KR101589910B1 - Process for Preparation and Conversion of Taltirelin Crystalline Form - Google Patents

Abstract

The present invention relates to a novel process for the preparation of crystalline α of decytrin (N - [(s) -hexahydro-1-methyl-2,6-dioxo-4-primidinyl] -L-histidyl-L-prolinamido tetrahydrate) As well as to a method of converting the same. More particularly, the present invention relates to a process for preparing crystalline? -Tetralenes by dissolving amorphous or crystalline? -Tetralenes and then performing drowning-out crystallization using evaporation crystallization, cooling crystallization and specific anti-solvent And a method of converting a crystal form.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a process for preparing a crystalline α-

The present invention relates to a novel process for the preparation of crystalline?

Taltirelin is an internationally accepted generic name for N - [(s) -hexahydro-1-methyl-2,6-dioxo-4-primidinyl] -L-histidyl-L-prolinamidotetrahydr-ate. The above-mentioned deathrelin is well known as a preventive or therapeutic agent for neurodegenerative diseases including spinal cord cerebellar degeneration.

Drugs can have different physical or chemical properties depending on the crystal form. These physicochemical properties can have a great influence on the proper dosage form of the drug, optimization of the manufacturing process, and absorption in the body. In addition, the discovery of the most suitable crystalline form of a solid drug substance in the course of drug development can reduce development time and cost.

All compounds having a crystal have a compound-specific crystal form, and the crystal form can be a single crystal form or two or more polymorphic forms. Among the crystalline polymorphic compounds, in particular, in the case of crystalline polymorphic compounds having medicinal uses, physical properties such as solubility and melting point are changed as the moisture content and the like are changed, so that even a compound having the same chemical formula changes the stability and physiological activity of the substance do. Therefore, it is required that the crystalline polymorphic compound used for pharmaceutical use is present in a crystal form having higher stability and physiological activity.

It is also known that two or more types of crystals exist. As the crystalline form of the desilterine, crystalline form α and crystalline form β are known.

The prior art for the above-mentioned desilteries is disclosed in U.S. Patent Publication No. 4665056 and European Patent EP0168042, which discloses a method for synthesizing dehyrylline. The preparation method of the crystalline form α and the crystalline form β is described in Shoji. M., Horishi. O, Crystallization behavior of taltirelin polymorphs in a mixture of water and methanol, J. Crystal Growth, Vol. 212, Issues 1-2, 2000, 239-245. According to the contents of the above-mentioned documents, the production method and conversion of the crystalline form β from the crystalline form α of the ultraviolet absorber are specified in detail. Crystalline? Can be obtained by recrystallization from an aqueous solution containing 30 wt% methyl alcohol, and crystal-type conversion occurs depending on the content of methyl alcohol. As the concentration of methyl alcohol increases, the crystal growth rate of crystalline α decreases, while the crystal growth rate of crystalline β increases.

In another article [Shoji. M., Horishi. O, crystal structures and solvent-mediated transformation of Taltireline polymorphs] have been proposed to inhibit the conversion of crystalline β to crystalline α. The solubility of crystalline α is higher than that of crystalline β and has good properties as a drug, while it has a property of converting to crystalline β under the influence of solvent because it is a metastable state.

The above method is disclosed in the production method of the crystalline form β from the crystalline form α by cooling in a water-methanol solvent, and a method of producing the crystalline form α, which is a quasi-stable crystalline form, has not been proposed. For this reason, a new production method of crystalline α of the desilterine is required.

Therefore, the inventors of the present invention have found that a crystalline form α of a pharmacologically superior tetrathiene exhibiting a high physiological activity in spinal cord cerebellar degeneration, which is one of neurodegenerative diseases, can be prepared by a specific preparation method using a amorphous or crystalline β- alpha -tetralin can be produced. Thus, the present invention has been completed.

U.S. Patent Publication No. 4665056 European Patent EP0168042

Shoji. M., Horishi. O, Crystallization behavior of taltirelin polymorphs in a mixture of water and methanol, J. Crystal Growth, Vol. 212, Issues 1-2, 2000, 239-245 Shoji. M., Horishi. O, Crystal structures and solvent-mediated transformation of Taltireline polymorphs, chemical Engineering Journal, Vol. 75, Issues 3, 1999, 193-200

It is an object of the present invention to provide a novel process for the preparation of a pharmaceutically elegant crystalline? -Tetralenine and a process for the conversion of a crystalline form.

