting in a much higher specific power intensity than is seen with the present invention.
  • the agitator may be constructed of any material capable of withstanding the forces generated within the present invention, such as, for example, fiberglass, steel, preferably stainless steel, PVC, titanium, glass and the like.
  • the agitator of the present invention is stainless steel or titanium.
  • the radial flow impeller has several aspects such as, for example, the number of blades, the size of the blades, the blade angle of attack and the revolutions per minute that may be manipulated to allow an operator to control the nature of the turbulent mixing and shear to which the crystals are exposed.
  • this indirect control of the degree of turbulence attenuation allows for mixing and dilution of the concentrated feed stream(s), suspension of the crystals, entrainment of bubbles and the implementation of crystal settling regions, such as the peripheral settling zone.
  • the blade size, rpm's and degree of separation affect not only the turbulence injected into the fluid by the impeller, but also the scale of turbulence (through turbulent energy dissipation, commonly referred to as epsilon).
  • epsilon turbulent energy dissipation
  • a small, higher speed impeller at the same power level as a larger impeller will produce a turbulence that is more energetic at the higher frequencies (and smaller scales), but that turbulence will decay more rapidly. This is especially true in crystallizers, as the high solids content leads to greater dissipation at the higher frequencies in the turbulent velocity spectrum.
  • the radial flow impeller of the present invention may comprise several configurations, such that the impeller comprises at least one blade, an optional top plate and a base plate.
  • the impeller comprises the configuration set forth in Figures 2, 3, 4 and 5.
  • the at least one blade of the impeller may be of any shape, so long as it provides the impeller with the proper diameter and provides the necessary pumping rate to circulate the fluid(s) throughout the apparatus.
  • the blade height is about one sixth (1/6) of the diameter of the agitator.
  • the width of the at least one blade varies with the blade angle, however typically it is determined to be equal to the agitator diameter divided by the quantity of (8 x cos of the blade angle). For example, utilizing an agitator having a 10 foot diameter (120 inches), wherein the at least one blade has a blade angle of 55 degrees, the blade height is about 120 inches x 1/6, or 20 inches, and the width is 120/(8 x cos 55) or (8 x 0.574) or about 26 inches.
  • the blades may have any angle capable of providing the necessary circulation of the fluid(s) throughout the apparatus.
  • the blade angle for the present invention typically ranges between about 45 degrees to about 65 degrees.
  • the blade angle is about 55 degrees.
  • blade lift the force on the blade in the radial direction, e.g. pumping fluid away from the impeller
  • blade drag the force on the blade in the direction of the blade movement
  • Separated flow refers to the blade lift and the blade drag forces being independent of one another, such that in this case, where the blade lift is constant, then the drag force is related to the effective area of the blade.
  • the energy from blade drag is nearly completely converted to turbulence.
  • Flow rate is controlled by the impeller rpm, turbulence energy by blade angle and rpm.
  • the revolutions per minute (RPM) of the agitator vary with the scale of the apparatus of the present invention. Generally, however, the maximum allowable RPM decreases as the apparatus increases in size.
  • the optional top plate (14) of the impeller generally extends over the distance of the individual blades, such that its width is substantially the same as the blade length and is generally an annular configuration. The presence of the top plate (14) profoundly affects the flow because the flow must go around the top plate (14) leading to a highly turbulent region having a highly separated flow just under the plate as well as negative pressures. This turbulent region has very high turbulence dissipation, and occurs over only a small portion of the total cross-section, but is not energy efficient. Removal of the plate, or increasing its inner diameter to where it is substantially a solid disc (rather than annular), would improve the efficiency of the impeller.
  • the agitator base plate (15), as shown in Figure 3, is located beneath the at least one blade of the agitator, and is substantially a solid structure having an opening capable of accepting a drive shaft.
  • the base plate (15) may further comprise at least one aperture (16), but preferably a plurality of apertures, to allow the base plate to act as a non-point source for the feed(s) and/or reactants to be introduced and distributed in the vessel.
  • a non-point source feed/reactant addition is achieved by introducing the feed/reactant underneath the base plate (15) of the agitator.
  • agitator base plate has a radius greater than the radius of the draft tube, up to the internal radius of the vessel.
