KR20190005679A - Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same - Google Patents

Abstract

The present invention provides 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine nicotinic acid salt, 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine formate, a method for manufacturing the same and a pharmaceutical composition comprising the salt. Novel salts of the present invention are excellent in stability, hygroscopicity and solubility to be stably formulated, and can be stored for a long period of time. Thus, the pharmaceutical composition containing the salts is useful for preventing or treating depression or anxiety.

Description

Novel 1- [2- (2,4-Dimethylphenylsulfanyl) phenyl] piperazine salt and a method for preparing the same The present invention relates to novel salts of 1- [2- (2,4-dimethylphenylsulfanyl) }

The present invention relates to new salts of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine, in particular nicotinate, formate, ≪ / RTI >

The 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine compound has the structure of the following formula (3).

(3)

1- [2- (2,4-Dimethylphenylsulfanyl) phenyl] piperazine or a pharmaceutically acceptable salt thereof is used as a serotonin reuptake inhibitor in the treatment of depression and anxiety, and 1- [2- (2,4 -Dimethylphenylsulfanyl) phenyl] piperazine is commercially available as Brintellix (R), which contains its hydrobromide as an active ingredient.

1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine or a pharmaceutically acceptable salt thereof is described in Korean Patent No. 10-0770194, (2,4-dimethylphenylsulfanyl) phenyl] piperazine is described.

Korean Patent No. 10-1445514, Korean Patent No. 10-1627901, Korean Patent Registration No. 10-1459168, International Patent Publication No. WO 2015-166379, WO No. 2015-114395, and WO No. 2016-079751 Have reported various salts of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine.

On the other hand, in order to maintain the homeostasis in general, the reduction of the content of the active ingredient should be suppressed from the stage of manufacturing the product to the storage period, and the increase of the impurities or the substance should be kept to a minimum.

Accordingly, the present inventors have intensively studied to improve the homeostasis of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine. As a result, unexpectedly, (2,4-dimethylphenylsulfanyl) phenyl] piperazine having the same or better physico-chemical stability than that of the compound of the present invention, non-hygroscopic and excellent solubility, .

Korean Patent No. 10-0770194 Korean Patent No. 10-1445514 Korean Patent No. 10-1627901 Korean Patent No. 10-1459168 International Patent Publication No. WO 2015-166379 International Patent Publication No. WO 2015144395 International Patent Publication No. WO2006-079751

It is therefore an object of the present invention to provide a process for the preparation of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine, which is one of the acceptable salts of 1- [2- - dimethylphenylsulfanyl) phenyl] piperazine and a process for the preparation thereof.

It is another object of the present invention to provide a pharmaceutical composition comprising the novel salt of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine.

In order to solve the above problems, the present invention provides a novel salt of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine, a process for producing the same, and a pharmaceutical composition comprising the salt.

Hereinafter, the present invention will be described in more detail.

1- [2- (2,4- Dimethylphenylsulfanyl ) Phenyl] piperazine Nicotinate  And a method for producing the same

In one embodiment, the present invention relates to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt represented by the following formula (1).

[Chemical Formula 1]

In the present invention, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate is preferably in a crystalline form.

Further, in a preferred embodiment, the present invention relates to an X-ray powder diffraction pattern characterized in that the 2? Diffraction angles are preferably 8.5 ° ± 0.2 °, 13.7 ° ± 0.2 °, 16.5 ° ± 0.2 ° and 19.9 The diffraction pattern has a diffraction pattern of &thetas; +/- 0.2 DEG, and more preferably 8.5 DEG +/- 0.2 DEG, 11.6 DEG +/- 0.2 DEG, 13.4 DEG +/- 0.2 DEG, 13.7 DEG +/- 0.2 DEG, 14.4 DEG +/- 0.2 DEG, 16.5 DEG +/- 0.2 DEG, 17.0 占 쏙옙 0.2 占 18.0 占 0.2 占 19.6 占 0.2 占 19.9 占 0.2 占 20.2 占 0.2 占 20.1 占 0.2 占 22.6 And has a diffraction pattern of ± 0.2 °, 23.0 ° ± 0.2 °, 24.0 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.2 ° ± 0.2 °, 27.7 ° ± 0.2 ° and 29.0 ° ± 0.2 °.

