KR100926414B1 - Preparation method of massive crystalline particles by separate feeding of reaction materials - Google Patents

Abstract

PURPOSE: A manufacturing method of massive crystalline particles is provided to separate the massive crystalline particles easily from a solid-liquid separation process by growing the size of the particles. CONSTITUTION: A manufacturing method of massive crystalline particles includes the following steps of: generating crystal nucleus by injecting reaction materials to a reactor; growing the crystals by injecting the reaction materials to a plurality of raw material inlets; and adjusting the temperature of each sector in the reactor. The temperature control of the reactor is performed by a heat jacket installed in the reactor. The reaction material is the amino acid or the nucleic acid. The crystallization reaction is performed in a continuous reaction in which taylor vortex is supplied.

Description

Preparation method of large crystal grains by split injection {preparation method of massive crystalline particles by separate feeding of reaction materials}

The present invention relates to a method for producing crystal grains, and more particularly, to produce a large crystal grain that can induce a crystal growth reaction to grow the size of the particles to facilitate the separation of the crystal grains in the solid-liquid separation process, which is a subsequent process It is about a method.

The crystallization reaction is adopted to separate any substance into pure form or is widely used to obtain crystals in which the particle size or shape is controlled. Conventional non-continuous crystallization reactors used in the prior art is difficult to ensure uniform mixing of the reactants for crystallization, it is difficult to form a crystal grain having a certain size or shape.

In order to solve this problem, a continuous reactor of the type shown in FIG. 2 has been proposed by the present inventors. Such a reaction apparatus generates a Taylor vortex in the flow of the reaction liquid by the rotation of the stirring rod, and as a result, enables uniform mixing as a whole, thereby making it possible to grow the crystal grains uniformly.

In most crystallization processes, the crystallization process is usually performed by two steps, a first crystallization step in which nucleation is formed and a second crystallization step in which crystals grow from the crystal nuclei. However, according to the conventional general crystallization reaction process, most of the crystals formed at the beginning of the reaction are dissolved over time, and the size of the crystals is significantly reduced. This can cause difficulties in pure separation of the crystals.

The present invention has been made to solve the problems of the prior art as described above, the object is to induce a crystal growth reaction to grow the size of the particles, the separation of the crystal grains in the solid-liquid separation process, which is a post-process It is to provide a method for producing large crystal grains to facilitate.

The technical problem as described above is achieved by the following configuration according to the present invention.

(1) injecting reaction raw materials into the reactor to generate crystal nuclei; A method for producing large crystal grains by split injection, comprising the steps of split-injecting a reaction raw material into a reactor in which the generated crystal nuclei exist.

(2) The method according to (1), wherein the large crystal grains by split injection are characterized in that the temperature is adjusted for each section of the reactor.

(3) The method according to the above (2), wherein the temperature control of the reactor is carried out by a thermal jacket installed in the reactor.

(4) The method according to (1), wherein the reactant is injected into a plurality of raw material inlets formed in the reactor by dividing and injecting the large crystal grains by split injection.

(5) The method according to (1) above, wherein the reaction raw material is an amino acid or a nucleic acid.

(6) The method for producing macrocrystal grains according to (1), wherein the crystallization reaction is performed in a continuous reactor fed with Taylor vortex provided by the rotation of the internal stirring rod.

According to the above configuration of the present invention, by introducing the reaction raw material by injecting the crystal growth reaction can be grown to large crystals without reducing the size of the particles to obtain a crystal grain of the desired size as well as the subsequent liquid It facilitates the separation of crystal grains in the separation process.

Hereinafter, the content of the present invention will be described in more detail with reference to the embodiments shown in the drawings.

The present invention comprises the steps of injecting the reaction raw material into the reactor to generate a crystal nucleus; It includes a method of producing a large crystal grains by split injection comprising the step of growing a crystal by split injection of the reaction raw material in the reactor in which the resulting crystal nucleus is present.

In the present invention, the reaction raw material includes a reactant which is a crystallization material or an antisolvent used for crystallization of the reactant. Hereinafter, the reactants will be mainly described and the antisolvent will be briefly mentioned.

