KR20240116208A - New crystalline salts of mirabegron, preparation method thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to the crystalline form of mirabegron ((R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid. Anilide) relates to a new salt, a manufacturing method thereof, and a pharmaceutical composition containing the same. The mirabegron new salt is in crystalline form, has excellent physical and chemical stability, and has improved solubility in water, making it highly usable as a pharmaceutical composition. It has the advantage of being able to be mass-produced with high purity and showing excellent effectiveness as a treatment for overactive bladder.

Description

New crystalline salts of mirabegron, preparation method thereof and pharmaceutical composition comprising the same}

The present invention relates to the crystalline form of mirabegron ((R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid. Anilide) relates to a novel salt, its preparation method, and a pharmaceutical composition containing it.

Mirabegron ((R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl represented by the formula: ]Anilide acetate) is a selective β3-adrenergic receptor agonist and is the first drug developed to treat overactive bladder (OAB) with a new mechanism.

[Chemical formula]

OAB mainly occurs in elderly patients and is known to be a disease that inhibits the patient's daily life as well as social activities due to symptoms such as urinary urgency, frequent urination, and urge incontinence. Existing treatments mainly focus on antimuscarinic drugs that inhibit bladder contraction, such as Tolterodine, Solifenacin, and Trospium. Although these drugs vary in degree, most of them cause dry mouth and dryness. It may cause side effects such as constipation, blurred vision, cognitive impairment, and digestive disorders. Mirabegron, which is currently sold under the brand names of Betamiga, Miravec, and Celebeta, not only has fewer side effects such as dry mouth, but unlike antimuscarinics, it does not affect the parasympathetic nervous system, so there is a risk of acute urinary retention during urination. This is small, and a synergistic effect can be expected when combined with antimuscarinics. Due to these advantages, the prescription of mirabegron-containing OAB treatment is increasing due to high medication compliance among elderly patients.

International Publication Patent WO 2003/037881 (published on July 26, 2006)

The purpose of the present invention is to provide a new crystalline salt of mirabegron with high solubility in water and excellent stability, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.

In order to achieve the above object, the present invention provides a new crystalline salt of mirabegron containing a salt of mirabegron represented by the following formula (1).

[Formula 1]

In Formula 1, X is an organic acid of nicotinic acid or vanillic acid.

In addition, the present invention provides a pharmaceutical composition for treating overactive bladder containing the above-described crystalline mirabegron novel salt as an active ingredient.

In addition, the present invention includes a first step of reacting mirabegron and an organic acid in a solvent; And a second step of preparing a new mirabegron salt by separating and drying the crystals produced in the first step, wherein the new salt is nicotinic acid salt or vanillic acid salt. A method for producing a new salt is provided.

The novel mirabegron salt according to the present invention is in crystalline form, has excellent physical and chemical stability, and has improved solubility in water, so it has excellent usability as a pharmaceutical composition, can be mass-produced with high purity, and has excellent effects as a treatment for overactive bladder. It has the advantage of representing .

Figure 1 is a powder X-ray diffraction pattern for mirabegron nicotinate prepared according to Example 4 of the present invention.
Figure 2 is a powder
Figure 3 shows the results of differential scanning calorimetry analysis of mirabegron nicotinate prepared according to Example 4 of the present invention.
Figure 4 shows the results of differential scanning calorimetry analysis of mirabegron vanillate crystalline form I prepared according to Example 7 of the present invention.
Figure 5 shows the results of differential scanning calorimetry analysis of mirabegron vanillate crystalline form II prepared according to Example 9 of the present invention.
Figure 6 shows the results of an accelerated stability test (Experimental Example 4) for mirabegron nicotinate obtained in Example 4 of the present invention, before the accelerated stability test (MRB-NCA) of the solid body and under accelerated conditions. This is a diagram comparing the X-ray diffraction patterns of each powder after 4 weeks of storage (MRB-NCA_accelerated 4 weeks).
Figure 7 shows the results of an accelerated stability test (Experimental Example 4) for mirabegron vanillate crystalline form I obtained in Example 8 of the present invention, before the accelerated stability test of the solid (MRB-VNA form I) and a diagram comparing the powder X-ray diffraction patterns after 4 weeks of storage under accelerated conditions (MRB-VNA form Ⅰ_accelerated 4 weeks).
Figure 8 compares the powder It is also a degree.

Hereinafter, the present invention will be described in detail.