  • the feed and/or reactants can flow through these apertures (16) and spread radially through a region of rapid mixing as it passes the blades of the agitator.
  • at least one sweeper blade (17), preferable a plurality of sweeper blades, are utilized to aid in the distribution of the feed and/or reactants.
  • the plurality of sweeper blades (17) are typically located on the underside of the base plate (15), extending axially along the longitudinal and/or latitudinal axis of the base plate (15), perpendicular to one another and may be of any length, but generally have a length smaller than or equal to the base plate diameter.
  • the height of the sweeper blades is tapered as they extend in the direction away from the drive shaft (e.g. a sweeper blade may have a height of 1.75 at its end closest to the drive shaft, and a height of about 1.25 at its opposing end.
  • Non-point source feed/reactant addition has been utilized in commercial practice where the agitator base plate has a radius equal to the radius of the draft tube, however the present invention extends the radius of the agitator base plate (15). This extension does not affect the internal circulation achieved by the agitator (13). The extension reduces the fraction of high concentration feed/reactant that bypasses the feed flow through apertures in the agitator base plate (15). The greater the radius of the agitator base plate (15), the less the feed/reactant that passes through the gap between agitator (13) and the inner wall of the apparatus vessel.
  • a point source such as a sparger pipe
  • this type of introductory device has the significant disadvantage of having a region of high supersaturation around the outlet and a resulting plume of high supersaturation as the fed liquid dilutes and is dispersed throughout the crystallizer vessel.
  • the apertures (16) of the base plate (15) may be of any shape and/or size including, but not limited to, slots, circular, triangular, or square or mixtures thereof. This ensures that the fluid(s) pass through the shear zone, thereby resulting in intimate mixing of the fluids.
  • the size and/or shape of the aperture (16) does not affect the size or shape of the crystals produced in accordance with the present invention, but are influential in the production of the shear force due to their affect on the flow pattern of the fluid within the apparatus.
  • the size of the crystals may be manipulated by changing the chemistry of the fluid stream(s), the impeller rpm, the flow rates of the various inlet streams and their flow rates relative to one another.
  • the agitator (13) of the present invention may have a wide range of diameters, such as, for example about 10 cm to about 550 cm, and it is dependent upon the scale of the apparatus being utilized.
  • the preferred agitator, an impeller can have a diameter (as measured from one blade tip to another, opposing, blade tip) ranging from about 0.4 to about 0.75 times the diameter of the vessel being used.
  • the measurements of the agitator (13) can vary as the scale of the apparatus changes, and how to effectuate such measurement changes, although, such changes will be defined by the scale varying method provided below.
  • the volumetric flow rate (or pumping rate, which is the volume of slurry pumped per unit of time)), and therefore, the linear velocities (e.g. the average linear velocity is the agitator pumping rate divided by the cross sectional area of the of the area of interest) generated by the agitator of the present invention scale with the diameter of the agitator (13).
  • an agitator having a diameter of about 10 feet generally produces a volumetric flow rate of about 112,800 gpm and linear velocities of about 3.2 ft/second at about 30 rpm.
  • the specific power input scales with the cube of the agitator angular velocity.
  • the agitator (13) is connected to a rotatably mounted drive shaft (18).
  • the drive shaft (18) is generally connected to a motor or driving force capable of rotating the agitator (13) at speeds sufficient to adequately mix and suspend the solution or slurry undergoing crystallization.
  • the rotatably mounted drive shaft (18) may be a solid shaft, or conversely, may be hollow to allow it to act as a single or multiple inlet pipe to deposit the fluid within the agitator-swept volume (19).
  • the agitator itself may also be hollow, wherein the at least one fluid stream may be fed through the agitator and dispersed at one or several points along the agitator, for example, along the at least one blade and/or blade tip.
  • the draft tube (23) of the present invention is generally used to direct the circulation of the fluid(s) which surrounds it, thereby providing for the intimate mixing of the feed/reactants leading to the formation and homogenous distribution of crystals/precipitate/particles. More particularly, the draft tube (23) provides a channel (24), between an outer portion of the draft tube wall (25) and the inner portion of the cylindrical shell (26) of the vessel. After entering into the swept volume (19) of the radial flow agitator, the fluid is directed substantially upwards towards the top of the draft tube by the baffles. The fluid then flows into the channel (24), and ultimately, is drawn back towards the impeller by traveling along the length of the draft tube (23) until it pours over the top of the tube.
