KR20190112613A - Crystallization device using non-solvent for drug crystal formation and method forming a drug crystal using the crystallisation device - Google Patents

Abstract

The present invention relates to a crystallization apparatus using a non-solvent for drug crystal formation and a method for manufacturing drug crystals using the same. More specifically, the present invention relates to: the crystallization apparatus using the non-solvent for drug crystal formation which controls a growth direction in a crystallization process for manufacturing drug crystals to uniformly grow drug crystals; and the method for manufacturing drug crystals using the same.

Description

Crystallization apparatus using a non-solvent for the preparation of drug crystals and a method for producing a drug crystal using the same {CRYSTALLIZATION DEVICE USING NON-SOLVENT FOR DRUG CRYSTAL FORMATION AND METHOD FORMING A DRUG CRYSTAL USING THE CRYSTALLISATION DEVICE}

The present invention relates to a crystallization apparatus using a non-solvent for the preparation of drug crystals and a method for producing a drug crystal using the same, and more particularly, by controlling the growth direction in the crystallization process for the preparation of drug crystals using a non-solvent The present invention relates to a crystallization apparatus using a non-solvent for the preparation of drug crystals that can be grown quickly, and a method for producing drug crystals using the same.

The growth direction of the crystal is influenced by the solvent, non-solvent, temperature, pressure, etc. used in the crystallization process. After these conditions are set, it is difficult to easily change the growth direction and difficult to control the crystal to have a uniform size. When drug crystals have a large aspect ratio, there is a problem in that the flowability is very poor and the processability is bad. In other words, since downstream processes such as packaging and filtration of drug crystals having a large aspect ratio are difficult, these problems are considered important in crystallization design in the actual industry.

To solve this problem, techniques for changing the form of the drug crystals (habit) through various variables have been developed. Among them, the solvent is changed in one way to change the size and aspect ratio of the crystals and to change the physical properties of the drug itself. The method has been proposed. However, the choice of solvent has many limitations in terms of solute characteristics, environmental aspects, and cost of the process, so the method of changing the solvent is limited.

Among the various crystal shapes, high aspect ratio needles (needles, acicular habits) or long rods (long rods) are very avoiding crystal shapes. The possibility of overcoming the limitations of the industrial process by changing the solvent's size and aspect ratio, and changing the physical properties of the drug by changing the solvent among the technologies that change the habit of the drug crystal through various variables Showed. In addition, research is being conducted to control the morphology of drug crystals through surface area changes through surface treatment. However, the choice of solvent has many limitations in terms of solute characteristics, environmental and cost aspects of the process, so that various solvents cannot be used.

In addition, the Kuet-Taylor reactor, which is one of the recently commercialized technologies, has a structure in which a fluid between two cylinders having shafts uses flow due to rotation of an inner cylinder, unlike a conventional reactor. The structure of the Kuet-Taylor reactor can give a uniform flow, so that the size of the drug crystal can be uniformly controlled through effective mass transfer, and the size of the crystal can be controlled by controlling the nucleation and supersaturation of the crystallization. On the other hand, as a special crystallization device ratio includes a high-speed rotation unit, there is a complicated disadvantage of adding and recovering the solvent. Such Kuet-Taylor reactors are only suitable in some fine chemical industries.

On the other hand, naproxen (Maproxen) is a non-steroidal anti-inflammatory analgesic (NSAID) family, which is used for rheumatoid arthritis and pain relief. Naproxen is a poorly soluble drug, mainly in the form of a white powder, with low solubility in water, and the crystals are mainly in the form of sticks and plates. As a research related to naproxen, there are studies to control crystal growth and size by adding a polymer, but since many studies are conducted on a laboratory scale, there is a problem that is difficult to apply industrially. No technique has yet been reported for controlling the growth of naproxen crystals without the use of additional materials such as polymers.

In addition, Flurbiprofen, Adefovir Dipivoxil, ibuprofen, and the like, which have a rod-shaped crystal shape, are widely used, and are used in the crystal growth process to improve their processability. Aspect ratio control is needed.

One object of the present invention is for the preparation of drug crystals, which can be easily controlled to reduce the aspect ratio of the crystal grains in the growth process of the crystal's drowning-out mode (crystallization using a non-solvent). It is to provide a crystallization apparatus using a non-solvent.

Another object of the present invention is to provide a method for producing drug crystals using the crystallization device.

Crystallization apparatus using a non-solvent for the production of drug crystals according to an embodiment of the present invention, the reaction unit containing any one of a non-solvent solution or a drug solution; And a supply unit including a nozzle for supplying the other one of the non-solvent solution or the drug solution to the reaction unit, wherein the discharge port for supplying the solution to the reaction unit through a fine opening having a diameter smaller than the diameter of the nozzle is the nozzle. Is provided.

The nozzle of the feed is submerged in the solution of the reaction.

The drug crystal grown in the reaction section is a crystal grain having a reduced aspect ratio than the drug powder used in the drug solution.

