KR20160048561A - Preparing method of silodosin crystal form γ - Google Patents

Abstract

Provided is a preparation method of silodosin γ crystal form. The preparation method of silodosin γ crystal form comprises the following steps: dissolving silodisin in at least one solvent selected from the group consisting of methyl isobutyl ketone, 1-propanaol, 1-butanol, isobutanol, and a mixed solvent of the same; seeding silodosin γ crystal form. The preparation method of the present invention does not use toluene as a crystallization solvent, thereby resolving a problem in manufacturing with respect to the use of toluene.

Description

[0001] The present invention relates to a method for preparing a γ-

The present invention relates to a novel process for preparing γ-crystal form.

(R) -1- (3-hydroxypropyl) -5- [2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] Ethylamino] propyl] indolin-7-carboxamide} has a selective urethral smooth muscle contraction inhibitory action and is used as a therapeutic agent for dysuria. It is developed by Utsui Pharmaceutical Co. in Japan and sold under the trade name Thrupas in Korea.

[Chemical Formula 1]

U.S. Patent No. 5,387,603 discloses a method for the treatment of dysuria and dysuria caused by enlarged prostate. Specifically, the patent document discloses a manufacturing method of silicon nitride, and discloses IR (infrared absorption spectroscopy), nonlinearity, and NMR (nuclear magnetic resonance spectroscopy) data of a silicon oxynitride manufactured by the above production method. However, indeed, no data on the polymorphism of the neoplasm was disclosed.

Korean Patent No. 10-0670592 discloses a study on the polymorphism of Shadrodine ginsenoside. Specifically, there are three types of crystal forms in the gypsum matrix. In the X-ray diffraction spectrum, 2θ is 5.5 ° ± 0.2 °, 6.1 ° ± 0.2 °, 9.8 ° ± 0.2 °, 11.1 ° ± 0.2 °, and 12.2 ° ± 0.2 ° , 16.4 DEG. + -. 0.2 DEG, 19.7 DEG. + -. 0.2 DEG and 20.0 DEG. + -. 0.2 DEG is referred to as .alpha. Crystal form, , 19.5 ° ± 0.2 °, 20.7 ° ± 0.2 ° and 21.1 ° ± 0.2 ° is referred to as β crystal form, 2θ is 6.0 ° ± 0.2 °, 10.6 ° ± 0.2 °, 12.6 ° ± 0.2 ° , 17.1 DEG. + -. 0.2 DEG, 17.9 DEG. + -. 0.2 DEG, 20.7 DEG. + -. 0.2 DEG and 23.7 DEG.

Specifically, the? -Crystalline type crystals are prepared by dissolving crude crystals in an appropriate amount of a mixed solvent of ethyl acetate, ethyl formate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, acetone / acetonitrile (1: 1) And precipitating the crystals.

In addition, the crystalline β-crystal form is prepared by dissolving crude crystals in an appropriate amount of methanol under heating, adding petroleum ether and vigorously shaking the solution to precipitate crystals rapidly or rapidly, dissolving in ethanol or 1-propanol and rapidly cooling Crystals can be produced.

Finally, the gamma crystal form of gamma crystal is prepared by dissolving the crude crystals in an appropriate amount of toluene, a mixed solvent of acetonitrile and toluene (1: 4), a mixed solvent of ethyl acetate and toluene (1:19) under heating, . ≪ / RTI >

The α-crystal form, the β-form crystal form and the γ-form form, which are prepared by the above-mentioned production method, are excellent in hygroscopicity and stability and can be used as an effective ingredient of each of these crystals as long as they are within the allowable range, Lt; / RTI >

However, since? -Crystalline type crystals are prepared by forcibly and rapidly precipitating crystals by adding a poor solvent to the heating solution, the apparatus for industrial production becomes large, and it is relatively difficult to obtain a certain crystal There is a problem in industrial manufacturing such as anticipated; Ethanol or 1-propanol and rapidly cooling it, it is disclosed that there is a problem that different crystal forms are mixed depending on the cooling rate, temperature and degree of stirring, and the yield and purity are hard to be constant.