In the method for preparing a large crystal grain according to the present invention, first, a predetermined amount of reactant is used to generate crystal nuclei, and then an additional amount of reactant is added to the generated crystal nuclei to bind the added reactant onto the previously formed crystal nucleus. Involve them in the reaction to grow crystals. It is then possible to induce sustained growth of the crystals by adding an additional amount of reactant several times to further grow the crystals.

Therefore, the method for producing macrocrystalline particles according to the present invention can be carried out for both continuous or discontinuous crystallization reaction.

The discontinuous crystallization reaction as shown in FIG. 1 is advantageous in terms of installation cost of the device in that the conventional batch crystallization reactor 1 can be used as it is. However, such a crystallization reactor is troublesome in terms of time and procedure in that the process of recovering the solution (3) containing crystals obtained by adding the reaction raw materials each time and mixing them with the stirrer (2) is performed manually.

The method for producing macrocrystalline particles of the present invention is also suitable for continuous reactors because it applies a method of dividing the reactant into the reactor.

A continuous reactor may be considered for various reactors, but one may use, for example, the Kuet Taylor type crystallization reactor of FIG. 2 which has been devised by the inventors.

Figure 2a is a specific configuration of the reactor applicable to the present invention, the reaction vessel 21, the stirring rod 22, the inlet (23, 23a, 23b, 23c) of the at least one crystallization reactant, the crystal outlet (24), If necessary, an inlet 25 for injecting seeds or other additives for crystallization and a heat supply unit 26 for supplying heat to the reactor are included. Reference numeral 27 represents a reactor inner space. Such reactors are particularly suitable for carrying out a continuous crystallization reaction.

Reactor 21 may be composed of a round cylindrical shape as a whole, the inlet (23, 23a ~ 23c) of the reactants may be arranged in a plurality at a predetermined interval in series at the top of the reactor. This inlet of the reactants allows for split injection of the reactants at regular time intervals. That is, a process of initially injecting a predetermined amount of reactants to generate crystal nuclei, and then reacting the reactants introduced into the next reactant inlet is combined with the previously generated nuclei to grow crystals. The crystals again react with the reactants introduced at the next reactant inlet to grow even larger. Through this process, it becomes possible to grow large crystal grains.

If the reactant is added to only one reactant inlet 23 to proceed with the crystallization reaction, as shown in FIG. 2A, a significant amount of the reactant is used to generate crystal nuclei, thereby limiting the growth of crystals. This in turn acts as a factor that makes the size of the crystal grains finally obtained small, making it difficult to separate the crystals from the reaction solution.

In addition, the inlets 23a to 23c of the excess reactant may be provided for the purpose of administering seeds or various additives for crystallization in addition to the use as inlets for the split injection of the reactants.

In addition, the inlets 23a to 23c of the excess reactant may also be provided for the purpose of injecting a device for measuring the reaction conditions to adjust the reaction conditions (eg, pressure, flow rate, pH, temperature, etc.). .

The stirring rod 22 is not particularly limited in shape but may be configured in a round cylindrical shape to uniformly mix the reactants and consequently to uniformly configure the temperature of the reactants. The stirring rod 22 may or may not have a space therein. In general, a space inside may be mainly used to control the temperature of the reactant by containing a heat transfer medium.

It is preferable that the stirring rod 22 is configured to be positioned on the central axis of the reaction tank 21 so as to rotate. To this end, a rotary motor may be connected to one end of the stirring rod 22. In addition, substantially the same effect can be expected also by rotating the reaction tank instead of rotating the stirring rod itself.

If the rotation speed of the stirring rod 22 is more than the threshold value, the fluids around the enclosure move under the centrifugal force in the vertical direction from the axis of rotation, thereby forming a Taylor vortex. As a result, the flow is very regular, the temperature distribution is very uniform, and the particle size of the uniform crystal can be obtained.

