KR20160097019A - Method of Preparing Crystal Compounds - Google Patents

Abstract

The present invention relates to a manufacturing method of a crystalline compound, a crystal of the compound manufactured thereby, and a composition comprising same for treating dysuresia. More particularly, the manufacturing method of the crystalline compound uses toluene and a C_4-C_8 ether solvent. Thus, the manufactured crystalline compound has a low content of residual solvent harmful to human bodies, and has excellent quality. The crystalline compound is represented by chemical formula 1.

Description

[0001] The present invention relates to a method for preparing crystalline compounds,

The present invention relates to a process for producing a crystalline compound, a crystal of the compound produced thereby, and a composition for treating a urinary disorder comprising the same, and more particularly to a process for producing a crystalline compound using toluene and a C ₄ -C ₈ ether solvent To a crystalline compound of a high quality having a low residual solvent content harmful to human body, crystals of a compound produced thereby, and a composition for treating urinary disturbance comprising the same.

A compound represented by the following formula (I): 1- (3-hydroxypropyl) -5 - [(2R) - ({2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] Ethyl} amino) propyl] indoline-7-carboxamide (hereinafter referred to as silodosin) has been used as an active ingredient in the treatment of micturition disorders such as prostatome enlargement.

(I)

Since the chemical structure of Shilohsin was first disclosed in the patent of Utsuisi Pharmaceutical (US Patent No. 5,387,603), a variety of products containing active ingredients of the therapeutic agent for voiding disorder have been introduced and used. In order for a substance of a single chemical structure to be used as an active ingredient in a solid pharmaceutical preparation for oral administration, it is essential that it exhibits appropriate physicochemical properties regarding solubility, stability, hygroscopicity, bioavailability, etc. This can be determined by the polymorphism It is well known.

Indeed, there are five known polymorphisms of gods. Indeed, the first report on the polymorphism of the god has been cited in three patents, alpha, beta and gamma in the Katsuei patent (Korean Patent No. 10-0670592). According to the patent of Wigetsei Pharmaceutical, the α-form can be obtained by recrystallizing tarsin crystals from a solvent such as acetone, ethyl acetate, acetonitrile, tetrahydrofuran, or a mixed solvent thereof. β-form crystals can be obtained by recrystallizing crude crystals from alcohols such as methanol and ethanol or from a solvent mixture of these solvents and petroleum ether. The γ-form can be obtained by recrystallizing crude crystals from toluene or a mixed solvent such as acetonitrile, ethyl acetate, isopropanol or the like. According to this patent, all three types of α, β, and γ types show similar stability and hygroscopicity, which are typical physicochemical properties suitable as active ingredients of oral solid pharmaceuticals.

On the other hand, a δ-type which can be used for producing a β-type crystal form and a ε-type which is a crystalline type with improved solubility have been known in the patent of Sandoz (European Patent No. 2,474,529). The δ form can be prepared by dissolving the crude crystals in tetrahydrofuran and then using an anti-solvent such as n-heptane, and the ε form can be prepared by suspending the δ form crystals in aqueous methanol.

All of the above-mentioned various types of crystalline polymorphism have disadvantages in that they are difficult to avoid in the industrial mass production process, despite their inherent stability and hygroscopicity, even though they have appropriate physicochemical properties to be used as active ingredients of medicines. In the case of β type, it is known that it is difficult to obtain a certain quality due to a forced or abrupt change of crystallization condition. Further, it is difficult to avoid the reduction of the yield due to the increase of the production steps in the method of separately passing the < RTI ID = 0.0 > type < / RTI > Particularly, since γ type is easy to mass-produce a certain crystal form, but because high boiling point toluene is used as a main solvent, the ICH, Q3C, and residual solvent (890 ppm toluene) is very difficult to produce.

In order to solve this problem, the inventors of the present application have found that by producing a crystalline compound through a novel production process using toluene and an ether solvent, it is possible to produce a high quality raw material which is economically industrially mass- And that the present invention has been completed.

It is an object of the present invention to provide a method for producing a gypsum syrup crystal capable of supplying a high-quality gypsum crystal raw material which is industrially easily mass-produced, economical, and meets a tolerance standard of a residual solvent.

Another object of the present invention is to provide a thread truncated crystal produced by the above-mentioned production method.

It is still another object of the present invention to provide a composition for the treatment of micturition disorder comprising the crystal as an active ingredient.