There is provided a process for producing crystalline? -Tetralenine, which is prepared by amorphous or crystalline? -Tetralenes from evaporation crystallization, cooling crystallization or a draw-in-crystallization process in which a non-solvent is added.

The evaporation crystallization method according to an embodiment of the present invention includes completely dissolving amorphous or crystalline beta -titryline to prepare amorphous or crystalline beta -titrylin solution; And evaporating an amorphous or crystalline? -Tetralin solution to prepare a tetralin crystalline form?; . ≪ / RTI >

The cooling crystallization method according to an embodiment of the present invention includes completely dissolving amorphous or crystalline beta -titryline to prepare an amorphous or crystalline beta -tetralin solution; And cooling the amorphous or crystalline? -Tetrahyerine solution to prepare crystalline? -Tetralenine; . ≪ / RTI >

The drying-out crystallization method according to an embodiment of the present invention includes the steps of completely dissolving amorphous or crystalline beta -titryline to prepare an amorphous or crystalline beta -tetralin solution; And adding a non-solvent to the amorphous or crystalline? -Tetralin solution to prepare crystalline? -Tetralenine; . ≪ / RTI >

Crystalline? -Tetralenes prepared by the method according to one embodiment of the present invention were analyzed by X-ray powder diffraction analysis to show that the X-ray powder diffraction patterns of the crystalline? 21.209, 21.511, 22.003, 22.296, 23.032, 23.94, 24.444, 25.636, 26.52, 27.172, 27.59, 28.373, 29.187, 29.67, 30.05, 30.446, 31.35, 31.98, 33.728.

The amorphous or crystalline β-tetrathyrine solution according to an embodiment of the present invention may be evaporated to 45 to 100 ° C.

The amorphous or crystalline β-tetrathrin solution according to an embodiment of the present invention can be evaporated at a rate of 0.01 to 2 cm ^{3 /} min. M ² by stirring at a speed of 200 to 1000 rpm.

The amorphous or crystalline β-tetrathrin solution according to an embodiment of the present invention may be quenched at a rate of 1 to 20 ° C./min.

0.2 to 2 parts by weight of non-solvent may be added to the amorphous or crystalline β-thyramine solution according to an embodiment of the present invention.

The non-solvent according to an embodiment of the present invention may be acetone, methanol, ethanol, isopropyl alcohol, acetonitrile or a mixture thereof.

The amorphous or crystalline β-decathyrin solution to which the non-solvent is added according to an embodiment of the present invention may be cooled to 1-50 ° C. and stirred at a rate of 200-1000 rpm.

The present invention provides a preparation method and a crystal form conversion method capable of easily and selectively obtaining metastable crystalline tetralin form α by using amorphous or crystalline β-titrile lanes. The selective acquisition of the crystalline form of alpha-tetralin having excellent solubility and pharmacological activity is expected to greatly help prevent or treat neurodegenerative diseases including spinal cord cerebellar degeneration.

1 is a schematic view of a process for producing crystalline? -Tetrillin according to the present invention
2 is an XRPD diffraction pattern of crystalline? -Tatrylin according to the present invention,
FIG. 3 is a DSC chart of the crystalline? -Tetralenine according to the present invention,
4 is a TGA recording chart of the crystalline? -Tetralenine according to the present invention,
5 is an IR spectrum of crystalline? -Tetralenine according to the present invention,
FIG. 6 is a SEM image of crystalline? -Tetralenin according to the present invention,
Fig. 7 is a Raman spectrum of crystalline α and crystalline β-triterpine according to the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS The invention will be described in detail with reference to the accompanying drawings. The following drawings are provided by way of example so that those skilled in the art can fully understand the spirit of the present invention. Therefore, the present invention is not limited to the following drawings, but may be embodied in other forms, and the following drawings may be exaggerated in order to clarify the spirit of the present invention.