  • the draft tube (23) of the present invention further includes at least one window (27), preferably a plurality of windows, located along the height of the draft tube.
  • window (27) preferably a plurality of windows, located along the height of the draft tube. This permits forced circulation of the slurry upwards on the outside of the draft tube and downwards on the inside of the draft tube.
  • the window(s) (27) of the present invention allow for the use of a greater percentage of the draft tube.
  • the draft tube (23) is a cylinder that is arranged concentrically within the vessel, wherein the draft tube has a diameter that is about 0.7 times the diameter of the vessel.
  • the draft tube is a tapered cylinder, wherein the tapered draft tube has a top diameter (28) and a bottom diameter (29), such that the top diameter is greater than the bottom diameter.
  • the draft tube may be tapered in either a linear or non-linear fashion or even a frustrum of a cone plus a straight cylinder.
  • the draft tube may be a substantially straight cylinder having a top shaped like the end of a horn or trumpet such that it is flared out, thus having a greater diameter than the bottom of the cylinder.
  • the configuration is determined by the settling rate of the crystals/precipitate/particles in the slurry, wherein such a determination could be made by those skilled in the art.
  • the tapered configuration accelerates the slurry flow while it rises up the exterior of the draft tube. Generally it is desirable that the slurry rising outside the draft tube has a speed equal to the speed of the slurry falling within the draft tube. This results in equal slurry flow speeds upwards and downwards on either side of the draft tube.
  • Equal speeds of the feed/reactant inside and outside of the draft tube avoids the generation of additional shear force during acceleration and deceleration.
  • the crystals will rise at a slower rate than the fluid containing them outside the draft tube (due to gravity). This can lead to accumulation or catastrophic pluggage of crystals outside the draft tube.
  • the tapered draft tube is an additional improvement beyond the cylindrical vessel diameter draft tube, since it forces the slurry to accelerate against gravity and thereby overcoming the settling and accumulation phenomenon outside the draft tube.
  • a guideline determining the dimensions of the tapered draft tube is to maintain essentially equal volumes in the outer and inner regions of the vessel either side of the draft tube.
  • the draft tube (23) further includes baffles (12) that act to direct the liquid flow in a vertical motion towards the top of the draft tube and prevent the liquid from swirling in a circular motion due to the agitator.
  • the baffles (12) have a strong effect on the degree of swirl maintained in the vessel, the rate of turbulence dissipation in the annulus and affect the distribution of material inside the baffles.
  • the draft tube (23) may be constructed of any material capable of withstanding the forces generated within the present invention, such as, for example, fiberglass, steel, preferably stainless steel, PVC, glass and the like.
  • the draft tube of the present invention is stainless steel.
  • Another embodiment includes a hollow draft tube such that a cavity exists between the walls of the draft tube. This cavity may be utilized for several purposes including but not limited to, the introduction of feed/reactant(s) into the apparatus and/or as a method of heat transfer for heating or cooling the apparatus and its contents.
  • the draft tube may be used as a heat exchanger.
  • Still another embodiment includes a draft tube having a peripheral settling zone, wherein the zone has substantially the same configuration as the peripheral settling zone that may be found on the vessel.
  • the peripheral settling zone may be found on the outside of the draft tube or in the cavity of the hollowed draft tube.
  • allowances must be made for differences in size, diameter, height and the like, due to the smaller size of the draft tube when compared to the vessel.
  • a higher velocity is needed in the up-flow direction relative to down-flow regions because in up-flow the particles are settling in a direction opposite the mean fluid direction, while in down flow both the settling velocity and the mean fluid velocity are in the same direction.
  • the ratio of average velocities in Up-flow versus down- flow varies with suspension properties, flow conditions and the types of feed/reactants used to form the crystals/precipitate/particles. Therefore, a general ratio cannot be set forth, that is optimized for every set of process conditions.
  • the linear velocity of the slurry ranges from about 0.1 to about 1.8 meters per second, and preferably is about 0.9 meters per second.
  • a higher up-flow velocity also improves mixing of the slurry/liquid in the recirculation zone. This zone is prone to segregation, particularly when the suspension level is allowed to get too high above the top of the draft tube.
