KR20200029751A - Vortioxetine nicotinate and processes for preparing the same - Google Patents

Abstract

The present invention provides vortioxetine nicotinate and a method for manufacturing the same. The vortioxetine nicotinate not only has a high water solubility, but also has a remarkably low hygroscopicity. In addition, the vortioxetine nicotinate can be manufactured in a crystalline form having excellent physicochemical and optical stability.

Description

Vortioxetine nicotinate and processes for preparing the same}

The present invention relates to a novel salt of vortioxetine and a method for preparing the same. More specifically, the present invention relates to vortioxetine nicotinate and a method for preparing the same.

Vortioxetine has a chemical name of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine, and has the structure of Formula 1 below. Botioxetine has antagonistic activity on 5-HT ₃ , 5-HT ₇ and 5-HD _1D receptors, has agonistic activity on 5-HT _1A receptors, and has partial agonistic activity on 5-HT _1B receptors As, it is used as a therapeutic agent for oral depression (WO 03/029232, WO 2007/144005, WO 2008/113359, etc.).

<Formula 1>

A method for preparing vortioxetine or a pharmaceutically acceptable salt thereof is disclosed in WO 03/029232, and an improved method for producing the same has been disclosed in WO 2007/144005, WO2015 / 125191, and the like. WO 2007/144005 also discloses polymorphs for various salts of vortioxetine, particularly acid addition salts, and discloses that the HBr salt of vortioxetine (botioxetine hydrobromide) is preferred in terms of solubility. have. In particular, HBr salt of vortioxetine can be separated into crystalline polymorphic forms of α, β, and γ, and it is disclosed that the β form is preferable in terms of hygroscopicity and solubility. Currently, the commercially used formulation containing vortioxetine, Brintellix ( ^TM ) tablet, contains β-type vortioxetine HBr salt as an active ingredient.

The HBr salt of vortioxetine has increased water solubility (e.g., α form: 2 mg / ml, β form: 1.2 mg / ml) compared to the free base form of vortioxetine (about 0.1 mg / ml). ), And also known as preferred in terms of hygroscopicity, the β-form vortioxetine HBr salt absorbs about 0.6% of water when exposed to high relative humidity. Therefore, there is a need in the art to improve the formulation, since it still has unsatisfactory properties in terms of water solubility and hygroscopicity, which may cause difficulties in formulation.

WO 2007/144005 also discloses that vortioxetine mesylate salt (i.e., methanesulfonate) has a high solubility, but methanesulfonic acid is at risk of producing alkyl mesylate impurities that can cause genetic toxicity ( Mutat.Res. 581 (2005) 23-34; Eur. J. Pharm. Sci. 28 (2006) 1-6).

The present invention has been conducted in various studies to develop a novel salt of vortioxetine having improved water solubility and low hygroscopicity. Surprisingly, it has been found that when vortioxetine is converted to the form of nicotinate, it is possible to not only significantly increase the water solubility of vortioxetine, but also to minimize hygroscopicity. It has also been found that vortioxetine nicotinate (ie, vortioxetine nicotinate) can be prepared in a crystalline form with good stability.

Accordingly, the present invention aims to provide a novel salt of vortioxetine, namely vortioxetine nicotinate.

In addition, an object of the present invention is to provide a method for producing the vortioxetine nicotinate.

According to one aspect of the invention, vortioxetine nicotinate is provided.

The vortioxetine nicotinate salt may be in a crystalline form. In one embodiment, the vortioxetine nicotinate may be in crystalline form with XRPD patterns showing peaks at 8.49, 11.66, 13.45, 13.75, 16.55, and 19.91 ° 2θ ± 0.2 ° 2θ. In another embodiment, the vortioxetine nicotinate can be in crystalline form with a differential scanning calorimetry (DSC) thermogram showing a melting endothermic peak at 130 ° C to 140 ° C. In another embodiment, the vortioxetine nicotinate may be in a crystalline form with a thermogravimetric analysis (TGA) thermogram showing weight loss at 170 ° C to 360 ° C.

According to another aspect of the invention, (a) vortioxetine and nicotinic acid are heated and stirred in an organic solvent, followed by stirring at room temperature; And (b) is provided a method for producing vortioxetine nicotinate comprising the step of drying the precipitate obtained in step (a).

In the production method of the present invention, the organic solvent may be selected from one or more selected from the group consisting of ethyl acetate, acetone, acetonitrile, and isopropyl alcohol, preferably ethyl acetate, acetone, or mixed solvents thereof You can.