In order to accomplish the above object, the present invention provides a process for producing a compound represented by the formula (1), comprising the steps of: introducing toluene and a C ₄ -C ₈ ether solvent into a crude crystal of the compound represented by the formula (1) Recrystallizing the crude crystals of the compound represented by formula (1) in toluene and adding a C ₄ -C ₈ ether solvent to the suspension to obtain crystals; Or a crude crystal of the compound represented by the formula (1) is obtained by recrystallization in toluene, and the dried crystal is further suspended in a C ₄ -C ₈ ether solvent to obtain a crystal. do.

(I)

The present invention also provides crystals of the compound represented by the formula (1) prepared by the above method.

(I)

The present invention also provides a composition for treating micturition disorder comprising the crystal as an active ingredient.

According to the present invention, in producing a raw material for threading, which is widely used as a therapeutic agent for dysuria such as enlarged prostate, it is possible to economically and easily produce a crystalline form of a crystalline polymorph having excellent physico-chemical properties such as stability and hygroscopicity. Quality industrial yarn can be easily and economically produced while easily solving the problem of the residual solvent standard which is inevitably generated when toluene is used as the main solvent.

Fig. 1 shows a gamma -form powder X-ray diffraction spectrum prepared by a prior art (Korean Patent Registration No. 0670592).
FIG. 2 is a diagram showing a powder X-ray diffraction pattern of γ-type crystals which were prepared in accordance with an embodiment of the present invention. The vertical axis indicates the intensity (cps), and the horizontal axis indicates 2? (Degrees).

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.

In one aspect, the present invention relates to a process for preparing a compound represented by the formula (I), which comprises: introducing toluene and a C ₄ -C ₈ ether solvent into a crude crystal of the compound represented by the formula (1) and recrystallizing the same; Recrystallizing the crude crystals of the compound represented by formula (1) in toluene and adding a C ₄ -C ₈ ether solvent to the suspension to obtain crystals; Or a crude crystal of the compound represented by the formula (1) is obtained by recrystallization in toluene, and the dried crystals are suspended again in a C ₄ -C ₈ ether solvent to obtain crystals. will be.

(I)

According as the inventors of the present application are indeed also God crystal form D, in particular by screen chamber recrystallized dosin crude crystals as a result, a toluene concentration in the development γ-form crystal polymorphism manufacturing method for producing the γ-type, specifically a C ₄ -C ₈ Ether was used as a solvent, or C ₄ -C ₈ ether was used as a mixed solvent simultaneously with toluene as a co-solvent. That is, the present invention has been made to solve the problems of the conventional method of producing gamma -type gypsum, for example, the compatibility of residual solvent allowance standards, and to provide an economical production method.

The gamma -type crystalline material which has been sintered may be prepared by heating the crude crystals in an appropriate amount of toluene to dissolve the crystals in a known manner, then allowing to stand at room temperature and gradually cooling. However, the? -Forms prepared by using toluene alone by a conventionally known method have problems of static electricity generation and fluidity in terms of properties after drying.

On the other hand, according to the present invention, the residual solvent content of toluene to produce a low γ-type, C ₄ -C ₈ using ether as a solvent, or at the same time as toluene as a co-solvent can be used for C ₄ -C ₈ ether, a mixed solvent have. In one embodiment, the ether solvent may be t-butyl methyl ether or isopropyl ether.

In one embodiment, the crude crystals of the compound of Formula 1 may be suspended and warmed in toluene to dissolve and the crystalline compound may be prepared by adding a C ₄ -C ₈ ether solvent in the dissolved state. For example, crude crystals of the compound represented by the formula (1) can be recrystallized from a mixed solvent of toluene and t-butyl methyl ether or a mixed solvent of toluene and isopropyl ether.

In another embodiment, the crude crystals of the compound of Formula 1 may be suspended and warmed to dissolve in toluene and then cooled to form crystals, followed by addition of a C ₄ -C ₈ ether solvent to obtain crystals. For example, t-butyl methyl ether or isopropyl ether may be added to a suspension of a? -Form crystal produced by recrystallization from toluene, followed by stirring.

In another embodiment, crystals of the compound of formula 1 recrystallized from toluene may be filtered and dried, and then suspended in a C ₄ -C ₈ ether solvent to obtain crystals. For example, crystals of the γ-form obtained by recrystallization from toluene may be filtered and dried, and then suspended again in an appropriate amount of t-butyl methyl ether or isopropyl ether to obtain crystals.