Each of the fine openings of the discharge port preferably has a diameter of 0.1 μm or more and 100 mm or less.

The discharge port is a mesh formed with fine openings or a porous structure having fine openings, and is provided at one end of the nozzle.

The flow rate of the solution discharged from the nozzle to the discharge port is preferably at least 0.01 mm / second or more.

The porous plate may be further disposed in the front direction in which the solution of the discharge port is discharged.

The porous plate is formed with pores penetrating the porous plate in a direction perpendicular to the plane of the porous plate, and each of the pores preferably has a diameter of 0.1 μm or more and 100 mm or less.

The thickness of the porous plate is preferably less than 100cm.

Crystallization method using a non-solvent crystallization device for the preparation of drug crystals according to an embodiment of the present invention, the reaction of the crystallization device using a non-solvent for the preparation of drug crystals, wherein the drug crystal grows to obtain crystal particles Supplying the part with either a non-solvent solution or a drug solution; The discharge port for supplying the remaining solution of the non-solvent solution or the drug solution from the drug solution supply unit having a nozzle of the crystallization device to the reaction unit, through the micro-opening having a diameter smaller than the diameter of the nozzle Supplying a solution to the reaction unit through the minute openings provided in the nozzle; And growing crystals from the solution supplied through the micro-openings in the reaction unit to form crystal particles having a reduced aspect ratio than the drug powder used in the drug solution.

Crystallization apparatus using a non-solvent for the production of drug crystals according to an embodiment of the present invention, the reaction unit containing any one of a non-solvent solution or a drug solution; A supply unit including a nozzle for supplying the other of the non-solvent solution or the drug solution to the reaction unit; And a porous plate disposed forward in the direction in which the solution of the supply part is supplied.

The porous plate floats above the solution of the reaction section, and the supply section is disposed above the solution of the reaction section, thereby dropping the solution into the porous plate floating above the solution of the reaction section.

Pores penetrating the plane of the porous plate are formed in the porous plate, and each of the pores preferably has a diameter of 0.1 μm or more and 100 mm or less.

The thickness of the porous plate is preferably less than 100 cm.

The nozzle is provided with a discharge port for supplying a solution to the reaction part through a micro-opening having a diameter smaller than the diameter of the nozzle.

Each of the fine openings of the discharge port preferably has a diameter of 0.1 μm or more and 100 mm or less.

The discharge port is a mesh formed with fine openings or a porous structure having fine openings, and is provided at one end of the nozzle.

The drug crystal grown in the reaction section is a crystal grain having a reduced aspect ratio than the drug powder used in the drug solution.

Crystallization method using a non-solvent crystallization device for the preparation of drug crystals according to an embodiment of the present invention, the reaction of the crystallization device using a non-solvent for the preparation of drug crystals, wherein the drug crystal grows to obtain crystal particles Supplying the part with either a non-solvent solution or a drug solution; The drug solution supply unit having the nozzle of the crystallization apparatus supplies the other one of the non-solvent solution or the drug solution to the reaction unit, and is disposed in front in the direction in which the solution of the supply unit is supplied, the porous having pores penetrating the plane Feeding the reaction part through the plate; And growing crystals from the solution supplied through the pores of the porous plate in the reaction unit to form crystal particles having a reduced aspect ratio than the drug powder used in the drug solution.

According to the crystallization apparatus using a non-solvent for producing a drug crystal of the present invention described above and a method of manufacturing a drug crystal using the same, it is possible to easily produce crystal particles having a reduced aspect ratio by using a drug powder having a high aspect ratio. Can be. The prepared crystal particles may have a uniform size. Using this crystallization apparatus, using drug powders of Flurbiprofen, Adefovir Dipivoxil or ibuprofen, it is possible to easily prepare crystal grains having reduced aspect ratio of the crystal particles of the drug. Workability can be improved.

1A and 1B illustrate a crystallization apparatus using a non-solvent for preparing a drug crystal according to an embodiment of the present invention.
FIG. 2 is a view for explaining a case of growing a crystal using the crystallization apparatus described with reference to FIG. 1 and a case of using a conventional method.
3 to 7 are optical microscopy images showing the crystal shape of each of the crystal samples and the comparative samples prepared by using the crystallization apparatus according to an embodiment of the present invention.
8 and 9 are graphs showing the results of evaluation of the flowability characteristics of Crystal Sample 1 and Comparative Sample 1 prepared using the crystallization apparatus according to the present invention.
10 is a view for explaining a crystallization apparatus using a non-solvent for the preparation of drug crystals according to an embodiment of the present invention.
FIG. 11 is a view for explaining a case of growing a crystal using the crystallization apparatus described with reference to FIG. 10 and a case of using a conventional method.
12 to 14 are optical microscopy images showing the crystal form of each of the crystal samples and the comparative samples prepared by using the crystallization apparatus according to an embodiment of the present invention.
Various embodiments are now described with reference to the drawings, wherein like reference numerals are used to refer to like elements throughout. In the following description, for purposes of explanation, various descriptions are set forth in order to provide an understanding of the present invention. It is evident, however, that such embodiments may be practiced without these specific details. In other instances, well-known structures and devices are shown in block diagram form in order to facilitate describing the embodiments.