In addition, since the recrystallization solvent is a mixed solvent containing toluene or toluene and the toluene has a high boiling point, it takes a long time to remove it, and it is difficult to completely remove the residual solvent, and further, It is a class II substance that must regulate the remaining amount to 890 ppm or less in accordance with the ICH Guideline. Therefore, the pharmaceutical industry has disclosed a problem of avoiding use in the final process.

On the other hand, International Patent Publication No. 2012/077138 discloses a new preparation method of? -Crystalline type and? -Crystalline type for the purpose of obtaining better yield and purity, but fails to disclose any method for producing γ-crystal form.

Therefore, although the manufacturing problems of the? -Crystalline type and the? -Crystalline type, which have been proven through the above-mentioned International Patent Publication, have been solved, there still remains a manufacturing problem of the? -Crystalline type.

The inventors of the present invention have researched to solve the manufacturing problem of gamma crystal form and to make gamma crystal form of gamma crystal form also be used as an effective ingredient of a therapeutic agent for voiding dysfunction. As a result, the present invention has been accomplished.

United States Patent No. 5,387,603 Korean Patent No. 10-0670592 International Patent Publication No. 2012/077138

It is an object of the present invention to provide a novel process for preparing gamma crystal form which is tangentially roasted without using a toluene solvent.

The present invention provides a novel process for preparing gamma crystal form of gamma crystal using a new solvent which is easy to remove without using a toluene solvent as a crystallization solvent.

Specifically, the production method according to the present invention is a method for dissolving trombic acid in a crude siloxane in any one solvent selected from the group consisting of methyl isobutyl ketone, 1-propanol, 1-butanol, isobutanol, And seeding the gamma crystal form stained with gamma ray.

In addition, the production method according to the present invention may further include the step of adding hexane, heptane, petroleum ether or the like to the crystallization solvent as an anti-solvent. Specific examples of the semi-solvent include n-heptane, n-hexane, cyclohexane, petroleum ether, and t-butyl methyl ether. The amount of the semi-solvent may vary depending on the kind of the solvent, but the volume ratio of the solvent to the half-solvent may be 1: 1 to 1: 5.

In addition, the preparation method according to the present invention may further include a step of seeding the γ-crystal form of gallic acid, followed by primary stirring at 15 to 30 ° C. and secondary stirring at 0 to 10 ° C.

When the gamma crystal form is formed through the above steps, it may further include isolating the gamma crystal form which is streaked from the solution.

Further, the isolated γ-crystal filtrate may be dried to finally obtain γ-crystal form which is tangentially roasted.

On the other hand, since the dissolution step requires completely dissolving the manure in the chamber, the amount of the crystallization solvent used may vary depending on the type of the solvent selected. Preferably, it can be used in a proportion of 5 to 20 mL per g of the gum. However, the present invention is not limited thereto.

In addition, the dissolution temperature in the dissolution step may vary depending on the type of the solvent selected and the amount of the solvent used. Preferably, the dissolution step may be carried out at 30 to 80 ° C. However, the present invention is not limited thereto.

On the other hand, the? -Crystalline? -Silicon crystal used in the seeding step can be prepared and used according to the method described in Korean Patent No. 10-0670592.

In addition, the amount of the? -Crystalline seeds sprouted in the seeding step is preferably 0.01 to 1% by weight on the basis of the grain size.

Also, the seeding temperature in the seeding step may vary depending on the type of the solvent selected and the amount of the solvent used. Preferably, the seeding step may be performed at 25 to 60 < 0 > C. If the seeding temperature is lower than 25 ° C, another crystal form (for example, β-crystal form) may be formed. If the seeding temperature is higher than 60 ° C, seeding may melt.