The process by which the Taylor vortex is formed in the solution according to the rotation of the stirring rod 22 is described by FIG. 2B. This allows the flow of fluid in the reactor 21 to be characterized as vortex cells periodically arranged along the axis of the stir bar 22. For example, when the fluid flows in the space between the stirring rod 22 and the reaction tank 21, the fluid around the stirring rod tends to go out in the direction of the fixed reaction tank by centrifugal force as the stirring rod 22 rotates. do. This causes the fluid layer to become unstable, forming a Taylor vortex. The vortex region appears when the speed of rotation of the stirring rod 22 is above the threshold. Each flow element consists of annular vortex pairs that rotate in opposite directions.

As described above, in the reaction apparatus of the present invention, by using the Taylor vortex, the flow is very regular and uniformly mixed, and the temperature distribution is uniform in all the regions, so that it is possible to obtain crystals of uniform particle size.

When the reactant is added by split injection, as described above, the size of the particles can be further increased in the direction of the reaction solution, which is very effective for finally growing the large crystal grains.

In the reaction space 27, which is a space between the stirring rod 22 and the reaction tank 21, a crystallization reaction by the reactant proceeds. As a raw material that can be used for the crystallization reaction, all raw materials used for various known crystallization reactions can be used. Such a reactant may be added continuously or at regular time intervals by dividing a predetermined amount through the reactant inlets 23 and 23a to 23c provided at the upper end of the reaction tank 22. For convenience of illustration, it is shown in FIG. 2A to allow up to five reactant inlets, but this is merely illustrative and the spacing and number of these inlets are only those that can be selected by those skilled in the art.

Specific crystallization raw materials that can be used in the present invention, that is, the kind of reactants include, for example, various amino acids (tryptophan, lysine, alanine, methionine, phenylalanine, leucine, isoleucine, glycine, valine, arginine, arginate, glutamine, glutamate, Amino acids such as serine, threonine or derivatives thereof, nucleic acids (nucleic acids such as guanosine monophosphate, cytosine monophosphate, adenosine monophosphate, thymine monophosphate or derivatives thereof), proteins (oligopeptides and polypeptides) Organic compounds such as benzoic acid, p-xylene, chlorobenzene, and the like, as well as inorganic metal salts such as copper sulfate, sodium chloride, sodium acetate, potassium chromate, sodium sulfate, calcium acetate, sodium chromate, barium acetate, and the like. As a result, any substance that can precipitate as a crystal in a supersaturated state under specific conditions may be used as a reactant in the present invention.

The reactants introduced through the crystallization reactant inlets 23, 23a to 23c flow through the reactor interior space 27 in the form of a solution or a melt, which can remain inside the reactor for a predetermined residence time for the crystallization reaction.

The kind of crystallization reaction to which the reactor of the present invention can be applied is not particularly limited. Therefore, it can be applied to all crystallization reactions such as reactive crystallization, salt crystallization, molten crystallization, cooling crystallization, evaporative crystallization and the like.

In addition, when the reaction includes cooling crystallization, the crystallization reaction may be controlled by a refrigerant included in or flowing through the stirring rod 22. In this case, the refrigerant absorbs heat from the crystallized raw material in solution so that the raw material becomes supersaturated. In this state, crystal formation starts at the surface of the initial stirring rod 22 and gradually diffuses in the vertical direction of the rotation axis.

The temperature control inside the reactor 21 by heat exchange can be controlled to an appropriate level from the thermodynamic equilibrium relationship. That is, if the basic physical quantities such as the heat capacity of the solution contained in the reactor 21 and the stirring rod 22, the heat capacity of the medium flowing therein are known, it is desirable to control the temperature inside the reactor 21 at a desired level. It is possible. In this case, the control of the temperature can be adjusted through the control of the amount of heat supplied by the heat supply unit 26 installed in the reaction tank (21). Preferably, the heat supply unit 26 may be implemented in the form of a warm jacket.

3 shows an example in which a warm jacket 26 is installed outside the reaction tank for the crystallization reaction apparatus according to the present invention.

The heat supply unit 26 may be installed over a part or the whole of the entire reaction tank, it is also possible to perform the temperature control for each of the divided areas by separately installed by the area partitioned according to the reactant inlet.