The present invention provides a new salt of mirabegron in crystalline form, including the salt of mirabegron represented by the following formula (1).

[Formula 1]

In Formula 1, X is an organic acid of nicotinic acid or vanillic acid.

The molar ratio of mirabegron and organic acid may be 0.5:2 to 2:0.5 or 1:2 to 2:1.

By including nicotinic acid or vanillic acid as described above, physicochemical stability can be excellent and solubility in water can be improved.

When the organic acid is nicotinic acid, the powder °, may have peaks at diffraction angles (2θ±0.2°) of 25.2° and 29.5°.

When the novel mirabegron salt of the present invention is mirabegron nicotinate, it may have a heat absorption peak at 90 to 125 ± 3° C. in differential scanning calorimetry (DSC) analysis.

When the organic acid is vanillic acid, the powder X-ray diffraction pattern shows It may have a peak at a diffraction angle (2θ±0.2°). If it has the above peak, it may be mirabegron vanillic acid crystalline form I.

When the novel mirabegron salt of the present invention is mirabegron vanillate crystalline form I, it may have heat absorption peaks at 65 to 85 ± 3 °C and 175 to 180 ± 3 °C in differential scanning calorimetry (DSC) analysis.

When the organic acid is vanillic acid, the powder X-ray diffraction pattern shows diffraction angles (2θ ± 0.2 It may have a peak at °). If it has the above peak, it may be mirabegron vanillic acid crystalline form II.

When the novel mirabegron salt of the present invention is mirabegron vanillate crystalline form II, it may have a heat absorption peak at 175 to 180 ± 3 ° C in differential scanning calorimetry (DSC) analysis.

In addition, the present invention provides a pharmaceutical composition for treating overactive bladder containing the above-described crystalline mirabegron novel salt as an active ingredient.

Corresponding features may be substituted for the parts described above.

The pharmaceutical composition of the present invention is prepared in unit dose form or in multi-dose form by formulating it using a pharmaceutically acceptable carrier according to a method that can be easily performed by those skilled in the art. It can be manufactured by placing it in a container.

The pharmaceutically acceptable carriers are those commonly used in preparation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, Includes, but is not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. In addition to the above ingredients, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.

In the present invention, the content of additives included in the pharmaceutical composition is not particularly limited and can be appropriately adjusted within the content range used in conventional formulations.

The pharmaceutical compositions include injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules, tablets, creams, gels, patches, sprays, ointments, warning agents, lotions, liniments, pastes, and cataplasma. It may be formulated in the form of one or more external skin preparations selected from the group consisting of products, but is not limited thereto.

The pharmaceutical composition of the present invention may additionally contain pharmaceutically acceptable carriers and diluents for formulation. The pharmaceutically acceptable carriers and diluents include excipients such as starch, sugar and mannitol, fillers and extenders such as calcium phosphate, cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, gelatin, alginate, polyvinyl pyrrolidone. It includes, but is not limited to, binders such as talc, calcium stearate, lubricants such as hydrogenated castor oil and polyethylene glycol, disintegrants such as povidone and crospovidone, and surfactants such as polysorbate, cetyl alcohol, glycerol, etc. The pharmaceutically acceptable carrier and diluent may be biologically and physiologically friendly to the subject. Examples of diluents include, but are not limited to, saline, aqueous buffers, solvents, and/or dispersion media.

The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, or topically) depending on the desired method. For oral administration, it can be formulated as tablets, troches, lozenges, aqueous suspensions, oily suspensions, powders, granules, emulsions, hard capsules, soft capsules, syrups, elixirs, etc. In the case of parenteral administration, it can be formulated as an injection, suppository, powder for respiratory inhalation, aerosol for spray, ointment, powder for application, oil, cream, etc.

The dosage of the pharmaceutical composition of the present invention is determined by the patient's condition, weight, age, gender, health, dietary constitution specificity, nature of the preparation, degree of disease, composition administration time, administration method, administration period or interval, and excretion rate. And the range may vary depending on the drug form, and may be appropriately selected by a person skilled in the art. For example, it may range from about 0.1 to 100 mg/kg, but is not limited and may be administered once or in divided doses several times a day.

The pharmaceutical composition may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally, or topically) depending on the desired method. The pharmaceutically effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time, administration route, etc. of the pharmaceutical composition, and those skilled in the art will be able to determine the desired treatment. Effective dosage can be easily determined and prescribed. The pharmaceutical composition of the present invention may be administered once a day, or may be administered in several divided doses.