The method for preparing crystalline α-desilyline according to the present invention and the method for converting a crystalline form will be described in detail below. Unless otherwise defined in technical terms and scientific terms used herein, The description of the known functions and configurations that may unnecessarily obscure the gist of the present invention will be omitted in the following description and the accompanying drawings.

The terms used in this specification are defined as follows.

&Quot; metastability " means a somewhat stable intermediate state with a higher energy than the ground state.

&Quot; Amorphous " means that the X-ray powder diffraction analysis does not show a specific peak of a particular diffraction angle.

 The present invention relates to a novel process for producing crystalline α-triterpine represented by the above-mentioned formula (1).

(Formula 1)

The present invention relates to a process for producing crystalline? -Tetralenine and a process for converting crystalline form using amorphous or crystalline? -Tetralenine, which comprises performing evaporation crystallization, cooling crystallization, or a draw- Crystalline? -Tatrylin can be obtained by converting the crystal form from amorphous or crystalline? -Tetralen.

The evaporation crystallization method includes completely dissolving amorphous or crystalline beta -tetralin to prepare an amorphous or crystalline beta -titrilin solution; And evaporating the amorphous or crystalline? -Tetrahyerine solution to produce crystalline? Of the desilterine; ≪ RTI ID = 0.0 > a < / RTI >

At this time, depending on a factor selected from at least one of the solute selected from the amorphous or crystalline β-thioterelin, the solvent for dissolving it, the solvent for dissolving it, the ratio of the solvent, the evaporation rate, the evaporation temperature, the cooling rate, The production method of lean may be varied, but is not limited thereto.

One or more selected from the amorphous or crystalline beta -tetraleners used for preparing the crystalline alpha -titrylin may be selected. The amorphous tetrathrin has an unstable property, and the crystalline beta tetrathlylene has a stable property and can be preferably a crystalline beta tetrathiene.

The solvent used to dissolve the amorphous or crystalline beta -tetralysin may be water, methanol or ethanol, but preferably it may be water or ethanol.

At this time, the amorphous or crystalline β-thyrotheline is completely dissolved in 20 to 100 parts by weight of water based on 100 parts by weight of amorphous or crystalline β-tetrathiene to prepare an amorphous or crystalline β-decyltriazine solution. When water used as a solvent for dissolving amorphous or crystalline beta -titrylin is less than 20 parts by weight based on 100 parts by weight of the amorphous or crystalline beta -tetralin, crystals may not be formed, and when more than 100 parts by weight, Is not dissolved.

The amorphous or crystalline beta -titrylin solution can be evaporated to crystallize by evaporating to 45-100 < 0 > C. If the evaporation temperature is less than 45 ° C, the temperature is too low to evaporate the water used as the solvent. Since the solvent used is water, it can not exceed 100 ° C at 1 atm.

The amorphous or crystalline β-desilyline solution is stirred at 45 to 100 ° C. at a rate of 200 to 1000 rpm to evaporate at a rate of 0.01 to 2 cm ^{3 / (} min. M ² ), thereby controlling the degree of supersaturation.

The stirring speed is an important factor for determining the nucleation and growth rate of crystals and the mixing of crystals. When the stirring speed is low, the mixing of the solid is not smooth. When the stirring speed is high, the mass transfer rate causing nucleation and crystallization of the crystal is large Crystalline < RTI ID = 0.0 > a < / RTI >

Also, the evaporation crystallization method may include completely dissolving amorphous or crystalline β-thiotrienin to prepare an amorphous or crystalline β-decathyrin solution; And cooling the amorphous or crystalline? -Tetrahyerine solution to prepare crystalline? -Tetralenine; Or a salt thereof.

The amorphous or crystalline beta desaturase solution may be cooled crystallization to quench the solution at 20 to 0 DEG C at 0.1 to 20 DEG C / min to control the degree of supersaturation. At this time, when the cooling rate is less than 0.1 캜 / minute, the crystallization rate is slow and the degree of supersaturation is low, so that the α-detalin can not be obtained. When the cooling rate is more than 20 ° C./minute, the supersaturation is undesirably large. When the cooling temperature is lower than 0 ° C, the solvent is crystallized. When the cooling temperature is higher than 20 ° C, cooling crystallization is not preferable.