Butyl methyl ether or isopropyl ether, at a temperature of, for example, 40 ° C or higher, and may be suspended at a temperature below the boiling point of each solvent. For example, the boiling point of t-butyl methyl ether is about 55.2 ° C, so it can be carried out at a temperature of 40-55.2 ° C when suspended in t-butyl methyl ether. Also, the boiling point of isopropyl ether is about 68.5 DEG C, so it can be carried out at 40-68.5 DEG C temperature in suspension in isopropyl ether.

When prepared according to the method presented by the present invention, the purity of the finally obtained gypsum crystalline material was found to be equal or slightly improved compared to the purity of the initially used crude crystals.

The powder X-ray diffraction pattern (PXRD) of Chenopodiumdicoboride prepared according to the method proposed by the present invention has a 2? Of 6.0 占 0.2 占 10.6 占 占 0.2 占 12.6 占 0.2 占 17.1 占 0.2 占 17.9 Lt; RTI ID = 0.0 > 0.2 < / RTI > and 20.7 +/- 0.2 degrees.

On the basis thereof, the present invention relates to crystals of a compound represented by the formula (1) prepared by the above method from another viewpoint.

(I)

According to the present invention, the purity of the finally obtained stalactite crystalline material was found to be equal to or slightly improved compared to the purity of the initially used crude crystals. Also, the γ-form obtained by suspending γ-formyl trosin containing a large amount of toluene in t-butyl methyl ether or isopropyl ether showed almost no change in purity.

Further, when the γ type was produced according to the method proposed by the present invention, there was almost no phenomenon of degradation in yield compared to the initial used crystal.

Furthermore, when the γ form was prepared according to the method proposed by the present invention, the residual solvent content of toluene was found to be 890 ppm or less, which is the allowable standard of the amount of the international residual solvent as a result of gas chromatography analysis.

When these results are summarized, it has been proved that the method for producing gamma -type, which is proposed in the present invention, is an economically useful method which is industrially applicable.

The crystals produced according to the present invention exhibited suitable properties for use as oral pharmaceutical ingredients. This is different from the fact that the γ-form prepared by using the known method toluene alone has a problem of static electricity generation and poor fluidity in terms of properties after drying.

On the basis thereof, the present invention relates to a composition for treating micturition disorder comprising the crystal as an active ingredient from a different viewpoint.

The dysuria according to the present invention may include, for example, dysuria caused by neurogenic dysuria, a bladder outlet obstruction typified by men's enlargement of the prostate gland, weakening of the pelvic structure of the woman, or a local disease of the urethra and bladder But is not limited thereto.

The composition according to the present invention can be formulated according to a conventional method, for example, in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories, Can be used. Examples of carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. The base of suppositories may be witepsol, macrogol, tween, cacao butter, laurin, glycerogelatin and the like.

The preferred dosage of the composition of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. The compositions of the present invention may be administered to mammals, such as rats, mice, livestock, humans, and the like in a variety of routes, all manner of administration being contemplated, for example, rectal or intravenous, muscular, subcutaneous, Or by intracerebral injection.

[Example]

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.

Reference Example 1: Gas Chromatographic Analysis Conditions

The column was maintained at 100 ° C for 10 minutes using a DB-624 capillary and then heated to 200 ° C at a rate of 20 ° C per minute. The detector was FID and the carrier gas was nitrogen gas. Approximately 89 mg of toluene was precisely weighed into a 100 ml volumetric flask, and the standard solution was selected with DMF to prepare a standard solution. Approximately 100 mg of the sample was precisely weighed into a 10 ml volumetric flask and drawn with DMF to prepare a sample solution.

Reference Example 2: Powder X-ray diffraction (PXRD) analysis conditions

Powder X-ray diffraction analysis was performed using a diffractometer equipped with a miniflex goniometer. Scanning mode was 2θ / θ, scanning was continuous scanning, X-ray was 30 kV / 15 mA and Cu-Kα irradiation source, scattering slit was 4.2 °, The ice slit was 0.3 mm, Kb filter, and the angular interval was measured as 0.05 to 0.05 in terms of 5 to 30 2 theta.

Reference Example 3: Preparation of? -Type crystal form by using toluene alone

13 g of stearic acid crystals were suspended in 130 ml of toluene and heated to completely dissolve them. After cooling slowly to room temperature, it was filtered, washed with toluene and dried to give 12.5 g (96%). As a result of powder X - ray diffraction analysis, it was identified as γ type, and the result of analyzing residual solvent of toluene by gas chromatography was confirmed to be 2500 ppm.