  • a nearly particle free liquid layer may be formed above the circulating suspension. This problem can be reduced by utilizing a higher up-flow suspension velocity.
  • the momentum of the faster fluid(s) leaving the channel outside the draft tube carries it higher into the zone above the draft tube and improves the mixing in this zone.
  • the vessel may have a portion of its interior as well as any internal parts, including but not limited to, the agitator (13), draft tube (23), and the like, coated using permanent or thermally removable coating in order to minimize secondary nucleation and aid in rapid de-encrustation.
  • Suitable soft coatings include, but are not limited to, polyethylene, poly(tetrafluoroethylene), polypropylene, neoprene, latex, rubber and the like.
  • Soft coatings are contemplated by the present invention because the collision of crystals with hard surfaces, such as the steel walls of the vessel, as well as any parts therein, such as the blades of the agitator, are major contributors to the secondary nucleation rate.
  • Soft coatings on the internals and moving parts reduce the fragmentation of crystals upon collisions and are of a particular advantage for biological products. Thus the secondary nucleation rate can be reduced and a larger crystal size can be achieved.
  • the use of soft coatings to the internal and moving parts of the apparatus of the present invention are particularly useful in conjunction with biological products.
  • Still another embodiment of the present invention further contemplates the use of optional secondary baffles (9) attached to the sidewall of the vessel to reduce the large recirculation zone inside the draft tube (23) at the top (mentioned above).
  • the draft tube can be modified to use the secondary baffles (9) to create a gentler change in direction of the liquid as it makes the turn from up-flow to down-flow at the top of the draft tube.
  • the recirculation results from the momentum of the liquid making the 180 degree change of direction from up- to down-flow at the top of the draft tube.
  • the flow of liquid cannot instantaneously make the sharp 180 degree change of direction, particularly that portion of the up-flow for which the change is most severe at the position immediately adjacent to the draft tube.
  • the flow separates from the draft tube at the top as it turns and does not follow the inside of the draft tube, but instead forms a core of down flow inside a weakly recirculating zone inside and adjacent to the draft tube.
  • the tapered shaping of the top of the draft tube decreases both the size and velocity of the zone. It is also a means of increasing the up-flow velocity locally into the zone above the draft tube, having the benefit of improved mixing of this zone, as described above.
  • the apparatus (30) operates by having fluid(s) (feed/reactant(s)) introduced into the apparatus via the at least one port (11) and/or through at least one feed/reactants pipe.
  • the fluid(s) is deposited inside the vessel (1), preferably in close proximity to the agitator (13) and fed to the agitator.
  • the fluids are caused to rapidly rotate within the agitator-swept volume (19) due to the rotation of the agitator.
  • the centrifugal force that is generated by the spinning agitator pumps the fluids in a radial direction towards the side wall (2) of the vessel (1) and eventually past the baffles (12).
  • the chemistry of the feed/reactant(s) and the resultant supersaturation dictates the formation and growth of crystals, such that various mechanisms include those conventional mechanisms known in the crystallization/precipitation/particle formation art including, but not limited to, those methods described below.
  • the size of the crystals obtained according to the process of the present invention may be controlled by adjusting the parameters of the process. For example, increasing the rpm of the crystallizer will often lead to finer particles, and adjusting the rate of addition and/or agitation will alter the particle size by altering the degree of supersaturation and mixing.
  • a person of ordinary skill in the art may determine, using routine experimentation, the parameters that are the most optimal in each individual situation.
  • the choice of solvent depends upon the solubility of the substance to be crystallized/precipitated.
  • a substantially saturated or supersaturated solution is obtained upon the mixing of the feed/reactant(s) fluid stream(s) injected through their respective pipes.
  • at least one fluid is typically a solvent containing the substance to be precipitated.
  • the at least one associated second fluid is an antisolvent, a reactant, a precipitant, a pH changing agent, a neutralizing agent, a dissolved salt or buffer, a cooling or heating fluid, a pressurized gas.
  • an antisolvent can be, a water- soluble substance which is dissolved, for example, in water, and is precipitated by using a suitable water miscible antisolvent (e.g. acetone, isopropanol, dimethyl sulfoxide, etc., or mixtures thereof), for example, 20 weight % methanol with 80 weight %, ethanol.