The vortioxetine nicotinate according to the present invention not only has a high water solubility (about 5.00 mg / ml), but also has a remarkably low hygroscopicity. In addition, the vortioxetine nicotinate may be prepared in a crystalline form having excellent physicochemical and optical stability. Therefore, vortioxetine nicotinate according to the present invention can be usefully used to formulate into solid preparations such as tablets and capsules. In addition, since vortioxetine nicotinate according to the present invention can be stably maintained without changing the purity in solution, it can be usefully used to formulate a liquid formulation.

1 shows a ¹ H-NMR spectrum of vortioxetine nicotinate obtained according to the present invention.
2 shows the XRPD spectrum of vortioxetine nicotinate obtained according to the present invention.
3 shows a DSC thermogram of vortioxetine nicotinate obtained according to the present invention.
4 shows the TGA thermogram of vortioxetine nicotinate obtained according to the present invention.

The present invention provides a novel salt of vortioxetine, namely vortioxetine nicotinate. The vortioxetine nicotinate has the structure of Formula 2 below, and is also referred to as 'vortioxetine nicotinate'.

<Formula 2>

The vortioxetine nicotinate according to the invention has a high water solubility, i.e., a water solubility of about 5.00 mg / ml. In particular, the vortioxetine nicotinate has a significantly higher water solubility than vortioxetine free base (about 0.1 mg / ml), 2.5 times compared to the vortioxetine HBr salt α-form (about 2.0 mg / ml), Botioxetine HBr salt has a water solubility about 4 times higher than the β-form (1.2 mg / ml).

In addition, vortioxetine nicotinate according to the present invention exhibits significantly low hygroscopicity (hygroscopicity of about 0.05% at room temperature and accelerated conditions, respectively), and exhibits excellent physicochemical and optical stability, thereby providing solid preparations such as tablets and capsules It can be usefully used to formulate. In addition, since vortioxetine nicotinate according to the present invention can be stably maintained without changing the purity in solution, it can be usefully used to formulate a liquid formulation.

In addition, it has been found by the present invention that vortioxetine nicotinate according to the present invention can be obtained in a stable crystalline form with no change in crystal form.

In one embodiment, the vortioxetine nicotinate has an X-Ray Powder Diffraction (XRPD) pattern showing peaks at 8.49, 11.66, 13.45, 13.75, 16.55, and 19.91 ° 2θ ± 0.2 ° 2θ. It may have, for example, may have the XRPD spectrum of FIG. 2.

In another embodiment, the vortioxetine nicotinate may have a differential scanning calorimeter (DSC) thermogram showing a melting endothermic peak at 130 ° C to 140 ° C, for example, the DSC thermogram of FIG. 3. .

In another embodiment, the vortioxetine nicotinate may have a thermogravimetric analysis (TGA) thermogram showing weight loss at 170 ° C to 360 ° C, for example, the TGA thermogram of FIG. 4. .

The present invention also (a) vortioxetine and nicotinic acid heated and stirred in an organic solvent, and then stirred at room temperature; And (b) provides a method for producing vortioxetine nicotinate comprising the step of drying the precipitate obtained in step (a).

In the production method of the present invention, the organic solvent usable in step (a) may be selected from one or more of the group consisting of ethyl acetate, acetone, acetonitrile, and isopropyl alcohol. In particular, it has been found by the present invention that when ethyl acetate and / or acetone are used, a stable crystal form with no change in crystal form is obtained. Therefore, the organic solvent may be ethyl acetate, acetone, or a mixed solvent thereof.

The heating and stirring in step (a) can be carried out, for example, by stirring at a temperature of 50 ° C to 90 ° C, preferably 55 ° C to 80 ° C, for 5 minutes to 20 minutes, preferably 7 minutes to 15 minutes, , But is not limited thereto. In addition, stirring at room temperature in step (a) is performed, for example, by stirring at a temperature of 20 to 30 ° C, preferably about 25 ± 3 ° C for 10 to 25 hours, preferably 15 to 20 hours. It can be, but is not limited to.

The drying in step (b) may be performed according to a conventional drying method, for example, natural drying at room temperature, warming drying at 30 ° C to 60 ° C, drying under reduced pressure, etc. Can be adjusted accordingly.

Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are intended to illustrate the present invention, and the present invention is not limited by the following examples and test examples.

In the following examples and test examples, high-speed liquid chromatography (HPLC) analysis was performed under the following conditions.

-Analysis column: C18, 4.6 x 250 mm, 5 ㎛

-Mobile phase: Buffer / acetonitrile (gradient)

-Buffer: Take 2.00 ml of trifluoroacetic acid, put it in a 4L volumetric flask and dissolve with water to align the mark.

-Wavelength: 230 nm

-Column temperature: 35 ℃

-Flow rate: 1.0 mL / min.

-Injection volume: 20 uL

X-ray powder diffraction (XRPD) analysis was performed using PANalytical's X-pert Pro X-ray powder diffractometer, 3-40 ° using CuK _α1 line (λ _α1 = 1.54060Å) operated at 40mA, 40kV. The 2θ value of was measured at a scan rate of 3 ° per second.