In addition, the present invention includes a first step of reacting mirabegron and an organic acid in a solvent; And a second step of preparing a new mirabegron salt by separating and drying the crystals produced in the first step, wherein the new salt is nicotinic acid salt or vanillic acid salt. A method for producing a new salt is provided.

The new salt of mirabegron prepared in the same manner as above may be a salt of mirabegron represented by Formula 1 above.

In addition, when the novel mirabegron salt is produced using the above method, it can be mass-produced with high purity.

The solvent may include one or more selected from the group consisting of methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, and water. Specifically, the solvent may include one or more selected from the group consisting of methanol, ethanol, ethyl acetate, and water.

The mixing amount of the solvent may be 0.1 to 20 times the volume (ml/g) based on the total weight of the mixture of mirabegron and eugenic acid, but is not limited thereto.

Specifically, the first step may be performed by reacting at a temperature of 20 to 50°C, 20 to 40°C, or 30 to 45°C.

Additionally, in the first step, the mirabegron and the organic acid may be used in a ratio of 0.5:2 to 2:0.5 or 1:2 to 2:1.

The second step is a step of generating crystals from a mixture of mirabegron, an organic acid, and a solvent. The solvent is evaporated with gradual stirring, or a supersaturation state is induced through cooling, addition of an anti-solvent, and addition of crystal seeds. Alternatively, crystals can be generated through sufficient stirring.

In the second step, the crystals produced in the first step are separated, washed, and dried to prepare crystalline mirabegron organic acid salt.

Specifically, in the second step, the generated crystals may be separated using a reduced pressure filtration device, but the process is not limited thereto.

Additionally, in the second step, the separated crystals may be washed using a solvent, and the solvent may include one or more selected from the group consisting of methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, and water. . Specifically, the solvent may include methanol, ethanol, ethyl acetate, or water.

In addition, in the second step, the separated crystals may be dried at a temperature of 30 to 80°C or 40 to 60°C. The drying may be vacuum drying, but is not limited thereto.

In the second step, the dried crystals may be further dried at a temperature of 70 to 100° C. for 2 to 4 days.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

<Example 1> Preparation of crystalline mirabegron-nicotinate

123 mg of nicotinic acid was added to a solution of 400 mg of mirabegron dissolved in 5 mL of methanol, and then stirred at room temperature for 1 hour. The resulting crystals were separated using a reduced-pressure filtration device and then dried under vacuum at 40°C to obtain 330 mg of crystalline mirabegron-nicotinate (yield: 63.1%).

<Example 2> Preparation of crystalline mirabegron-nicotinate

400 mg of mirabegron and 123 mg of nicotinic acid were added to 5 mL of methanol, stirred at room temperature to completely dissolve, and then 5 mL of ethyl acetate was added and stirred for an additional hour. The resulting crystals were separated using a reduced-pressure filtration device and then vacuum-dried at 40°C to obtain 420 mg of crystalline mirabegron-nicotinate (yield: 80.3%).

<Example 3> Preparation of crystalline mirabegron-nicotinate

A mixture of 15 mL of methanol and 30 mL of ethyl acetate was added to 5 g of Mirabegron and stirred at 40°C to completely dissolve. Afterwards, 1.55 g of nicotinic acid was added and 50 mg of mirabegron-nicotinic acid salt prepared according to Example 1 or Example 2 was added to the solution cooled to 30° C., and then stirred for additional 2 hours. The resulting crystals were separated using a reduced-pressure filtration device, washed with ethyl acetate, and dried under vacuum at 40°C to obtain 6.23 g of crystalline mirabegron-nicotinate (yield: 95.1%).

<Example 4> Preparation of crystalline mirabegron-nicotinate

A mixture of 90 mL of methanol and 180 mL of ethyl acetate was added to 30 g of Mirabegron and stirred at 40°C to completely dissolve. Afterwards, 270 mL of ethyl acetate was added to the solution containing 9.3 g of nicotinic acid, then cooled to room temperature and further stirred for 2 hours. The resulting crystals were separated using a reduced-pressure filtration device, washed with ethyl acetate, and dried under vacuum at 40°C to obtain 38.5 g of crystalline mirabegron-nicotinate (yield: 98.0%).

<Example 5> Mirabegron-vanillate crystalline form I production

400 mg of mirabegron and 168 mg of vanillic acid were dissolved by adding 10 mL of methanol and the methanol was completely evaporated at room temperature. The resulting solid was recovered and dried under vacuum at 40°C to remove residual solvent, thereby obtaining 540 mg of mirabegron-vanillate crystalline Form I (yield: 95.1%).