According to one embodiment of the present invention, the crystallization solvent may be methyl isobutyl ketone. At this time, the dissolution step may be performed at 40 to 70 ° C. The seeding step may be performed at 30 to 60 < 0 > C.

According to another embodiment of the present invention, the crystallization solvent may be 1-propanol or 1-butanol. At this time, the dissolution step may be performed at 30 to 70 ° C. In addition, the seeding step may be performed at 25 to 40 < 0 > C.

According to another embodiment of the present invention, the crystallization solvent may be isobutanol. At this time, the dissolution step may be performed at 30 to 80 ° C. In addition, the seeding step may be carried out at 25 to 50 < 0 > C.

The crystals obtained according to the production method of the present invention can be obtained by a crystal modification of γ-tocopherol γ crystal and an X-ray diffraction analysis spectrum (2θ of 6.0 ° ± 0.2 °, 10.6 ° ± 0.2 °, 12.6 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.7 ° ± 0.2 °, and 23.7 ° ± 0.2 °).

As described above, in the production method of the present invention, any one of methyl isobutyl ketone, 1-propanol, 1-butanol, isobutanol or a mixed solvent thereof is selected without using toluene as a crystallization solvent, crystal form can be produced.

Therefore, the production method of the present invention has opened up the possibility that the γ-crystal form of gum arabic, which was difficult to use as an active ingredient due to a manufacturing problem, can be used as an active ingredient in the same manner as α-crystal form and β-form crystal form.

The present invention, which provides a novel method for preparing γ-crystal form, is advantageous in that toluene is not left in the raw material drug because no toluene solvent is used.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an X-ray diffraction spectrum of a γ-crystal form of γ-tocopherol prepared according to the method described in Example 1 of the present invention. FIG.
Fig. 2 is an X-ray diffraction spectrum of gum arabic crystal prepared by the method described in Example 2 of the present invention.
Fig. 3 is an X-ray diffraction spectrum of gum arabic crystal form prepared according to the method described in Example 3 of the present invention.
Fig. 4 is an X-ray diffraction analysis spectrum of gamma-crystal form of gum arabic prepared according to the method described in Example 4 of the present invention.
Fig. 5 is an X-ray diffraction spectrum of a γ-crystal form of γ-tocopherol prepared according to the method described in Comparative Example 1 of the present invention.
Fig. 6 is an X-ray diffraction spectrum of a filamentous β-crystal form prepared according to the method described in Comparative Example 2 of the present invention.
Fig. 7 is an X-ray diffraction spectrum of a filamentous β-crystal form prepared according to the method described in Comparative Example 3 of the present invention.

Hereinafter, preferred embodiments and comparative examples are provided to facilitate understanding of the present invention. However, the following examples and comparative examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.

Example  One : Methyl isobutyl ketone  In solvent Indeed  γ crystal type manufacturing

To the reactor was added 2 g of Trosin as a control, followed by addition of methyl isobutyl ketone (20 mL), followed by heating to 65 ° C and stirring. When all of the solids dissolved, the stirring of the heated mixture was stopped, and the solution was cooled to 50 DEG C and seeded with gamma crystal form (0.02 g) which had been stigmatized with silane. After cooling to room temperature, the mixture was stirred for 12 hours, stirred at 5 ° C for 1 hour, and then filtered. The filtrate was vacuum-dried, and the γ-crystal form was confirmed by X-ray diffraction analysis (FIG. 1).

Example  2: 1- Propanol  In solvent Indeed  γ crystal type manufacturing

To the reactor was added 2 g of Trosin as a control, 1-propanol (10 mL) was added, and the mixture was stirred at 60 ° C. When all of the solids dissolved, the stirring was stopped, and the solution was cooled to 35 DEG C and seeded with gamma crystal form (0.02 g) which was fired to the yarn. After cooling to room temperature, the mixture was stirred for 12 hours, stirred at 5 ° C for 1 hour, and then filtered. The filtrate was vacuum-dried, and the γ crystal form was confirmed by X-ray diffraction analysis (FIG. 2).