The purity of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinic acid salt of the present invention is about 99.90% or more and the rate of temperature increase is 5 ° C / min in differential scanning calorimetry , An initiation temperature of 133.3 ° C (oneset) and an endothermic peak of 134.0 ± 1.5 ° C were observed. As a result of checking the number of water molecules contained in the Karl-Fisher moisture measurement method, 1- [2- (2, Dimethylphenylsulfanyl) phenyl] piperazine nicotinate was found to be an anhydrous with a water content of 0.06%.

The 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt of the present invention has physicochemical stability, non-hygroscopicity and solubility of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide, which is a known salt of piperazine, in particular in the case of solubility, 1- [2- (2,4- Dimethylphenylsulfanyl) phenyl] piperazine hydrobromide. Therefore, the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt of the present invention can be effectively used as an active ingredient of a therapeutic agent for depression or anxiety.

In another embodiment, the present invention relates to a process for the preparation of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl] piperazine which comprises crystallizing by reacting 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine with nicotinic acid in a reaction solvent, 4-dimethylphenylsulfanyl) phenyl] piperazine nicotinic acid salt in the form of crystals.

In the production process of the present invention, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is commercially available or commercially available from Korean Patent No. 10-1627901 And nicotinic acid, which is also commercially available, can be used.

In the production process of the present invention, the amount of nicotinic acid is 0.8 to 2.0 equivalents, preferably 0.9 to 1.1 equivalents based on 1 equivalent of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine. If the amount of nicotinic acid is less than 0.8 equivalents, the yield of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinic acid salt decreases. If the amount of nicotinic acid is more than 2.0 equivalents, - (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt content and increase the cost.

In the production method of the present invention, the reaction solvent can be mostly used if it is a solvent which does not participate in the reaction for forming 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate, (Methyl ether, t-butyl methyl ether, etc.), nitriles (acetonitrile, propionitrile and the like), and the like. Preferably one or more solvents selected from the group consisting of t-butyl methyl ether and acetonitrile. The solvent used in the present invention is preferably used alone, but it is also possible to use two or more kinds of optional solvents. The amount of the solvent used in the reaction for producing 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate is 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine 1 And is 1 to 30 times by volume, preferably 5 to 20 times by volume.

In the production process of the present invention, the temperature for the production of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate is 0 to 70 ° C, preferably 10 to 45 ° C.

In one specific embodiment, in the production process according to the present invention, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is dissolved in a reaction solvent in the reaction solvent, Nitric acid may be added while maintaining the temperature range. The method for adding nicotinic acid to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is not particularly limited, but 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] Piperazine may be added and dissolved by stirring, and then nicotinic acid may be added at a time, or a solid may be added in portions.

1- [2- (2,4- Dimethylphenylsulfanyl ) Phenyl] piperazine Formate  And a method for producing the same

In another aspect, the present invention relates to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate salt represented by the following general formula (2).

(2)

In the present invention, the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate salt is preferably in a crystalline form.

Further, in a preferred embodiment, the present invention relates to an X-ray powder diffraction pattern in which the 2? Diffraction angles are 9.8 占 .2 占, 12.7 占 쏙옙 0.2, 16.4 占 쏙옙 0.2, 19.7 占 쏙옙 0.2 ° and 22.7 ° ± 0.2 °, and more preferably 9.8 ° ± 0.2 °, 12.7 ° ± 0.2 °, 14.8 ° ± 0.2 °, 16.4 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.7 ° ± 0.2 ° °, 21.9 ° ± 0.2 °, 22.7 ° ± 0.2 °, 23.5 ° ± 0.2 °, 24.5 ° ± 0.2 ° and 28.7 ° ± 0.2 °.

Further, the purity of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate salt of the present invention is about 99.80% or more and the rate of temperature increase is 5 ° C / min in differential scanning calorimetry , An initiation temperature of 144.3 ° C (oneset) and an endothermic peak of 144.9 ± 1.5 ° C and 147.7 ± 1.5 ° C were observed. As a result of checking the number of water molecules contained in the Karl-Fisher moisture measurement method, The 2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formic acid salt was found to be anhydrous with a water content of 0.10%.

The 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate of the present invention is also characterized by its physicochemical stability, non-hygroscopicity and solubility in the known 1- [2- (2,4-dimethylphenylsulfanyl ) Phenyl] piperazine salt, which is the same as or better than 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide. Thus, the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate of the present invention can be usefully used as an active ingredient of a therapeutic agent for depression and anxiety.

The present invention relates to a process for the preparation of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine which comprises crystallizing by reacting 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine with formic acid in a reaction solvent, Phenyl] piperazine < / RTI > formate.