Hereinafter, with reference to the accompanying drawings will be described in detail an embodiment of the present invention. As the inventive concept allows for various changes and numerous embodiments, particular embodiments will be illustrated in the drawings and described in detail in the text. However, this is not intended to limit the present invention to a specific disclosed form, it should be understood to include all modifications, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the drawings, similar reference numerals are used for similar elements.

The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting of the invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this application, the terms "comprises" or "having" are intended to indicate that there is a feature, step, operation, component, part, or combination thereof described on the specification, and one or more other features or steps. It is to be understood that the present invention does not exclude, in advance, the possibility of the presence or the addition of an operation, a component, a part, or a combination thereof.

1A and 1B illustrate a crystallization apparatus using a non-solvent for preparing a drug crystal according to an embodiment of the present invention.

As shown in Figure 1a, the crystallization apparatus using a non-solvent for the production of drug crystals according to an embodiment of the present invention, the reaction section 10; A supply unit 20 including a nozzle 30; It includes a discharge port 40 provided in the nozzle.

The reaction unit 10 is a portion containing either a non-solvent solution or a drug solution. In this case, the other one is supplied through the supply unit. For example, if the non-solvent solution is contained in the reaction part, the drug solution is dropped through the supply part. On the contrary, if the drug solution is contained in the reaction part, the non-solvent solution is dropped through the supply part.

In addition, the reaction part 10 is a part which drug crystal grows by nonsolvent crystallization, and obtains crystal grains.

The supply unit 20 is a portion for supplying a solution different from the other of the non-solvent solution or the drug solution, that is, the solution contained in the reaction unit 10. The supply part includes a nozzle 30 at the end of the supply part. As shown in FIG. 1A, the nozzle of the feed is preferably immersed in the solution of the reaction.

The solution supply part includes a flow path through which the solution flows and a nozzle 30 connected to one end of the flow path, and the discharge port 40 is connected to the other end of the nozzle connected to the flow path. The solution flowing through the flow path by the nozzle is ejected, discharged or dropped, but in the present invention, the solution is supplied to the reaction part through fine openings having a diameter smaller than the diameter of the nozzle through the discharge port provided in the nozzle.

Each of the fine openings of the discharge port may have a diameter of 0.1 μm or more and 1 mm or less. In this case, the discharge port may be provided in one end of the nozzle as a mesh having fine openings or a porous structure having fine openings. The mesh may be a mesh formed of a polymer such as polypropylene. The porous structure may be a metal or a ceramic.

In one embodiment, the flow rate of the solution discharged from the nozzle to the discharge port is preferably at least 0.01 mm / second or more. If the flow rate of the solution discharged to the discharge port is slower than 0.01 mm / second, there is a problem that the discharge port is blocked by the drug powder dissolved in the solvent when the drug solution is supplied. Therefore, it is good to discharge so that the drug solution must be uniformly supplied to the reaction part and control the flow rate to be 0.01 mm / sec or more.

The drug solution used is a solution obtained by dissolving drug powder in a solvent. The solvent for dissolving the drug powder may be an alcohol compound or a polar solvent such as dimethyl sulfoxide (DMSO). In this case, the solvent may be used without particular limitation in consideration of the solubility of the drug powder, and the non-solvent may be water.

The drug powder is a rod-shaped solid powder, which is dispersed in a solvent to form a drug solution. Aspect ratio in the present invention means the ratio between the length of the particles and the diameter (or width) of the particles along the direction perpendicular to the longitudinal direction, by having a discharge port in the nozzle, the discharge port having fine openings By using a conventional crystallization device that does not have the crystal grains having an aspect ratio of more than 10: 1, crystal grains having an aspect ratio reduced to a half level of less than 5: 1 can be produced. In this case, the aspect ratio of the drug powder used for the drug solution may be at least 10: 1. When the aspect ratio of the drug powder already has a small aspect ratio of 10: 1 or less, since the intrinsic crystal aspect ratio itself has a low value, crystal particles are formed to have a small aspect ratio even without using the crystallization apparatus described in FIG. 1. On the other hand, when the aspect ratio of the drug powder is greater than 10: 1, by using the crystallization apparatus according to the present invention described in Figure 1 has the advantage that can be significantly reduced to the aspect ratio to a level of 5: 1 or less.

In one embodiment, the drug solution may be obtained by dissolving a drug powder of Flurbiprofen, Adefovir Dipivoxil or ibuprofen.