Differential Scanning Calorimetry (DSC) analysis was performed using DSC 823e Differential Scanning Calorimeter from Mettler Toledo, under conditions of starting temperature -10 ° C, ending temperature 200 ° C, heating rate 10 ° C / min, nitrogen gas supply rate 50mL / min. It was measured.

Thermogravimetric analysis (TGA) was performed using Mettler Toledo's TGA / SDTA 851 thermogravimetric analyzer, and was measured under conditions of a start temperature of 30 ° C, an end temperature of 700 ° C, and a heating rate of 10 ° C / min.

Example 1

A mixture of vortioxetine (200 g, 0.67 mol) and nicotinic acid (82.5 g, 0.67 mol) in ethyl acetate (1 L) was heated and stirred at 75 ° C for 10 minutes, followed by stirring at room temperature for 18 hours. The wet body obtained by filtering the precipitated solid was dried at 50 ° C. for 12 hours to obtain 260.87 g of vortioxetine nicotinate. (Yield 92.34%)

The melting point, purity, moisture content, and ¹ H-NMR analysis result (FIG. 1) of the obtained product are as follows.

Melting Point: 133 ℃

Purity: 99.96%

Moisture content: 0.07%

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.244 (s, 3H), 2.312 (s, 3H), 3.239-3.257 (m, 4H), 3.338-3.362 (m, 4H), 6.489 -6.512 (dd, 1H), 6.872-6.913 (td, 1H), 7.017-7.037 (d, 1H), 7.085-7.109 (m, 2H), 7.157 (s, 1H), 7.255-7.274 (d, 1H) , 7.398-7.432 (dd, 1H), 8.296-8.326 (td, 1H), 8.517-8.534 (dd, 1H), 9.062-9.069 (q, 1H)

In addition, the XRPD spectrum, DSC thermogram, and TGA thermogram of the obtained product are as shown in FIGS. 2 to 4, respectively. In the measured X-ray powder diffraction spectrum, the diffraction angle (2θ), the distance (d) between the crystal planes and the relative intensity (the relative intensity of the intensity (I) of each peak to the intensity of the largest peak (I ₀ ), I / I ₀ ) is as shown in Table 1 below.

° 2θ ± 0.2 ° 2θ d I / I ₀ ° 2θ ± 0.2 ° 2θ d I / I ₀ 8.4946 10.40948 42.29 23.2583 3.82454 8.87 10.2946 8.59306 7.45 23.4659 3.79117 8.94 11.6590 7.59034 28.18 23.9929 3.70908 24.83 12.4309 7.12068 8.71 24.5511 3.62600 8.24 13.4459 6.58537 40.39 25.3207 3.51751 15.57 13.7530 6.43896 67.09 25.7344 3.46190 8.29 14.4502 6.12984 38.76 26.0958 3.41477 21.68 14.6784 6.03506 6.43 26.3291 3.38504 14.86 15.3983 5.75447 0.87 27.7128 3.21908 32.93 16.5505 5.35638 100.00 28.2799 3.15582 20.65 17.0570 5.19844 46.77 29.0013 3.07893 23.14 17.8107 4.98014 38.27 30.2065 2.95878 8.56 18.0287 4.92041 35.57 30.5692 2.92449 5.42 18.6298 4.76297 37.55 31.0087 2.88404 2.55 19.6112 4.52677 37.16 31.9864 2.79808 2.77 19.9149 4.45842 60.42 32.4813 2.75658 1.27 20.2800 4.37898 35.94 34.5267 2.59781 4.45 20.5136 4.32964 18.10 35.6985 2.51518 8.28 21.0702 4.21651 5.97 36.0369 2.49234 2.71 21.5627 4.12131 8.03 36.5460 2.45878 3.20 22.1701 4.00975 15.47 38.1276 2.36034 2.20 22.6843 3.92000 31.03 39.0068 2.30915 1.34 22.9941 3.86788 26.16

From the results of FIG. 2 and Table 1, vortioxetine nicotinate obtained according to the present invention exhibits characteristic peaks at 8.49, 11.66, 13.45, 13.75, 16.55, and 19.91 *? * Θ ± 0.2 *? * Θ It can be seen that the crystalline form has an XRPD pattern.