  • a suitable water miscible antisolvent e.g. acetone, isopropanol, dimethyl sulfoxide, etc., or mixtures thereof
  • An additional antisolvent example could include, a less water-soluble substance which may be dissolved, for example, in an organic solvent such as light petroleum or ethyl acetate, and precipitated with, for example, with diethyl ether or cyclohexane.
  • a reactive precipitation/crystallization example could include a substance dissolved in water at high pH and precipitated with acidified water at a lower pH.
  • An additional reactive example could include a rapid reaction between two inorganic ions, initially dissolved in separated aqueous solutions.
  • An example of such a reactive precipitation or crystallization could take many forms, such as, the formation of a mineral salt (e.g.
  • AI(OH) 3 or Ca 5 (P0 4 ) 3 OH, or a photonic material, such as CaF 2 ) or the crystallization/precipitation of a compound that forms a solid phase upon subjection to a pH change e.g. adjusting the pH of a protein solution with an acid or base towards the isoelectric point of the protein, resulting in precipitation; additionally an example could be a carboxylic acid containing compound such as ibuprofen, which is poorly water soluble at low pH but considerably more soluble at higher pH).
  • a salting out precipitation/crystallization example could include a substance such as a protein or peptide dissolved in a buffered aqueous solution and precipitated or crystallized through mixing intimately with a solution of a salt dissolved for example in water (such as sodium chloride or ammonium sulphate).
  • a cooling driven crystallization/precipitation example could include a substance dissolved in a solvent and crystallized/precipitated by shock cooling, where a second liquid stream could be a refrigerated solvent such as for example water, ethylene glycol or ammonia.
  • Temperature of operation is one parameter that can affect solubility of substances, and thus, the yield of the process. For many materials, the yield can be maximized by operating at low temperatures. However, careful choice of antisolvents enables increased yields at room temperature operation of the process. Maximizing the yield of this process, however, is not an essential aspect of the process according to the present invention. The present invention simply requires the temperature to be appropriate so that crystallization results.
  • solubility data is available in tables found, for example, in the Handbook of Chemistry and Physics, 73 rd edition, CRC Press or in scientific literature.
  • rate of addition of the solvent(s) and anti-solvent(s) through the pipes may be controlled by any known method, a non-limiting example being a pump.
  • a non-limiting example being a pump.
  • those persons skilled in the art will recognize and understand those methods with which flow rates to typical crystallizer devices may be restricted, such as including, but not limited to, using metering valves.
  • the rates of solvent and antisolvent addition are limited only by the equipment used to control it.
  • the fluids are added at a rate equivalent to the outflow, i.e., the sum of the inlet flow rates for the solvent(s) and antisolvent(s) is equal to the rate of the slurry exiting the process.
  • the ratio of the two or more inlet streams may be any value as determined by the phase diagrams of the materials, as would be well known to one skilled in the art.
  • one or more of the fluids is a slurry/suspension
  • seeding of the crystals/precipitates may result, wherein the crystals/precipitates formed according to the process are caused to crystallize/precipitate onto either the same substance being crystallized/precipitated, or onto a different substance that is, for example, suspended in at least one of the fluid streams being fed into the vessel.
  • the precipitate/crystallized particles may be removed from the fluid mixture (e.g. filtration, centrifugation and the like).
  • the precipitated compound may be dried by conventional methods generally known to persons skilled in the art. Examples of such methods include, but not limited to, tray-drying, oven-drying, flash-drying and air-drying.
  • the crystallized or precipitated particles may be separated out of the combined fluid mixture by using solid/liquid separation techniques generally known to persons skilled in the art, for example, filtration, settling, centrifugation, and the like.
  • the present invention may be utilized for the production of any variety of small, high surface area particles that can be used as carrier particles for liquids or as seeds for crystallization or precipitation.
  • the crystals/precipitate formed by the process of the invention can, in many cases, also be concurrently or subsequently coated with moisture barriers, taste-masking agents, or other additives that enhance the attributes of the crystallized pharmaceuticals.
  • the active substance crystals/particles can be formulated with other agents (such as excipients, surfactants, polymers) to provide the substance in an appropriate dosage form (e.g.