On the other hand, according to an embodiment of the present invention, as shown in Figure 1b, the porous plate 40 may be further disposed in front of the discharge port. The porous plate is disposed in the front in the direction in which the solution of the discharge port is discharged, and in this case, it is preferable that the plane of the discharge plate is perpendicular to the discharge direction.

Pores are formed in the porous plate through the porous plate in a direction perpendicular to the plane of the porous plate, each of the pores preferably has a diameter of 0.1 ㎛ or more and 100 mm or less, the thickness of the porous plate is less than 100cm do.

The reason for the additional arrangement of the porous plate is to improve the discharging port by improving the distal end of the nozzle as shown in the embodiment of FIG. 1A, soaking in the solution, and then proceeding to crystallization. The nonsolvent and the solvent may be mixed at the nozzle end to start crystallization at the nozzle end or inside the nozzle, resulting in a problem of clogging the nozzle. To solve this problem, porous plates were used. In such a porous plate will be described in more detail in the following examples.

FIG. 2 is a view for explaining a case of growing a crystal using the nonsolvent crystallization apparatus described in FIG. 1A and a case of using a conventional method.

In FIG. 2, (a) is the case of using the nozzle of FIG. 1a, (b) is the case of using the conventional nozzle which is not equipped with the discharge opening which concerns on this invention, and (c) is actually uniform in the case of (a). SEM images of seed crystals formed and supplied are shown.

Referring to FIG. 2 in conjunction with FIG. 1A, a micro-sized drug solution drop is provided into the non-solvent in the present invention as in (a) to be uniformly mixed with the non-solvent. In this state, isotropic crystal growth is induced on the mesh surface, thereby obtaining crystal grains having a low aspect ratio.

On the other hand, in the case of using a general nozzle in Figure 2 (b), the drug solution droplets discharged from the general nozzle is mixed into a significantly non-uniform droplet compared to the droplet supplied from the discharge port of (a) and in this state anisotropic ( anisotropic crystal growth occurs, and only stick-shaped crystal grains having an aspect ratio of at least 10: 1 are obtained.

In fact, when the crystallization apparatus of FIG. 1A is used, it can be confirmed that seed crystals having a low aspect ratio are obtained near the discharge port as shown in FIG. 2C according to the principle of FIG. Isotropic crystal growth is induced for seed crystals having a low aspect ratio, and finally crystal grains having a low aspect ratio are obtained.

As described above, by using the crystallization apparatus described with reference to FIG. 1, it is possible to easily produce crystal particles having a reduced aspect ratio by using a drug powder having a large aspect ratio. The prepared crystal particles may have a uniform size. Using this crystallization apparatus, using a drug powder of Flurbiprofen, Adefovir Dipivoxil or ibuprofen having a rod-shaped crystal shape with a high aspect ratio, the aspect ratio was reduced than before. By easily preparing the crystal particles, the processability of the crystal particles of the drug can be improved. In particular, the crystal grains in which the aspect ratio is reduced may be improved in flowability and thus further improve workability.

Hereinafter, the structure and the characteristic of the resultant obtained using the crystallization apparatus which concerns on this invention through the manufacture example of the specific crystal grain of Example 1 are demonstrated.

Preparation of Crystal Sample 1

5 g of naproxen powder was dissolved in 100 mL of glass by stirring for 20 minutes in 100 mL of methanol to prepare a naproxen solution. At this time, the stirring speed for dissolving the naproxen solution was 100 rpm. Subsequently, 400 mL of distilled water to be used as a nonsolvent was prepared and added to the naproxen solution to proceed with nonsolvent crystallization. In this case, a crystallization apparatus having substantially the same configuration as that described in FIG. 1 was used, wherein a polypropylene mesh was provided as a discharge hole having fine openings, the diameter of the entire discharge hole was 25 mm, and the size of each of the fine openings was 700 μm. Was used. In addition, the flow velocity at this time was made to be 0.01 mm / sec.

In the non-solvent crystallization step, the temperature was maintained at 25 ° C. using a thermostat, for which crystallization was performed in a 1 L reactor. In addition, the injection rate of distilled water was 400 mL / hour for 1 hour, the stirring speed was 250 rpm.

Preparation of Crystal Samples 2 to 4

Substantially the same process as the preparation of Crystal Sample 1, except that 2.5 g of flubiprofen was used instead of naproxen powder, and a polyethylene (polytetrafluoroethylene) membrane having a size of 0.45 μm of micro-openings was used as the outlet of the porous structure. Through Crystal Sample 2 was prepared.

Also, except that 2.5 g of adefovir difficile was used and the injection rate of distilled water was set to 133.3 mL / hour, crystal sample 3 was prepared through substantially the same process as the preparation of crystal sample 1.

Also, except that 2 g of ibuprofen was used together with 100 mL of DMSO, Crystal Sample 4 was prepared through a process substantially the same as the preparation of Crystal Sample 1.

Preparation of Comparative Samples 1 to 6

Comparative samples 1, 2, and 3 were prepared by performing substantially the same process as preparing the crystal samples 1, 2, and 3, respectively, except for using a normal nozzle without a mesh or a membrane.