Also, the evaporation crystallization method may include completely dissolving amorphous or crystalline β-thiotrienin to prepare an amorphous or crystalline β-decathyrin solution; And adding a non-solvent to the amorphous or crystalline beta -titrilin solution to prepare the tetralin crystalline form alpha; Or a salt thereof.

Out-crystallization in which 20 to 200 parts by weight of non-solvent is added to the amorphous or crystalline beta -titryline solution based on 100 parts by weight of the amorphous or crystalline beta -titrylin solution. At this time, when the amount of the non-solvent is less than 20 parts by weight based on 100 parts by weight of the amorphous or crystalline type β-thyreline solution, crystals are not generated. When the amount is more than 200 parts by weight, excessive solvent loss is not preferable.

The amorphous or crystalline β-decathyrin solution to which the non-solvent is added may be a drying-out crystallization in which the degree of supersaturation is controlled by cooling to 1-50 ° C. and stirring at a speed of 200-1,000 rpm. If the cooling temperature is lower than 0 ° C, the solvent may be precipitated. If the cooling temperature is higher than 50 ° C, it is not preferable because of difficulty in controlling the controlled drain-out crystallization.

The non-solvent used for the drying-out crystallization may be an organic solvent mixed with water such as acetone, methanol, ethanol, isopropyl alcohol, acetonitrile and the like, preferably acetone, isopropyl alcohol or acetonitrile.

The present invention relates to a process for producing crystalline? -Tetralenine and a process for converting crystalline form using amorphous or crystalline? -Tetralenine, which comprises performing evaporation crystallization, cooling crystallization, or a draw- Crystalline? -Tetrillin can be obtained by conversion from amorphous or crystalline beta -titrylin.

The crystalline β-desaturyline raw material used in the present invention contains characteristic peaks at 8.18, 16.28, which are the main characteristic peaks in the X-ray powder diffraction analysis of cu target emission.

The crystalline? -Tetralenes of Formula 1 according to the present invention were characterized by X-ray powder diffraction analysis of cu target spins with characteristic peaks indicated by 2? 7.099, 7.507, 10.875, 12.055, 12.696, 14.239, 15.06, 15.306, 15.900, 16.626 , And includes characteristic peaks as shown in Table 1, 18.463, 20.712, 21.109, 21.511, 22.003, 22.296, 23.032, 23.94, 24.444, 25.636, 26.52, 27.172, 27.59, 28.373, 29.187, 29.67, 30.05, 30.446, 31.35, 31.98, 33.728 2).

When the sharp XRD peak is detected at any 2θ value, it means that the peak is at the 2θ value ± 0.1, and when a broad XRD peak is detected at any 2θ value, it means that the peak is in the 2q value ± 0.3 it means.

The crystalline? -Tetralenes obtained by the process of the present invention have two endothermic peaks at 84.04 ° C and 122.15 ° C in differential scanning calorimetry (DSC) (See Fig. 3).

The production method of the crystalline? -Tetralenine of the present invention will be described in more detail as follows.

(Example 1) Method for producing crystalline? -Tetrillin using evaporation crystallization

Example 1-1

0.20 g of crystalline beta -tetrillin was added to 0.2 g of water and stirred at 10 DEG C to completely dissolve the crystalline beta -tetrillin. It is heated to 75 DEG C and stirred at 300 rpm. At this time, the solvent is evaporated at a rate of 0.01 to 0.57 cm < ³ > / min.m < ² > to form supersaturation to produce crystalline nuclei. After the crystalline nuclei were formed, the crystals were separated by keeping at 1 ° C for 2 hours for crystal growth and then filtration. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having a characteristic diffraction angle as shown in FIG.

Examples 1-2

0.50 g of amorphous decathyrin is added to 0.5 g of water and stirred at 10 캜 to completely dissolve the amorphous acetal. It is heated to 80 DEG C and stirred at 300 rpm. At this time, the solvent is evaporated at a rate of 0.02 to 0.3512 cm < ³ > / min.m < ² > to form supersaturation to produce crystalline nuclei. After the crystalline nuclei were formed, the crystals were separated by keeping at 1 ° C for 2 hours for crystal growth and then filtration. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having characteristic diffraction angles as shown in FIG.