Example 2

A mixture of vortioxetine (10 g, 0.03 mol) and nicotinic acid (4.12 g, 0.03 mol) in acetone (50 mL) was heated and stirred at 55 ° C for 10 minutes, followed by stirring at room temperature for 18 hours. The wet body obtained by filtering the precipitated solid was dried at 50 ° C. for 12 hours to obtain 13.35 g of vortioxetine nicotinate. (Yield 94.51%)

Example 3

A mixture of vortioxetine (10 g, 0.03 mol) and nicotinic acid (4.12 g, 0.03 mol) in acetonitrile (50 mL) was heated and stirred at 80 ° C for 10 minutes, followed by stirring at room temperature for 18 hours. The wet body obtained by filtering the precipitated solid was dried at 50 ° C. for 12 hours to obtain 13.78 g of vortioxetine nicotinate. (Yield 97.57%)

Example 4

A mixture of vortioxetine (10 g, 0.03 mol) and nicotinic acid (4.12 g, 0.03 mol) in isopropyl alcohol (50 mL) was heated and stirred at 80 ° C for 10 minutes, and then stirred at room temperature for 18 hours. The wet body obtained by filtering the precipitated solid was dried at 50 ° C for 12 hours to obtain 12.64 g of vortioxetine nicotinate. (Yield 89.49%)

Test Example 1: Water solubility evaluation

The water solubility of vortioxetine nicotinate prepared in Example 1 was measured in purified water at about 20 ° C. As a result, the water solubility of vortioxetine nicotinate was about 5.00 mg / ml, and showed a significantly increased water solubility compared to that of vortioxetine free base (about 0.1 mg / ml).

Test Example 2: Stability evaluation

The stability test was performed while the vortioxetine nicotinate prepared in Example 1 was stored at room temperature conditions (about 28 ° C., relative humidity 50%) and accelerated conditions (about 40 ° C., relative humidity 75%) for 1 month. The results are shown in Table 2 below.

Specimen Constellation moisture Purity (total analog content) Crystalline Early White 0.07% 0.04% No crystal form change 1 week at room temperature White 0.12% 0.06% 2 weeks at room temperature White 0.12% 0.05% 3 weeks at room temperature White 0.11% 0.05% Normal temperature 4 weeks White 0.11% 0.04% 1 week acceleration White 0.09% 0.05% 2 weeks acceleration White 0.09% 0.04% 4 weeks acceleration White 0.12% 0.04%

As can be seen from the results in Table 2, vortioxetine nicotinate obtained according to the present invention did not show a significant change in properties, purity, and content under both room temperature and accelerated conditions. The moisture content showed only an increase of about 0.05% under room temperature conditions and accelerated conditions, respectively. Therefore, the vortioxetine nicotinate obtained according to the present invention not only has excellent physicochemical stability but also shows little hygroscopicity.

Test example  3: Light stability  evaluation

The vortioxetine nicotinate prepared in Example 1 was stored under a 4,000 LUX light source for 2 weeks to perform a light stability test to analyze the purity of vortioxetine, that is, the total related substance content and crystal form change, and the results were as follows. Table 3.

Specimen Constellation Purity (total analog content) Crystalline Early White 0.04% No crystal form change 1 week White 0.04% 2 weeks White 0.04%

As can be seen from the results in Table 3, vortioxetine nicotinate obtained according to the present invention exhibited excellent light stability.

Test example  4: Stability evaluation in solution

The vortioxetine nicotinate prepared in Example 1 was dissolved in 20% acetonitrile or purified water, and then stored at room temperature (about 28 ° C.) and light-shielding conditions for 1 month, followed by purity of vortioxetine, that is, total flexibility The material content was analyzed, and the results are shown in Table 4 below.

Specimen Purity (total analog content) Early 0.04% 20% ACN 4 weeks 0.05% Aqueous solution 4 weeks 0.05%

As can be seen from the results of Table 4, it was confirmed that the vortioxetine nicotinate obtained according to the present invention did not exhibit a significant change in purity in solution and was stable in solution.

Claims (8)

Vortioxetine nicotinate. The vortioxetine nicotinate according to claim 1 in crystalline form. The vortioxetine nicotinate salt of claim 2, having an XRPD pattern showing peaks at 8.49, 11.66, 13.45, 13.75, 16.55, and 19.91 ° 2θ ± 0.2 ° 2θ. The vortioxetine nicotinate salt of claim 2, having a differential scanning calorimeter (DSC) thermogram showing a melting endothermic peak at 130 ° C to 140 ° C. The vortioxetine nicotinate according to claim 2, having a thermogravimetric analysis (TGA) thermogram showing weight loss at 170 ° C to 360 ° C. (a) heating and stirring vortioxetine and nicotinic acid in an organic solvent, followed by stirring at room temperature; And (b) drying the precipitate obtained in step (a). The method of claim 6, wherein the organic solvent is at least one selected from the group consisting of ethyl acetate, acetone, acetonitrile, and isopropyl alcohol. The method of claim 7, wherein the organic solvent is ethyl acetate, acetone, or a mixed solvent thereof.

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