In addition, Comparative Sample 4 was prepared by substantially the same process as the preparation of Crystal Sample 1, except that 15 g of acetaminophen was used, and substantially the same process as Comparative Sample 4, except that a general nozzle without a mesh was used. Through Comparative Sample 5 was prepared.

Also, Comparative Sample 6 was prepared by performing substantially the same process as preparing Crystal Sample 4.

Structural Analysis: Optical Microscope

Images of the crystal samples and the comparative samples prepared above were obtained by optical microscopy, and aspect ratio analysis was performed. Optical microscope images are shown in FIGS. 3 to 7, respectively.

3 to 7 are optical microscopy images showing the crystal form of each of the crystal samples and the comparative samples prepared using a non-solvent crystallization apparatus according to an embodiment of the present invention.

In FIG. 3, (a-1) and (a-2) are for Crystal Sample 1, (b-1) and (b-2) are for Comparative Sample 1, and in the case of Crystal Sample 1, the plate shape. With the crystal form of, the aspect ratio analysis of the particle was found to be 3.71: 1 (± 0.66), while in the case of Comparative Sample 1 it can be seen that the aspect ratio is 16.38: 1 (± 0.51). That is, it can be seen that the aspect ratio of Crystal Sample 1 is significantly lower than that of Comparative Sample 1.

In FIG. 4, (a-1) and (a-2) are for crystalline sample 2, (b-1) and (b-2) are for comparative sample 2, and in the case of crystalline sample 2, the plate shape. The aspect ratio of the particles was determined to be 4.63: 1 (± 1.54), whereas in the case of Comparative Sample 2, the aspect ratio was 19.86: 1 (± 4.76). In other words, it can be confirmed that the aspect ratio of the crystal sample 2 is significantly lower than the comparative sample 2.

In FIG. 5, (a-1) and (a-2) are for crystalline sample 3, (b-1) and (b-2) are for comparative sample 3, and in the case of crystalline sample 3, a plate shape The aspect ratio of the particles was determined to be 6.71: 1 (± 1.87), whereas in Comparative Sample 3, the aspect ratio was 41.73: 1 (± 6.99). That is, it can be confirmed that the aspect ratio of the crystal sample 3 is significantly lower than the comparative sample 3.

In FIG. 6, (a-1) and (a-2) are for Comparative Sample 4, (b-1) and (b-2) are for Comparative Sample 5, and Comparative Sample 4 has an aspect ratio of 1.11: Although 1 (± 0.16), Comparative Sample 5 also shows that the aspect ratio is 1.13: 1 (± 0.35). That is, in the case of acetaminophen, when the drug powder having a low aspect ratio is used originally, even when using the crystallization apparatus of the present invention described in FIG.

In FIG. 7, (a-1) and (a-2) are for Crystal Sample 4, (b-1) and (b-2) are for Comparative Sample 6, and the aspect ratio of Crystal Sample 4 is 3.93: 1 (± 1.16), and in the case of Comparative Sample 6, the aspect ratio is 10.73: 1 (± 1.16). That is, it can be seen that the aspect ratio of the crystal sample 4 is significantly lower than that of the comparative sample 6.

Characterization: flow

Flowability characteristics were evaluated for each of Crystal Sample 1 and Comparative Sample 1. In order to evaluate the flowability, the dried sample was filtered through a cellulose filter having a pore size of 0.45 μm, and the obtained sample was dried in a vacuum oven for 3 days and then evaluated through Carr's compressibility Index. The results are shown in FIGS. 8 and 9.

8 and 9 are graphs illustrating the results of evaluation of the flow characteristics of Crystal Sample 1 and Comparative Sample 1 prepared using the nonsolvent crystallization apparatus according to the present invention.

8 and 9, when comparing the Carr's compressibility Index results, it can be seen that the flowability characteristics of the crystal sample 1 are better than the comparison sample 1.

The crystallization apparatus using a non-solvent for the preparation of drug crystals according to an embodiment of the present invention has been described so far, and the following describes a crystallization apparatus using a non-solvent for the preparation of drug crystals according to an additional embodiment of the present invention. I'll do it. The overlapping description of parts that overlap with the above-described parts will be omitted.

10 is a view for explaining a crystallization apparatus using a non-solvent for the preparation of drug crystals according to an embodiment of the present invention. FIG. 11 is a view for explaining a case of growing a crystal using the crystallization apparatus described with reference to FIG. 10 and a case of using a conventional method.

Crystallization apparatus using a non-solvent for the preparation of drug crystals according to an embodiment of the present invention, the reaction unit 10 containing any one of a non-solvent solution or a drug solution; A supply unit 20 including a nozzle 30 supplying the other of the non-solvent solution or the drug solution to the reaction unit; And a porous plate 50 disposed forward in the direction in which the solution of the supply part is supplied.