<Example 6> Mirabegron-vanillate crystalline form I production

A mixture of 3 mL of methanol and 6 mL of ethyl acetate was added to 1 g of mirabegron and stirred at 40°C to completely dissolve. After that, 0.42 g of vanillic acid was added, 12 mL of ethyl acetate was added, and the mixture was further stirred for 1 hour. The resulting crystals were separated using a reduced-pressure filtration device, washed with ethyl acetate, and then vacuum-dried at 40° C. to obtain 1.32 g of mirabegron-vanillate crystal form I (yield: 93.0%).

<Example 7> Mirabegron-vanillate crystalline form I production

0.42 g of vanillic acid was added to a solution in which 1 g of mirabegron was dissolved in 12.5 mL of methanol and stirred for 1 hour. The resulting crystals were separated through reduced pressure filtration and dried under vacuum. The obtained powder was added to 15 mL of purified water and stirred for 24 hours. The crystals were separated using a vacuum filtration device, washed with purified water, and dried under vacuum at 40°C to obtain 1.2 g of mirabegron-vanillate crystal form I (yield: 84.5%).

<Example 8> Preparation of mirabegron-vanillate crystalline form I

Each solution was prepared by dissolving 1.19 g of mirabegron in 15 mL of methanol and dissolving 0.5 g of vanillic acid in 5 mL of methanol. Afterwards, the two solutions were mixed and stirred for 30 minutes to 1 hour to form solid particles. 20 mL of purified water was added and stirred for an additional 2 hours. The resulting crystals were separated using a reduced-pressure filtration device, washed with purified water, and then vacuum-dried at 40° C. to obtain 1.26 g of mirabegron-vanillate crystal form I (yield: 74.6%).

<Example 9> Preparation of mirabegron-vanillate crystalline form II

12.5 mL of methanol was added to 1 g of mirabegron and 0.42 g of vanillic acid, and stirred for 1 hour. The resulting crystals were separated through reduced pressure filtration and dried under vacuum at 40°C. The obtained powder was left in an oven at 90°C for 3 days to obtain 1.24 g of mirabegron-vanillic acid crystal form II (yield: 87.3%).

<Example 10> Preparation of mirabegron-vanillate crystalline form II

A mixture of 3 mL of methanol and 6 mL of ethyl acetate was added to 1 g of mirabegron and stirred at 60°C to completely dissolve. Afterwards, a solution of 0.42 g of vanillic acid dissolved in 3 mL of methanol was added, and 50 mg of mirabegron-vanillic acid crystal form II prepared according to Example 9 was added. After stirring for 10 minutes, the resulting crystals were separated using a reduced-pressure filtration device, washed with ethyl acetate, and then vacuum-dried at 60° C. to obtain 1.21 g of mirabegron-vanillate crystal form II (yield: 85.2%).

<Comparative Example 1> Preparation of mirabegron α-form crystals

A mixture of 5 g of mirabegron β-form crystals, 60 mL of water, and 40 mL of ethanol is heated and dissolved at about 80°C, then cooled to 50°C, and 50 mg of α-form crystals are added. The reaction was cooled to 20°C and stirred for 1 hour, and the resulting crystals were filtered, washed, and vacuum dried to obtain 4.6 g of mirabegron α-form crystals.

<Comparative Example 2> Preparation of mirabegron β-type crystals

(R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol-hydrochloride 8.00g, 2-aminothiazol-4-ylacetic acid 4.32g, concentrated hydrochloric acid 2.64g and water 120ml Add 5.76 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloride (EDC·HCl) to the mixed solution at room temperature and stir for 2 hours. A mixture of 2.40 g of sodium hydroxide and 40 ml of water is added dropwise to the reaction solution and crystallized. The suspended reaction mixture was stirred for more than 2 hours, and the resulting crystals were filtered, washed with water, and dried under vacuum to obtain 9.15 g of Mirabegron β-form crystals.

<Experimental Example 1> Powder X-ray diffraction (PXRD) analysis

Powder X-ray diffraction analysis was performed on the crystalline forms prepared in the above examples and comparative examples. The powder X-ray diffraction pattern of each sample was obtained using a Bruker D2 PHASER X-ray diffraction analysis instrument using Cu-Kα with a wavelength of 0.154 nm. The diffraction angle (2θ) in the range of 4° to 40° was measured under the conditions of a step size of 0.02° and a scan speed of 10°/min, and the results are shown in Figures 1 and 2.