  • a surfactant, emulsifier, stabilizer may be introduced as another fluid stream into the shear zone, resulting in the stabilization of the precipitated dispersion.
  • the apparatus of the present invention can also be utilized in processes other than forming crystals/precipitate or particles including, but not limited to (i) the use of this vessel as a fermentor, (ii) the use of the annular settling zone for liquid/liquid extraction during fermentation, and (iii) the use of this vessel for heterogeneous catalyst reactions.
  • This vessel (1) can also be used as a fermentor for cell culture purposes.
  • the minimal power input characteristic of the agitator (13) would enable mechanically sensitive microorganisms to be suspended without exposure to high shear forces.
  • a filamentous yeast could be used in a cell culture, which would otherwise be broken up by the agitators commonly used in cell culture processes.
  • in situ product removal can be used to overcome this constraint by using an immiscible extraction solvent as an emulsion in the vessel.
  • the emulsion can be introduced to the fermentor at a number of possible locations, so that it circulates around the vessel (1) with the cells, products and medium.
  • the feed/reactant streams are introduced underneath the agitator base plate and/or from an upstream sparger that is in close proximity to the agitator inside the draft tube.
  • the toxic (or other) product would partition into the extraction solvent.
  • the extraction solvent can be continuously concentrated and drawn off using the peripheral settling zone (10).
  • the extraction solvent such as an organic liquid (where its specific gravity is less than the cell culture medium) rises in the annular zone and concentrates progressively towards the top.
  • the concentrated or coalesced dispersion can be continuously drawn off from the fermentor via the take off nozzle at the top of the peripheral settling zone (10). This material can be sent to a stripping process to separate the product from the extraction solvent. Regenerated extraction solvent can be returned to an emulsification step and then back into the fermentor vessel.
  • the present invention can also be used for heterogeneous catalyst reactions since the high rate of internal circulation enables good mass transfer.
  • the low specific power input enables less attrition of the catalyst particles than a conventional stirred tank reactor. While this advantage has general utility for heterogeneous catalysis, immobilized enzymes and cross-linked enzyme crystals (CLEC R ), (a trademark of the Altus Corporation), are mechanically sensitive heterogeneous catalysts that benefit well from the reduced specific power intensity features of this apparatus.
  • CLEC R cross-linked enzyme crystals
  • Bio products may be natural, synthetic or semi-synthetic (e.g., peptides, proteins, enzymes, nucleotides and the like) have been demonstrated to be crystallized in bulk vessels (e.g., glucose isomerase enzyme). Also biological products have been demonstrated to precipitate in a non-crystalline or semicrystalline state (for example soy protein isolates). In these cases of precipitation, the physical properties of the biological product precipitation process follows a number of process operational principles of crystallization such as the benefit of good suspension of the particles and the benefits of as low of a specific power intensity as practically possible. Biological products typically crystallize into particles that are more sensitive to mechanical damage than smaller molecules, salts or minerals.
  • this crystallizer vessel has particular utility for the crystallization of biological products.
  • One reason for this is that breakage of crystals is minimized, leading to significantly less secondary nucleation and thus a larger mean crystal size and narrower size distribution. Larger crystals tend to be more pure than smaller crystals, since the impurities are found mostly in mother liquor which adheres to the surface of crystals. Larger crystals have less surface area per unit volume. A larger crystal size also makes downstream solid/liquid separation easier to achieve. Crystallization of biological products is commonly achieved through the use of salting out techniques or pH adjustment. In these instances of crystallization, the means of introducing the concentrated salting out solution or acid/base has a major impact on the rate of nucleation and formation of crystals/precipitates.
  • the non-point source feed/reactant technique used for this vessel gives a significant advantage over more common sparger type feed/reactant introduction pipes for crystallizing biological products. This approach avoids the formation of very fine precipitates around the point of introduction, leading to larger, better formed crystalline particles.
  • biological product as well as many pharmaceutical crystallization processes are most suited to batch operation.
  • the liquid level in the vessel increases during the time course of the crystallization batch. For a vessel with a draft tube, this presents a liquid circulation problem early in the batch when the low liquid height prevents the passage of liquid/slurry over the top of the draft tube to recirculate back down towards the agitator.