In this case, as shown in FIG. 10, the porous plate floats on the solution of the reaction part, and the supply part is disposed above the solution of the reaction part, thereby dropping the solution into the porous plate floating on the solution of the reaction part. That is, the solution supplied through the supply part is one in which the solution is dropped or discharged into the porous plate.

The porous plate is formed with pores penetrating the porous plate in a direction perpendicular to the plane, and each of the pores preferably has a diameter of 0.1 μm or more and 100 mm or less. On the other hand, a porous plate having a thickness of less than 100 cm is used.

Unlike the embodiment of FIG. 1, the porous plate has the advantage that the same effect can be obtained while using the existing nozzle as it is. To solve this problem, the problem of nozzle clogging was solved by placing porous material in the area where solvent and non-solvent meet the existing non-solvent crystallizer to act as nucleation plate, and the same effect without modifying the crystallizer used in the current industry at all. Could get Regardless of the design of the various crystallizers, only the porous plate needs to be placed where the solvent and nonsolvent meet. Significant decreases in aspect ratios and significant increases in particle size were identified using various drugs and nucleation plates. The nucleation plate can be used for the purpose of reducing the aspect ratio or increasing the particle size, and it is convenient for the operation that can be easily removed and used as it is as a general crystallization equipment when it is not necessary.

As the solution passes through the porous material of the porous plate, the non-solvent and solvent are brought into uniform contact with each other, and the surface of the porous material induces heterogeneous nucleation, allowing nucleation at low supersaturation. Under these conditions, the resulting nuclei grow relatively uniformly in all directions, resulting in low aspect ratios and relatively large particles. These low aspect ratio and large grain size crystal grains, which were initially formed earlier, act as seed crystals to easily induce secondary nucleation, and these crystals also follow the initial crystal shape.

Therefore, the nucleation plate needs a certain surface area, a space where the solvent and the fold can be mixed, that is, a pore (0.1 mm or more and 100 mm), and the non-solvent droplets should be able to sufficiently cover the surface where the solvent meets the solvent. Preference is given to a thickness (<100 cm) which does not disturb the flow in the entire crystallizer. Almost all materials can be used in various materials, but light materials are advantageous to exist on the surface of the solution. In addition to drug crystallization, the present crystallization method is applicable to a number of crystallization processes using nonsolvent crystallization methods such as fine chemicals, electronic materials, and food.

In the case of high aspect ratios or small crystal grains with poor flowability, many problems arise in processing, and the present invention offers the possibility of easily improving them. This provides a crystallization method capable of mass production while controlling the aspect ratio and particle size of the crystal grains without additional material changes or processing conditions. This simple approach not only reduces the energy, time and cost of using new equipment to control the aspect ratio of the particles in the industrial process, but also solves the problem of the overall downstream process in the industry due to poor flowability.

The drug solution used is a solution obtained by dissolving drug powder in a solvent. The solvent for dissolving the drug powder may be an alcohol compound or a polar solvent such as dimethyl sulfoxide (DMSO). In this case, the solvent may be used without particular limitation in consideration of the solubility of the drug powder, and the non-solvent may be water.

The drug powder is a rod-shaped solid powder, which is dispersed in a solvent to form a drug solution. The aspect ratio of the present invention is that by providing a porous plate in front of the nozzle, the crystal grain having an aspect ratio of more than 10: 1 is obtained using a conventional crystallization apparatus, but the aspect ratio reduced to half is less than 5: 1. Crystal particles can be produced.

In one embodiment, the drug solution may be obtained by dissolving a drug powder of Flurbiprofen, Adefovir Dipivoxil, ibuprofen or Naproxen.

FIG. 11 is a view for explaining a case of growing a crystal using the nonsolvent crystallization apparatus described with reference to FIG. 10 and a case of using a conventional method.

Referring to FIG. 11 together with FIG. 10, the right figure shows an embodiment of the present invention, in which case the solution dropped from the nozzle passes through the porous plate to be uniformly mixed with the solution of the reaction part. In this state, isotropic crystal growth is induced to obtain crystal particles having a low aspect ratio.

On the other hand, in the absence of a porous plate, as shown in the left figure of FIG. 10, the drug solution droplets ejected from the nozzle are significantly mixed into highly nonuniform droplets, in which anisotropic crystal growth occurs resulting in an aspect ratio of at least 10: 1. Only stick-shaped crystal particles with

In summary, isotropic crystal growth is induced for seed crystals having a low aspect ratio, and finally crystal grains having a low aspect ratio are obtained. In addition, by using the crystallization apparatus described with reference to FIG. 10, it is possible to easily produce crystal particles having a reduced aspect ratio by using a drug powder having a large aspect ratio. The prepared crystal particles may have a uniform size. Using this crystallization device, using Naproxen, Flurbiprofen or ibuprofen drug powder having a rod-shaped crystal shape with a high aspect ratio, crystal particles having a reduced aspect ratio than the original were used. By making it easy, the processability of the crystal grain of a drug can be improved. In particular, the crystal grains in which the aspect ratio is reduced may be improved in flowability and thus further improve workability.