In the present invention, not only a refrigerant but also a high temperature medium such as hot water may be used as the heat transfer medium. This depends on the nature of the reaction carried out in the reactor and one skilled in the art will be able to select an appropriate heat transfer medium. When a refrigerant is used, it is not required to be limited to a special kind, for example, water, ethylene glycol and the like can be used. The selection of specific solvents differs depending on the reaction. For example, when cooling to 0 ° C. or lower is required, water becomes a solid phase, and thus it is difficult to use. In this case, ethylene glycol is suitable.

Figure 4 includes a crystal separation process system comprising a crystallization reaction apparatus according to the present invention.

The reactant 43 to be crystallized is introduced into the reactor 45 of the present invention through the liquid pump 44 in a uniform solution state by the stirrer 41. At this time, the reactant 43 is divided into a plurality of reactant inlets provided at the top of the reactor is added. The amount of reactant to be split-in depends on the kind of crystallization reaction, the reactants used and the reaction conditions. Therefore, after observing the movement time and reaction stage of the reaction liquid in the reactor, the control of the pump 44 and the flow control valve 51 to open and close the appropriate amount of reactants in a timely manner It is good.

In the present invention described above, the reactant is dividedly added, but the same result can be obtained even if the antisolvent is separately added. That is, even if the reaction product is administered once, when the anti-solvent is divided and added, the process of generating the crystal nuclei is mainly performed by adding the first predetermined amount of the anti-solvent. It is also possible to induce the growth reaction of the resulting crystals. Specific examples of the antisolvent include various organic solvents, and more specifically, methanol.

If necessary, a material 42 which can be a seed for crystallization can likewise be introduced into the crystallization reactor 45 through the liquid pump 44 in a uniform state by the stirrer 41.

The rotation of the stirring rod by the operation of the rotary motor 50 as described above in the crystallization reactor 45 provides the Taylor vortex to the reactants to enable uniform mixing. In addition, by injection, the size of the crystals grows and is discharged to the outlet as the reaction proceeds.

The discharged solution is separated through the solid-liquid separator 46 into a liquid portion containing impurities and crystals present in a pure crystalline state.

The crystals thus separated are discharged through the discharge port, and are transferred to the solid-liquid separator 46 to obtain crystallized raw material purified with high purity.

Hydrogen ion concentration of the crystallized material produced in the reactor can be measured using a pH meter (47). The solid or liquid crystallized material separated by the solid-liquid separator 46 is attached to the stage using conductive carbon tape, which can be analyzed by an electron microscope 48 which can analyze the shape and size of individual particles. have.

In addition, the crystallized material of the solid or liquid separated by the solid-liquid separator 46 may be provided to the particle size analyzer 49 using ultrasonic waves, and the crystals are coalesced with physical weak force so that the particle size is analyzed every minute. Over time, no change in particle size, or agglomerated aggregates with strong force are not separated by ultrasonic waves, thereby measuring the size of the agglomerated crystals.

Hereinafter, the contents of the present invention will be described in detail with reference to specific examples, but the scope of the present invention should not be construed as being limited by these examples.

Example 1 Preparation of Macrocrystalline Particles by Split Injection of Reactant

In the case where 0.9 L of GMP (Guanosine 5'-Monophosphate) solution with a concentration of 200 g / L and 0.9 L of antisolvent methanol were injected into a continuous reactor at once, according to FIG. 5, the particle size was increased after 20θ as the reaction time (θ) increased. It can be seen that the tendency to decrease.

In contrast, the same GMP solution was continuously divided into three inlets (injection at a ratio of 50% at the first inlet, 30% at the second inlet, and 10% at the third inlet) continuously from the beginning of the reaction to the completion of the reaction. When injected into the equation reactor as shown in Figure 5 it was confirmed that the reduction rate of the particle size after 15θ is significantly lower than when the injection is not divided (see Table 1 below).