  • open windows can be placed in the draft tube to enable passage of liquid/slurry from the outside of the draft tube to the inside of the draft tube, when the liquid/slurry level is less than the height of the draft tube. This enables recirculation of the slurry/liquid for the period of the batch when the liquid level is below the draft tube height.
  • the biological products include, for example, foods and food ingredients.
  • the water soluble and water insoluble foods and food ingredients that can be crystallized or precipitated include, but are not limited to, 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, anti-microbial agents, antioxidants, polypeptides, , small organic molecule therapeutics, co-factors, 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.
  • Further substances that can be crystallized/precipitated in the apparatus of the present invention include, but are not limited to biopharmaceuticals as defined above, drug compounds, such as, for example crop protection chemicals.
  • the present invention provides the ability to create drug crystals that are either finer or more coarse than typically produced by bulk crystallization (about 50 micron), and thus the present invention will enable poorly water soluble drugs to have a higher dissolution rate without the need/cost/contamination associated with milling processes or without the need to introduce solubility enhancing agents such as cyclodextrins or surfactants.
  • the pharmaceutical or biopharmaceutical substances may be those delivered via a pulmonary delivery mechanism, a parenteral delivery mechanism, a transdermal delivery mechanism, an oral delivery mechanism, an ocular delivery mechanism, a suppository or vaginal delivery mechanism, an aural delivery mechanism, a nasal delivery mechanism and an implanted delivery mechanism.
  • the present invention also contemplates the use of an ultrafiltration operation (or other cross flow filtration device) in a closed loop with a biological product crystallizer.
  • Supersaturation can be induced via concentration at the ultrafiltration membrane interface. This has distinct advantages over salting out or reactive crystallization, since the higher supersaturation is well distributed over the area of the membrane, rather than at the region of feed/reactant introduction.
  • the use of a membrane process in tandem to the crystallizer would enable a smaller volume batch to be used than the more dilute option where salting out is used to induce crystallization.
  • the tandem use of a membrane process to concentrate presents a useful combination of crystallizer and membrane process undergoing continuous recirculation. If a fine destruction system is used prior the membrane unit, the flux would be greatest. If a fines destruction unit is not used, a cross flow ultrafiltration device would be preferred to minimize fouling of crystals on the membrane surface. Similar utility of a membrane process in tandem to the crystallizer can be achieved for microfiltration, nanofiltration and reverse osmosis membranes. The utility of these configurations is not restricted to biological molecules.
  • Clean in place (CIP) and/or sterilize in place (SIP) features of a batch crystallizer are an additional feature that can be utilized in the present invention to meet the processing requirements for food or therapeutic products.
  • Food grade crystallization processes similarly require CIP and SIP capability.
  • Nozzles and lines for automatic introduction of cleaning fluids and sterilizing fluids at the completion of a batch are also hereby provided for this system.
  • Crystallization of biological products is a rapidly emerging application of crystallization/precipitation technology in the biotechnology and food industries.
  • Use of the gentle agitation system here, the non-point sou reed feed/reactant introduction system and tandem use of membrane concentration processes provides key advantages over the currently used agitated tank style crystallizers in operation.
  • the introduction of CIP and SIP systems are one requirement to meet hygienic production standards.
  • the present invention further relates to a method for varying the scale of the apparatus of the present invention. It is critical to control the specific power intensity of the apparatus.
  • the specific power intensity (SPI) often controls the crystal habit, and for example the flowability of a powder product.
  • the present invention provides a method for designing an agitator which gives the required pumping rate and specific power intensity at any scale.
  • the "agitator pumping rate" can be defined using a mathematical expression which helps to describe the necessary circulating flow around the draft tube to both suspend the crystals uniformly and to dilute regions of supersaturation production and mix them as uniformly as possible throughout the desired crystallizing volume.
  • the agitator pumping rate is given in Perry's Chemical Engineer's Handbook. Seventh Edition, McGraw-Hill, NY, 1997 (equation 18-2) as shown in Equation I below:
  • I Q NQ * D3 * N, where Q is the agitator discharge rate (in M 3 /sec for instance), NQ is the discharge coefficient (dimensionless), D is the agitator diameter (in meters for instance), and N is the rotation speed (in revolutions per second for instance).