Meanwhile, in the embodiment of FIG. 10, similar to the embodiment of FIG. 1A, a discharge port 40 may be provided at the nozzle part to supply a solution to the reaction part through a micro-opening having a diameter smaller than the diameter of the nozzle. Preferably, each of the fine openings of the discharge hole has a diameter of 0.1 μm or more and 1 mm or less, and the discharge hole may be provided at one end of the nozzle as a mesh having fine openings or a porous structure having fine openings. The effect of this discharge port has been described in detail in the embodiments of FIGS. 1 and 2.

Hereinafter, the structure and the characteristic of the resultant obtained using the crystallization apparatus which concerns on this invention through the manufacture example of the specific crystal grain of Example 2 are demonstrated.

Preparation of Crystal Sample 1

A naproxen solution was prepared by dissolving 5 g of naproxen powder in 100 mL of glass by stirring for 20 minutes in 100 mL of methanol (MeOH). At this time, the stirring speed for dissolving the naproxen solution was 100 rpm. Subsequently, 400 mL of distilled water to be used as a nonsolvent was prepared and added to the naproxen solution to proceed with nonsolvent crystallization. At this time, a crystallization apparatus having substantially the same configuration as that described in FIG. 10 was used, and thus, a porous plate was used. The pore size was 700 μm.

In the non-solvent crystallization step, the temperature was maintained at 25 ° C. using a thermostat, for which crystallization was performed in a 1 L reactor. In addition, the injection rate of distilled water was 400 mL / hour for 1 hour, the stirring speed was 250 rpm.

Preparation of Crystal Samples 2 to 3

Crystal sample 2 was prepared through substantially the same process as the preparation of crystal sample 1, except that 2.5 g of flubiprofen was used instead of naproxen powder.

Also, except that 2 g of ibuprofen was used together with 100 mL of DMSO, Crystal Sample 3 was prepared through a process substantially the same as the preparation of Crystal Sample 1.

Preparation of Comparative Samples 1 to 3

Comparative Samples 1, 2, and 3 were prepared by performing a crystallization process without a porous plate in performing substantially the same process as preparing Crystal Samples 1, 2, and 3, respectively.

Structural Analysis: Optical Microscope

Images of the crystal samples and the comparative samples prepared above were obtained by optical microscopy, and aspect ratio analysis was performed. Optical microscope images are shown in FIGS. 12-14, respectively.

12 to 14 are optical microscopy images showing the crystal shape of each of the crystal samples and the comparative samples prepared using a non-solvent crystallization apparatus according to an embodiment of the present invention.

In Figure 12 (a-1) and (a-2) is for the crystal sample 1, (b-1) and (b-2) is for the comparative sample 1, in the case of the crystal sample 1 of the plate-shaped form In the case of Comparative Sample 1, the aspect ratio was 17: 1 (± 6) and the particle size was 42μm (±). 14) can be confirmed. That is, compared with Comparative Sample 1, the aspect ratio was reduced and the particle size was increased. This corresponds to the result which is supposed to improve the flowability of the powder.

In FIG. 13, (a-1) and (a-2) are for Crystal Sample 2, (b-1) and (b-2) are for Comparative Sample 2, and in the case of Crystal Sample 2, a plate shape In the aspect ratio analysis of particles, the ratio was 4: 1 (± 1) and the particle size was 75μm (± 23), whereas in the case of Comparative Sample 2, the aspect ratio was 20: 1 (± 9) and the particle size was 34μm ( ± 16). That is, compared to Comparative Sample 2, in Crystal Sample 2, the aspect ratio was reduced and the particle size was increased.

In FIG. 14, (a-1) and (a-2) are for Crystal Sample 3, (b-1) and (b-2) are for Comparative Sample 3, and in the case of Crystal Sample 3, the plate shape The aspect ratio of the particles was 3.71: 1 (± 1.1), and the particle size was 35μm (± 8), whereas for Comparative Sample 3, the aspect ratio was 10: 1 (± 4) and the particle size was 17μm ( It can be confirmed that it is ± 4). That is, compared with Comparative Sample 3, the aspect ratio of Crystal Sample 3 was reduced and the particle size was increased.

Characterization: flow

Table 1 below is a result of measuring the aspect ratio and particle size of the drug crystal grains obtained through non-solvent crystallization of the crystal samples 1 to 3 and Comparative Samples 1 to 3 according to the present invention.