Example  3: 1- Butanol  In solvent Indeed  γ crystal type manufacturing

To the reactor was added 2 g of gum arabic, and 1-butanol (14 mL) was added. The mixture was heated to 60 ° C and stirred. When all of the solids dissolved, the stirring was stopped, and the solution was cooled to 35 DEG C and seeded with gamma crystal form (0.02 g) which was fired to the yarn. After cooling to room temperature, the mixture was stirred for 12 hours, stirred at 5 ° C for 1 hour, and then filtered. The filtrate was vacuum-dried, and the γ crystal form was confirmed by X-ray diffraction analysis (FIG. 3).

Example  4 : Isobutanol  In solvent Indeed  γ crystal type manufacturing

To the reactor was added 1.6 g of Trosin, and isobutanol (16 mL) was added thereto, followed by stirring at 65 ° C. When all of the solids dissolved, the stirring was stopped, and the solution was cooled to 35 DEG C and seeded with gamma crystal form (0.02 g) which was fired to the yarn. After cooling to room temperature, the mixture was stirred for 12 hours, stirred at 5 ° C for 1 hour, and then filtered. The filtrate was vacuum-dried, and the γ crystal form was confirmed by X-ray diffraction analysis (FIG. 4).

Comparative Example  1: According to the manufacturing method of Korean Patent No. 10-0670592 Indeed  γ crystal type manufacturing

A γ crystal form was prepared by the method disclosed in Example 3 of Korean Patent No. 10-0670592. X-ray diffractometry was used to confirm the gamma crystal form (Fig. 5).

Comparative Example  2 : Methyl isobutyl ketone  In solvent Seed  without Indeed  β crystal type manufacturing

To the reactor was added tris (2 g), and methyl isobutyl ketone (20 mL) was added thereto, followed by heating to 65 ° C and stirring. When all of the solids dissolved, the stirring was stopped, and the mixture was cooled to room temperature without seeding, followed by stirring for 12 hours, followed by stirring at 5 ° C for 1 hour and then filtration. The filtrate was vacuum-dried, and the β-crystal form was observed by X-ray diffraction analysis (FIG. 6).

Comparative Example  3: According to the manufacturing method of Korean Patent No. 10-0670592 Indeed  β crystal type manufacturing

A β-crystal form was prepared by the method disclosed in Example 2 of Korean Patent No. 10-0670592. X-ray diffractometry was used to confirm the crystal form of xanthan gum (Fig. 7).

Claims (9)

Dissolving gadolone in any one solvent selected from the group consisting of methyl isobutyl ketone, 1-propanol, 1-butanol, isobutanol and a mixed solvent thereof; And
Seeding the gamma crystal form;
Lt; RTI ID = 0.0 > gamma < / RTI > crystal form. The process according to claim 1, further comprising the step of adding hexane, heptane or petroleum ether as an anti-solvent. The process according to claim 1, further comprising the step of seeding the gamma crystal form which is fired and then the primary agitation at 15 to 30 ° C and the secondary agitation at 0 to 10 ° C. The process according to claim 1, wherein the solvent is methyl isobutyl ketone, and the dissolution step is carried out at 40 to 70 占 폚. The process according to claim 1, wherein the solvent is methyl isobutyl ketone, and the seeding step is carried out at 30 to 60 ° C. The process according to claim 1, wherein the solvent is 1-propanol or 1-butanol, and the dissolution step is carried out at 30 to 70 ° C. The process according to claim 1, wherein the solvent is 1-propanol or 1-butanol, and the seeding step is carried out at 25 to 40 ° C. The process according to claim 1, wherein the solvent is isobutanol and the dissolution step is carried out at 30 to 80 ° C. 3. The process of claim 1, wherein the solvent is isobutanol and the seeding step is performed at 25 to 50 < 0 > C.

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