  • the "specific power intensity” (SPI) describes the degree of the intensity of the mixing imparted by the agitator to the slurry passing through it during each revolution as the slurry travels around the draft tube path (as opposed to an average value for the vessel which is often used in the mixing literature).
  • SPI is defined as the power input of the agitator divided by the slurry mass in the swept volume of the agitator.
  • SPI Agitator power/(Agitator volume * Rho), where agitator power (in watts for instance) is the input to the slurry from the agitator as given below in Equation IV, and the denominator is the mass in the swept volume of the agitator (in this case with units of meter cubed divided by kilograms per meter cubed, or simply kilograms). Rho is the slurry density (in kilograms per cubic meter, for instance).
  • the "agitator volume” is the area of the agitator multiplied by its height, (by elementary geometry) and is expressed in Equation III. Therefore, the mass in the swept volume is:
  • Equation IV Np * N 3 * D5 * Rho
  • Np the power number (dimensionless)
  • N the rotation speed (in revolutions per second, for instance)
  • D the agitator diameter (in meters for instance)
  • Rho the slurry density (in kilograms per cubic meter, for instance).
  • the pumping rate and specific power intensity (SPI) values do not scale linearly with each other, so that as one changes the scale of the unit, these important agitator design parameters change, thus the conundrum for the designer is to decide which parameter to keep constant, which parameter to vary, or to compromise and vary both parameters.
  • the pumping rate (Equation I) is directly proportional to the rotation speed, whereas for the specific power intensity (Equation V) it is proportional to the third power of the rotation speed, so one cannot scale up or down geometrically and keep both proportionally the same.
  • the present invention provides a method to control these two primary variables by the act of changing the agitator height (H in the equation) since the discharge coefficient NQ and the power number (Np) both scale linearly with height for this agitator.
  • H in the equation the discharge coefficient
  • Np the power number
  • the agitator having a 3.1-inch height gives an SPI lower than the commercial-size unit; and a minor reduction in the height, and proportional increase in speed yields an apparatus design equal to the commercial-size unit having the same flow and SPI.
  • the particles utilized in the test were 150 to 200 micron sand particles, specific gravity 2.9 g/cm 3 , 1% by weight, to the fluid which was water. The measured results are shown below in Table 1.
  • a 3 wt. %, weak sulfuric acid stream of 40 gpm from an ion- exchange resin regeneration was to be neutralized with a 20 wt % lime slurry to produce synthetic or chemical gypsum, as shown by the reaction:
  • a 10 liter draft tube pilot crystallizer was utilized, wherein the draft tube had a diameter equal to 5.5 inches, at about 200 rpm, giving an SPI of about 8 W/kg.
  • the resultant crystals were needle-like, and rather fine (less than 100 microns mean diameter, wt. % (by Coulter Counter TM).
  • a double draw-off procedure was used to concentrate the crystals, by doubling their residence time (by doubling the concentration), which resulted in a dramatic increase in the crystal size.
  • a 10 ft. vessel diameter Burke type unit with the addition of a settling zone on top was utilized.
  • the commercial unit met the full expectations of the pilot test.
  • the mean diameter of the produced crystals by CC was greater than 400 microns (wt % basis).

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  • Physics & Mathematics (AREA)
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Abstract

L'invention concerne un appareil conçu pour être utilisé dans la production de particules par précipitation ou cristallisation ou par des moyens analogues. L'invention concerne également des procédés permettant de former les cristaux/précipités ou les autres particules.
PCT/US2003/040240 2002-12-16 2003-12-16 Appareil et procede permettant de former des cristaux/precipites/particules WO2004058377A1 (fr)

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AU2003293576A AU2003293576A1 (en) 2002-12-16 2003-12-16 Apparatus and method for forming crystals/precipitate/particles
EP03790524A EP1572314A1 (fr) 2002-12-16 2003-12-16 Appareil et procede permettant de former des cristaux/precipites/particules
JP2004563683A JP2006510484A (ja) 2002-12-16 2003-12-16 結晶／沈殿体／粒子を生成させる装置および方法

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CN1747770A (zh) 2006-03-15
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JP2006510484A (ja) 2006-03-30
EP1572314A1 (fr) 2005-09-14

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