Example 1: Recrystallization in a mixed solvent of toluene and t-butyl methyl ether

13 g of stearic acid crystals were suspended in 130 ml of toluene and heated to completely dissolve them. While maintaining the dissolved state, 65 ml of t-butyl methyl ether was gradually added thereto, and then slowly cooled to room temperature. Filtered, washed with t-butyl methyl ether and dried to give 12.7 g (98%). As a result of powder X - ray diffraction analysis, it was identified as γ type, and the result of toluene residual solvent analysis by gas chromatography was confirmed to be 820 ppm.

Example 2: Suspension tablets in a mixed solvent of toluene and t-butyl methyl ether

Seven grams of triclosan was suspended in 70 ml of toluene, and then heated to completely dissolve. After slowly cooling to room temperature to give crystals, 140 ml of t-butyl methyl ether was slowly added with stirring. Filtered, washed with t-butyl methyl ether and dried to give 6.7 g (96%). As a result of powder X - ray diffraction analysis, it was confirmed to be γ type, and the analysis of toluene residual solvent content by gas chromatography showed 650 ppm.

Example 3: Suspension tablet in t-butyl methyl ether

14 g of the γ-type crystalline powder prepared in Reference Example 3 (14 g) was added to 140 ml of t-butyl methyl ether, heated to the boiling point, and stirred for 1 hour. The mixture was slowly cooled to room temperature, filtered, washed with t-butyl methyl ether and dried to obtain 13.3 g (95%). The results of the powder X-ray diffraction analysis are shown in FIG. 2, and it can be confirmed that it is in the form of γ according to FIG. 2, and as a result of analyzing toluene residual solvent by gas chromatography, it was confirmed to be 210 ppm.

Example 4: Suspension tablet in isopropyl ether

14 g of the gamma -type crystalline powder prepared in Reference Example 3 was introduced into 140 ml of isopropyl ether and heated to the boiling point and stirred for 1 hour. The mixture was slowly cooled to room temperature, filtered, washed with isopropyl ether and dried to give 13.1 g (94%). As a result of powder X - ray diffraction analysis, it was confirmed to be γ type, and the content of toluene residual solvent by gas chromatography was 410 ppm.

Having thus described the present invention in detail, it will be apparent to those skilled in the art that this specific description is only a preferred embodiment and that the scope of the present invention is not limited thereby . It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (9)

Introducing toluene and a C ₄ -C ₈ ether solvent into the crude crystals of the compound represented by the formula (1) and then recrystallizing the same to obtain a compound; Recrystallizing the crude crystals of the compound represented by formula (1) in toluene and adding a C ₄ -C ₈ ether solvent to the suspension to obtain crystals; Or a crude crystal of the compound represented by the formula (1) is obtained by recrystallization in toluene, and the dried crystals are suspended again in a C ₄ -C ₈ ether solvent to obtain crystals.
(I)

The method according to claim 1, wherein the crystal has a 2? Of 6.0 占 0.2 占 10.6 占 0.2 占 12.6 占 0.2 占 17.1 占 0.2 占 17.9 占 0.2 占And a peak of 20.7 DEG +/- 0.2.
The method of claim 1, wherein the C ₄ -C ₈ ether solvent is t-butyl methyl ether or isopropyl ether.
The process according to claim 1, wherein the crude crystals of the compound represented by the formula (1) are suspended and warmed to dissolve in toluene, and the crystalline compound is recrystallized by adding a C ₄ -C ₈ ether solvent in a dissolved state ≪ / RTI >
The method according to claim 1, wherein the crude crystals of the compound represented by the formula (1) are suspended and warmed to dissolve in toluene, cooled to produce crystals, and then a C ₄ -C ₈ ether solvent is added to obtain crystals ≪ / RTI >
The process for producing a crystalline compound according to claim 1, wherein the crystals of the compound represented by formula (1) recrystallized from toluene are filtered and dried, and then suspended in a C ₄ -C ₈ ether solvent to obtain crystals.
A crystal of the compound represented by the formula (1) prepared by the process of any one of claims 1 to 6.
(I)

The crystal according to claim 7, wherein the toluene residual solvent content is 890 ppm or less.
A composition for treating micturition disorder comprising the crystal of claim 7 as an active ingredient.

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