Sample name Crystal Sample 1 Comparative Sample 1 Crystal Sample 2 Comparative Sample 2 Crystal Sample 3 Comparative Sample 3 Aspect ratio 3: 1
(± 0.6) 17: 1
(± 6) 4: 1
(± 1) 20: 1
(± 9) 3.7: 1
(± 1.1) 10: 1
(± 4) Particle size 56 μm
(± 10) 42 μm
(± 14) 75 μm
(± 23) 34 μm
(± 16) 35 μm
(± 8) 17 μm
(± 4) Carr? compressibility Index 43%
(± 1) 60%
(± 3)

By using porous nucleation plates, reduction of the aspect ratio of various drugs was confirmed. In addition, in terms of particle size, crystal samples 1 to 3 showed a tendency to increase by 1.35 times, 2.21 times, and 2.06 times particle sizes than Comparative Samples 1 to 3. These results also made the flow very good, and the Carr's compressibility Index decreased significantly.

The description of the presented embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the scope of the invention. Thus, the present invention should not be limited to the embodiments set forth herein but should be construed in the broadest scope consistent with the principles and novel features set forth herein.

Claims (19)

A reaction unit including any of a non-solvent solution or a drug solution; And
A supply unit including a nozzle for supplying the other of the non-solvent solution or the drug solution to the reaction unit,
The nozzle is provided with a discharge port for supplying a solution to the reaction portion through a fine opening having a diameter smaller than the diameter of the nozzle,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 1,
The nozzle of the supply portion is characterized in that the submerged in the solution of the reaction,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 1,
Drug crystals grown in the reaction unit,
Characterized in that the crystal particles having a reduced aspect ratio than the drug powder used in the drug solution,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 1,
Each of the fine openings of the discharge port is characterized in that the diameter of 0.1 ㎛ or more, 100 mm or less,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 4, wherein
Wherein the discharge port is characterized in that the mesh (mesh) formed with fine openings or a porous structure having fine openings is provided at one end of the nozzle,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 1,
The flow rate of the solution discharged from the nozzle to the discharge port is characterized in that at least 0.01 mm / second,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 2,
Characterized in that the porous plate is further disposed in the front in the direction in which the solution of the discharge port is discharged,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 7, wherein
The porous plate is formed with pores penetrating the porous plate in a direction perpendicular to the plane of the porous plate,
Each of the pores is characterized in that the diameter of more than 0.1 ㎛ 100 mm,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 7, wherein
The thickness of the porous plate is characterized in that less than 100cm,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
Supplying either a non-solvent solution or a drug solution to the reaction section of the crystallization apparatus using a non-solvent for producing a drug crystal, wherein the drug crystal grows to obtain crystal particles;
The discharge port for supplying the remaining solution of the non-solvent solution or the drug solution from the drug solution supply unit having a nozzle of the crystallization device to the reaction unit, through the micro-opening having a diameter smaller than the diameter of the nozzle Supplying a solution to the reaction unit through the minute openings provided in the nozzle; And
Growing crystals from the solution supplied through the micro-openings in the reaction section to form crystal particles having a reduced aspect ratio than the drug powder used in the drug solution,
Crystallization method using a non-solvent crystallization device for the preparation of drug crystals.
A reaction unit including any of a non-solvent solution or a drug solution;
A supply unit including a nozzle for supplying the other of the non-solvent solution or the drug solution to the reaction unit; And
It includes a porous plate disposed in the front in the direction in which the solution of the supply is supplied,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 11,
The porous plate is floating on the solution of the reaction portion,
The supply portion is disposed on the solution of the reaction portion, thereby dropping the solution into the porous plate floating on the solution of the reaction portion,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 11,
The porous plate is formed with pores penetrating the plane of the porous plate,
Each of the pores is characterized in that the diameter of more than 0.1 ㎛ 100 mm,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 11,
Characterized in that the thickness of the porous plate is less than 100 cm,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 11,
The nozzle is provided with a discharge port for supplying a solution to the reaction portion through a fine opening having a diameter smaller than the diameter of the nozzle,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 15,
Each of the fine openings of the discharge port is characterized in that the diameter of 0.1 ㎛ or more, 100 mm or less,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 15,
Wherein the discharge port is characterized in that the mesh (mesh) formed with fine openings or a porous structure having fine openings is provided at one end of the nozzle,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
The method of claim 11,
Drug crystals grown in the reaction unit,
Characterized in that the crystal particles having a reduced aspect ratio than the drug powder used in the drug solution,
Crystallization apparatus using a non-solvent for the preparation of drug crystals.
Supplying either a non-solvent solution or a drug solution to the reaction section of the crystallization apparatus using a non-solvent for producing a drug crystal, wherein the drug crystal grows to obtain crystal particles;
The drug solution supply unit having the nozzle of the crystallization apparatus supplies the other one of the non-solvent solution or the drug solution to the reaction unit, and is disposed in front in the direction in which the solution of the supply unit is supplied, the porous having pores penetrating the plane Feeding the reaction part through the plate; And
Crystal growth from the solution supplied through the pores of the porous plate in the reaction section to form crystal particles having a reduced aspect ratio than the drug powder used in the drug solution,
Crystallization method using a non-solvent crystallization device for the preparation of drug crystals.

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