Example 1-3

0.20 g of crystalline beta -tetrillin was added to 0.2 g of water and stirred at 10 DEG C to completely dissolve the crystalline beta -tetrillin. It is heated to 70 DEG C and stirred at 300 rpm. At this time, the solvent is evaporated at a rate of 0.01 to 0.229 cm < ³ > / min.m < ² > to form supersaturation to produce crystalline nuclei. After the crystalline nuclei were formed, the crystals were separated by keeping at 1 ° C for 2 hours for crystal growth and then filtration. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having characteristic diffraction angles as shown in FIG.

Examples 1-4

0.45 g of crystalline beta -tetrillin was added to 0.2 g of water and stirred at 10 DEG C to completely dissolve crystalline beta -tetrillin. It is heated to 65 DEG C and stirred at 300 rpm. At this time, the solvent is evaporated at a rate of 0.02 to 0.57 cm < ³ > / min.m < ² > to form supersaturation to produce crystalline nuclei. After the crystalline nuclei were formed, the crystals were separated by keeping at 1 ° C for 2 hours for crystal growth and then filtration. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having characteristic diffraction angles as shown in FIG.

Examples 1-5

0.40 g of crystalline beta -tetralenin is added to 0.2 g of water and stirred at 10 DEG C to completely dissolve the crystalline beta -tetralizer. It is heated to 85 DEG C and stirred at 300 rpm. At this time, the solvent is evaporated at a rate of 0.02 to 0.40 cm < ³ > / min.m < ² > to form supersaturation to produce crystalline nuclei. After the crystalline nuclei were formed, the crystals were separated by keeping at 1 ° C for 2 hours for crystal growth and then filtration. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having characteristic diffraction angles as shown in FIG.

Examples 1-6

0.80 g of crystalline beta -tetralenin was added to 0.2 g of water and stirred at 10 DEG C to completely dissolve crystalline beta -tetrillin. It is heated to 75 DEG C and stirred at 300 rpm. At this time, the solvent is evaporated at a rate of 0.02 to 0.3371 cm < ³ > / min.m < ² > to form supersaturation to produce crystalline nuclei. After the crystalline nuclei were formed, the crystals were separated by keeping at 1 ° C for 2 hours for crystal growth and then filtration. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having characteristic diffraction angles as shown in FIG.

(Example 2) Method of producing crystalline? -Tetrillin using cooling crystallization

Example 2-1

0.45 g of crystalline beta -titrylin was added to 0.2 g of water and stirred at 60 DEG C to completely dissolve crystalline beta -tetrillin. The fully dissolved solution is quenched at a rate of 15 [deg.] C / min to 1 [deg.] C to produce crystalline nuclei. Stirring did not occur during quenching. After the crystalline nuclei were formed, the crystals were separated by keeping at 1 ° C for 2 hours for crystal growth and then filtration. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having characteristic diffraction angles as shown in FIG.

Example 2-2

0.6 g of crystalline beta -titrylin beta beta was added to 0.2 g of water and stirred at 60 DEG C to completely dissolve crystalline beta -tetralenin. The fully dissolved solution is quenched at a rate of 15 [deg.] C / min to 1 [deg.] C to produce crystalline nuclei. Stirring did not occur during quenching. After the crystalline nuclei were formed, the crystals were separated by keeping at 1 ° C for 2 hours for crystal growth and then filtration. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having characteristic diffraction angles as shown in FIG.

(Example 3) Method for producing crystalline? -Tetralenine using drying-out crystallization

Example 3-1

0.6 g of crystalline beta -titrylin was added to 0.5 g of water and stirred at 50 DEG C to completely dissolve crystalline beta -tetrillin. 2.2 g of acetone is added to the solution of the crystalline form β of the desilyline and then quenched to 1 ° C. at a rate of 15 ° C./min to produce crystalline nuclei. Stirring did not occur during quenching. After the crystalline nuclei were formed, the crystals were separated by filtration after maintaining at 1 ° C for 8 hours for crystal growth. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having characteristic diffraction angles as shown in FIG.