Figure 1 shows the results of X-ray diffraction analysis of mirabegron nicotinate of Example 4 and mirabegron of Comparative Examples 1 and 2, and Figure 2 shows the results of mirabegron vanillate crystalline form I (MRB-) of Example 7. These are the results of X-ray diffraction analysis of mirabegron vanillate crystalline form II (MRB-VNA Form II) of Example 9, and mirabegron of Comparative Examples 1 and 2.

As shown in Figure 1, it was confirmed that mirabegron nicotinate according to the present invention had a unique diffraction pattern different from mirabegron and nicotinic acid. Specifically, in the , peaks at diffraction angles of 25.2° and 29.5° (2θ±0.2°) were confirmed.

In addition, as shown in Figure 2, it was confirmed that mirabegron vanillate crystalline Form I and crystalline Form II according to the present invention had a unique diffraction pattern different from that of mirabegron and vanillic acid. Specifically, in the , peaks at diffraction angles (2θ±0.2°) of 25.9° and 32.5° were confirmed, and mirabegron vanillate crystalline form II was 6.0°, 9.1°, 15.2°, 18.05°, 19.25°, 19.7°, 20.0°. Peaks at diffraction angles (2θ±0.2°) of °, 21.35°, 24.1°, and 24.5° were confirmed.

<Experimental Example 2> Differential scanning calorimetry (DSC) analysis

Differential scanning calorimetry analysis was performed on the crystalline form prepared in the above example. The powder of each sample was placed in an aluminum container and performed using Mettler DSC-3 equipment at a temperature increase rate of 3°C/min under real-time nitrogen gas injection in the temperature range of 25 to 250°C. The results are shown in Figures 3 to 5. showed.

Figure 3 shows the results of differential scanning calorimetry (DSC) analysis of mirabegron nicotinate in Example 4, Figure 4 shows the results of differential scanning calorimetry (DSC) analysis of mirabegron vanillate crystalline form I in Example 7, and Figure 5 is the differential scanning calorimetry (DSC) analysis result of mirabegron vanillate crystalline form II of Example 9.

As shown in Figure 3, mirabegron nicotinate of the present invention exhibited a heat absorption peak over a relatively wide range of 90 to 125 ± 3 °C.

In addition, as shown in Figures 4 and 5, mirabegron vanillate crystalline form I of the present invention showed heat absorption peaks at 65 to 85 ± 3 ℃ and 175 to 180 ± 3 ℃, and mirabegron bar Nilic acid salt form II showed a heat absorption peak at 175 to 180 ± 3 °C. Based on the DSC analysis results, it can be expected that the two crystal forms of mirabegron vanillate are polymorphs with a thermodynamically reversible relationship (enantiotropic system).

<Experimental Example 3> Solubility analysis

Mirabegron-nicotinic acid salt obtained in Example 4, Mirabegron-vanillic acid crystal form I obtained in Example 8, Mirabegron α form crystal obtained in Comparative Example 1, and Mirabegron α-form crystal obtained in Comparative Example 2. Solubility analysis of mirabegron β-form crystals was performed (n=3). Specifically, 200 mg of the crystal powder obtained in each of Example 4, Example 8, Comparative Example 1, and Comparative Example 2 was added to 3 mL of purified water, pH 4.0 buffer, and pH 6.8 buffer, respectively, in a constant temperature water bath at 37 ± 1 °C. It was stirred at 100 rpm for 24 hours. After stirring for 24 hours, the solution was taken using a 1 mL syringe and a 0.45 ㎛ syringe filter, then diluted, and the mirabegron concentration in the solution was analyzed using HPLC as shown in Table 1 below, and the results are shown in Table 2 below.

Mobile phase A = 20 mM phosphate buffer (pH 5.5): MeOH: ACN = 90: 5: 5 (v/v) B = MeOH: ACN = 50: 50 (v/v) Column YMC pack pro C18 (4.6 x 150 mm, 3 um) Flow rate 1 mL/min (A: B = 30: 70) Oven temp. 40℃ injection 5 uL Detector UV 254nm

pH 4.0 (mg/mL) pH 6.8 (mg/mL) water (mg/mL) Mirabegron crystalline form α 18.15 3.13 0.2 Mirabegron crystal form β 16.98 3.45 0.28 Mirabegron-nicotinate 61.72 32.05 55.28 Mirabegron-vanillate crystalline form Ⅰ 4.81 2.57 2.28

As shown in Table 2 above, it was found that mirabegron nicotinate and mirabegron vanillate crystalline form I according to the present invention had better solubility in water than mirabegron crystalline forms α and β. In particular, in the case of mirabegron nicotinate, it was confirmed that the solubility under all conditions was significantly improved compared to mirabegron. These results mean that the novel mirabegron salt of the present invention can be usefully used as a pharmaceutical raw material that shows better in vivo effects than the existing mirabegron crystalline forms α and β.