<Table 1> Diameter of the crystal grains (㎛) according to the reaction time (θ)

Split Injection Ratio Particle size (㎛) according to reaction time (θ) ^* 7 11 15 19 23 27 31 35 39 10: 0: 0 184.67 121.67 186.38 172.49 111.66 86.87 73.41 6: 3: 1 107.26 172.09 134.18 125.35 128.31 150.97 143.08 153.10 131.09

* θ = 5τ + 5 min (τ: residence time of crystal in reactor, min)

Example 2 Preparation of Macrocrystalline Particles by Antisolvent Split Injection

In the case where 0.9 L of Guanosine 5'-Monophosphate (GMP) solution having a concentration of 200 g / L and 0.9 L of antisolvent methanol were injected into a continuous reactor at once, according to FIG. 6, the size of crystal grains increased as the reaction time (θ) increased. The tendency to decrease can be observed.

In contrast, methanol, which is an antisolvent, was injected into the mixture through three inlets (injection at a ratio of 70% at the first input, 10% at the second input, and 20% at the third input) from the initial stage to the completion of the reaction. As shown in FIG. 6, it can be seen that since 20θ passes, the reduction rate of the particle size is significantly lower than that of the case where the injection is not divided. (See Table 2 below)

<Table 2> Diameter of Crystal Particles (㎛) According to Reaction Time (θ)

Split Injection Ratio Particle diameter (㎛) according to reaction time (θ) 7 11 15 19 23 27 31 35 39 10: 0: 0 184.67 121.67 186.38 172.49 111.66 86.87 73.41 7: 1: 2 198.52 157.93 144.66 135.61 127.23 131.72 113.28 134.91 105.37

As shown in FIG. 7, when the anti-solvent is dividedly injected under the same conditions as in the present invention or when the injection of the reactant is not performed at all, the process according to the present invention is used even when the reaction time is 30θ or more. It can be seen that the size is significantly suppressed. Therefore, according to the present invention, it can be seen that it is possible to easily prepare the desired macrocrystalline particles.

As described above, it has been described with reference to a preferred embodiment of the present invention, but those skilled in the art various modifications and changes of the present invention without departing from the spirit and scope of the invention described in the claims below I can understand that you can.

1 is a schematic configuration diagram of a discontinuous crystallization reactor applicable to the present invention.

2 is a schematic configuration diagram of a continuous crystallization reaction apparatus applicable to the present invention.

3 is an explanatory diagram showing a Taylor vortex in a continuous crystallization reactor applicable to the present invention.

Figure 4 is a block diagram of a crystal separation process system including a crystallization reaction apparatus according to the present invention.

Figure 5 shows the size of the crystal grains by reaction time obtained by the reactant split injection method according to the present invention.

Figure 6 shows the size of the crystal grains by reaction time obtained by the anti-solvent split injection method according to the present invention.

Figure 7 shows the size of the crystal grains by reaction time obtained by the reactant split injection, anti-solvent split injection and the control.

<Code Description of Main Parts of Drawing>

21: reactor

22: stirring rod

23, 23a-23c: reactant inlet

24: product outlet

25: additive inlet

26: warm jacket

27: reaction space

41: stirrer

42: seed containing solution

43: reactant solution

44: pump

45: crystallization reactor

46: solid-liquid separator

47: pH meter

48: electron microscope

49: particle size analyzer

50: rotary motor

51: flow control valve

Claims (6)

Injecting reaction raw materials into the reactor to generate crystal nuclei; A method for producing macrocrystalline particles by split injection, comprising the steps of: splitting and injecting a reaction raw material into a plurality of raw material inlets formed in the reactor to grow crystals in a reactor in which the generated crystal nuclei exist. The method according to claim 1, wherein the temperature is adjusted for each section of the reactor. The method of claim 2, wherein the temperature control of the reactor is performed by a thermal jacket installed in the reactor. delete The method according to claim 1, wherein the reaction raw material is an amino acid or a nucleic acid. The method according to claim 1, wherein the crystallization reaction is carried out in a continuous reactor fed with a Taylor vortex provided by the rotation of the internal stirring rod.

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