Example 3-2

0.5 g of crystalline beta -tetrillin was added to 0.2 g of water and stirred at 50 DEG C to completely dissolve crystalline beta -tetrillin. 2.2 g of acetone is added to the solution of the crystalline form β of the desilyline and then quenched to 1 ° C. at a rate of 15 ° C./min to produce crystalline nuclei. Stirring did not occur during quenching. After the formation of crystalline nuclei, crystal growth was maintained at 1 ° C for 7 hours and then filtered to separate crystals. The filtered product was dried at 40 < 0 > C for 24 hours without further washing. The final product was measured by X-ray powder diffraction spectroscopy (XRD), and as a result, it was confirmed that it was a crystalline? -Tetrillin having characteristic diffraction angles as shown in FIG.

(analysis)

1) X-ray diffraction spectroscopy (XRD, X-Ray Diffraction) measurement

Crystalline? -Tetralenes prepared by the examples were measured by XRD, and the peaks shown in FIG. 2 were obtained. Specific values are shown in Table 1 below. The XRD analyzer and operating conditions are as follows.

Model: SmartLab (Riguku)

X-ray generator: 9 kW

Power consumption: 45kV

Operating voltage: 200mA

Target: Cu

Sampling Width: 0.0200 deg

No. 2q d I / I ₀ (deg) (ang.) (%) One 7.099 12.442 34.59 2 7.509 11.766 24.54 3 10.875 8.129 3.1 4 12.055 7.336 37.35 5 12.696 6.967 23.29 6 14.239 6.215 74.14 7 15.06 5.879 17.82 8 15.306 5.784 75.1 9 15.900 5.569 3.66 10 16.626 5.328 23.15 11 18.463 4.802 13.46 12 20.712 4.2850 17.32 13 21.109 4.205 26.05 14 21.511 4.128 30.8 15 22.003 4.037 75.6 16 22.296 3.984 23.84 17 23.032 3.8583 87.02 18 23.94 3.714 37.01 19 24.444 3.6386 100 20 25.636 3.4720 10.18 21 26.52 3.358 1.77 22 27.172 3.279 47.54 23 27.59 3.230 14.07 24 28.373 3.1430 32.01 25 29.187 3.0572 42.81 26 29.67 3.009 16.84 27 30.05 2.971 5.88 28 30.446 2.9336 20.48 29 31.35 2.851 3.57 30 31.98 2.797 17.64 31 33.728 2.6553 3.42

The exact positions of the peaks shown in Table 1 (i.e., the 2 angle values mentioned above) should not be regarded as absolute values. This is because the exact position of the peaks may vary from machine to machine, from sample to sample, or from slight variations in accordance with the measurement conditions used, as will be understood by those skilled in the art.

In this regard, it is known in the art that an X-ray powder diffraction pattern having one or more measurement errors can be obtained depending on the measurement conditions (e.g., the apparatus used, the sample preparation, or the machine). Particularly, the intensity in the X-ray powder diffraction pattern is generally known to vary depending on the measurement conditions and the sample preparation method. Therefore, those skilled in the art will recognize that the diffraction pattern data presented herein should not be regarded as absolute. See Jenkins, R & Snyder, R.L. &Quot; Introduction to X-Ray Powder Diffractometry " John Wiley & Sons, 1996).

Therefore, the crystalline? -Tetralenes of the present invention are not limited to crystals that provide the same X-ray powder diffraction pattern as the X-ray powder diffraction pattern shown in FIG. 2, but are substantially the same as those shown in FIG. 2, Is to be understood as falling within the scope of the present invention. Those skilled in the art of X-ray powder diffraction can determine the substantial identity of the X-ray powder diffraction pattern.

2) Measurement of differential scanning calorimetry (DSC)

As a result of DSC (DSC1, Mettler tolledo) under the conditions of a rate of 10 ° C per minute and a feed rate of nitrogen of 40 ml per minute, the crystalline α-triterpine produced by the above-mentioned production method exhibited, at 84.04 ° C. and 122.15 ° C., And one exothermic peak appears at 220.80 占 폚 after exhibiting an endothermic peak. It is understood that the initiation and / or peak temperature values of the DSC may vary slightly from machine to machine, from method to sample or from sample to sample, and therefore the recited values are not considered to be absolute.