<Experimental Example 4> Accelerated stability test

Mirabegron-nicotinic acid salt obtained in Example 4, Mirabegron-vanillic acid crystal form I obtained in Example 8, Mirabegron α form crystal obtained in Comparative Example 1, and Mirabegron α-form crystal obtained in Comparative Example 2. Accelerated stability tests were conducted on Mirabegron β-form crystals. After storing for 2 and 4 weeks under accelerated conditions (40 ± 2 ℃, relative humidity 75 ± 5 %), samples were taken and HPLC analysis and powder X-ray diffraction analysis were performed to determine the purity of mirabegron under the conditions in Table 3 below. and the results are shown in Figures 6 to 8 and Table 4.

Column YMC pack pro C18 (4.6 x 150 mm, 3 um) or equivalent column Flow rate 0.8mL/min Oven temp. 30℃ injection 20 uL Detector UV 220nm Mobile phase A = 20 mM phosphate buffer (pH 5.5): MeOH = 92: 8 (v/v)
B = ACN

Initial (purity, %) 2 weeks (purity, %) 4 weeks (purity, %) Mirabegron crystalline form α 99.82 99.84 - Mirabegron crystalline form β 99.87 99.87 - Mirabegron-nicotinate 99.85 99.87 99.84 Mirabegron-vanillate crystalline form Ⅰ 99.78 99.77 99.78

As shown in Table 4 above, it was confirmed that the new crystalline salt of mirabegron according to the present invention exhibits excellent stability, similar to the known mirabegron.

In addition, PXRD was measured to determine whether there was a change in the crystal form of mirabegron nicotinate and mirabegron vanillate crystalline form I stored under accelerated conditions for 4 weeks, and it was confirmed that there was no change in the crystal form (Figures 6 to 6). Figure 7). On the other hand, as can be seen in Figure 8, in the case of mirabegron crystalline form β, it was confirmed that the phase transition to crystalline form α was in progress after 2 weeks.

Having described specific parts of the present invention in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred implementation examples and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

The scope of the present invention is indicated by the patent claims described below, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.

Claims (10)

A new salt of mirabegron in crystalline form, including a salt of mirabegron represented by the following formula (1):
[Formula 1]

In Formula 1,
X is an organic acid of nicotinic acid or vanillic acid. According to claim 1,
A new salt of mirabegron in crystalline form, characterized in that the molar ratio of mirabegron and organic acid is 0.5:2 to 2:0.5. According to claim 1,
The organic acid is nicotinic acid, and in the powder , a new salt of mirabegron in crystalline form, characterized by having peaks at diffraction angles (2θ ± 0.2°) of 25.2° and 29.5°. According to claim 1,
The organic acid is vanillic acid, and in the powder A new crystalline salt of mirabegron characterized by having a peak at an angle (2θ ± 0.2°). According to claim 1,
The organic acid is vanillic acid, and in the powder ) A new salt of mirabegron in crystalline form, characterized by having a peak at. A pharmaceutical composition for treating overactive bladder comprising the crystalline mirabegron novel salt according to any one of claims 1 to 5 as an active ingredient. A first step of reacting mirabegron and an organic acid in a solvent; and
A second step of separating and drying the crystals produced in the first step to prepare a new mirabegron salt,
A method for producing a new crystalline salt of mirabegron, characterized in that the new salt is nicotinic acid salt or vanillic acid salt. According to claim 7,
The solvent is a method of producing a new crystalline mirabegron salt comprising at least one selected from the group consisting of methanol, ethanol, ethyl acetate, and water. According to claim 7,
The first step is a method for producing a new crystalline mirabegron salt, characterized in that the reaction is performed at a temperature of 20 to 50 ° C. According to claim 7,
The second step is a method for producing a new crystalline mirabegron salt, characterized in that the separated crystals are dried at a temperature of 30 to 80 ° C.