3) Thermogravimetric analysis (TGA)

In order to examine the water content in the crystalline α-triterpine produced by the above-mentioned production method, a peak as shown in FIG. 3 was obtained by using TGA (model name: SDT2960, TA Instrument).

4) Infrared absorption spectrum (FT-IR) measurement

In order to investigate the infrared absorption spectrum of the crystalline? -Tetrahyerine produced by the above production method, a spectrum as shown in FIG. 4 was obtained by using an IR analyzer (model name: Nicolet 6700).

5) Scanning electron microscope (SEM) measurement

Crystalline? -Tartilin form and its surface are shown in FIG. 6 using a scanning electron microscope (Model: JSM-6300, JEOL LTD) according to a suitable solvent and temperature.

6) Raman spectral measurement

The spectra shown in FIG. 8 were obtained using Raman spectrum (Model: Kaiser Optical Systems, Ann Arbor MI, USA) to measure the molecular vibration and morphology of crystalline α-triterpine.

Claims (11)

X-ray powder diffraction analysis was carried out through a dry-out crystallization method in which evaporative crystallization, cooling crystallization or non-solvent was added from crystalline β-desilylenes having a 2θ diffraction angle of 8.18, 16.28 in an amorphous or X-ray powder diffraction analysis 23.032, 23.94, 24.444, 25.636, 26.52, 27.172, 27.59, 28.373, 29.187, 29.67, 29.67, 29.67, 29.97, 21.99, , 30.05, 30.446, 31.35, 31.98, 33.728.
The cooling crystallization method comprises completely dissolving the amorphous or crystalline beta -tetralenin in water to prepare an amorphous or crystalline beta -tetralin solution; And
And quenching the amorphous or crystalline β-tetrathyrin solution at a cooling rate of 0.1 to 20 ° C./min to produce the crystalline α-triterin,
The content of the solvent used in the evaporation crystallization, the cooling crystallization, or the drying-out crystallization method is 20 to 100 parts by weight based on 100 parts by weight of the amorphous or crystalline β-
Wherein the crystallization nuclei are generated through the evaporation crystallization, the cooling crystallization, or the drying-out crystallization method, and then the solvent is maintained in the solvent for 2 to 8 hours.
The method according to claim 1,
The evaporation crystallization method includes completely dissolving amorphous or crystalline beta -tetralin to prepare an amorphous or crystalline beta -titrilin solution; And
Evaporating the amorphous or crystalline? -Tetralin solution to produce crystalline? -Tetralin; ≪ / RTI > wherein the crystalline form of the < RTI ID = 0.0 > a < / RTI >
delete The method according to claim 1,
The drying-out crystallization method is characterized in that the evaporation crystallization method comprises completely dissolving amorphous or crystalline β-thyramine to prepare amorphous or crystalline β-decathyrin solution; And
Adding a non-solvent to the amorphous or crystalline beta -tetralin solution to prepare crystalline alpha -titrilin; ≪ / RTI > wherein the crystalline form of the < RTI ID = 0.0 > a < / RTI >
delete 3. The method of claim 2,
And crystallizing the amorphous or crystallized? -Tetrillin solution to evaporate the solution to 45 to 100 ° C.
The method according to claim 6,
Wherein the amorphous or crystalline β-thiotrienol solution is stirred at a rate of 200 to 1000 rpm and evaporated at a rate of 0.01 to 2 cm ^{3 / (} min. M ² ). .
delete 5. The method of claim 4,
And 0.2 to 2 parts by weight of non-solvent is added to the amorphous or crystalline beta -titrylin solution.
10. The method of claim 9,
Wherein the non-solvent is acetone, methanol, ethanol, isopropyl alcohol, acetonitrile or a mixture thereof. 10. The method of claim 9,
Wherein the amorphous or crystalline β-thyramine solution to which the non-solvent is added is cooled to 1-50 ° C. and stirred at a rate of 200-1,000 rpm.

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