In the production process of the present invention, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is commercially available or commercially available from Korean Patent No. 10-1627901 And formic acid can also be used commercially.

In the production process of the present invention, the amount of formic acid is 0.9 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents based on 1 equivalent of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine. If the amount of formic acid is less than 0.9 equivalents, the yield of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formic acid salt decreases. If the amount is more than 3.0 equivalents, Which can lead to an increase in cost.

In the production method of the present invention, the reaction solvent can be mostly used if it is a solvent that does not participate in the formation reaction of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate. For example, (Methyl ether, t-butyl methyl ether, etc.), nitriles (acetonitrile, propionitrile and the like), and the like. Preferably, t-butyl methyl ether or acetonitrile is used. The solvent used in the present invention is preferably used alone, but it is also possible to use two or more kinds of optional solvents. The amount of the solvent used in the reaction for producing 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate is 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine 1 And is 1 to 30 times by volume, preferably 5 to 20 times by volume.

In the production process of the present invention, the temperature for the production of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate is 0 to 70 캜, preferably 10 to 45 캜.

In one specific embodiment, in the production process according to the present invention, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is dissolved in a reaction solvent in the reaction solvent, Formic acid may be added while maintaining the temperature range. The method of adding formic acid to 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is not particularly limited, but a method of adding 1- [2- (2,4-dimethylphenylsulfanyl) Piperazine may be added and dissolved by stirring, and then formic acid may be added at once or liquid may be added in portions.

1- [2- (2,4- Dimethylphenylsulfanyl ) Phenyl] piperazine Nicotinate  And / or 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine Formate  Containing pharmaceutical composition

In another embodiment, the present invention relates to the aforementioned 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinate and / or 1- [2- (2,4-dimethylphenylsulfanyl) Phenyl] piperazine formate. ≪ / RTI > It is known that 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine is already used as a serotonin reuptake inhibitor in the treatment of depression or anxiety, and its pharmaceutically acceptable salt, The pharmaceutical composition comprising 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate or 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate, For the prevention or treatment of depression or anxiety. Preferably, the pharmaceutical composition according to the present invention contains the above 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt or 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] Piperazine formate, which may be formulated into various oral or parenteral preparations according to known methods. The pharmaceutically acceptable carrier, excipient and / or excipient may be formulated into a variety of oral or parenteral formulations according to known methods.

According to the present invention, the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt and the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] Physical and chemical stability, hygroscopicity and solubility.

Figure 1 shows the XRD pattern of the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinate prepared according to Example 1.
FIG. 2 shows a differential scanning calorimetry (DSC) analysis of the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate prepared according to Example 1. FIG.
FIG. 3 shows a hydrogen nuclear magnetic resonance spectrum (NMR) analysis chart of the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate prepared according to Example 1. FIG.
4 shows the XRD pattern of the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate salt prepared according to Example 2. Fig.
FIG. 5 shows a differential scanning calorimetry (DSC) analysis of the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate prepared according to Example 2. FIG.
6 shows a hydrogen nuclear magnetic resonance (NMR) spectral analysis of the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate prepared according to Example 2. FIG.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited to the following examples.

Hereinafter, the manufacturer of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine used in the examples is a product of Shandong Kangmeile Pharmaceutical Technology Co., Ltd .; reagents and solvents Were purchased from Sigma, Aldrich.

Example 1: 1 - [2- (2,4- Dimethylphenylsulfanyl ) Phenyl] piperazine Nicotinate  Manufacture of crystal form

20 g of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine was dissolved in 400 ml of t-butyl methyl ether and the temperature was raised to 40 to 45 ° C. 7.4 g of nicotinic acid was added thereto. And crystallized with stirring for 2 to 3 hours while maintaining the temperature at 40 캜 to 45 캜. The temperature of the mixed solution was cooled to 20 ° C to 25 ° C and agitated for 1 hour to agitate the crystals. The solid was filtered and washed with 100 ml of t-butyl methyl ether. Vacuum drying at 30 ° C yielded 23.9 g (84.7%) of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinate crystal.

_{^{1 H NMR (400MHz, CD 3}} OD): 9.07 (dd, 1H); 8.55 (dd, 1 H); 8.33 (dt, 1 H); 7.44 (ddd, 1 H); 7.30 (d, 1 H); 7.20 (bs, 1 H); 7.16-7.10 (m, 2H); 7.06 (ddd, 1 H); 6.93 (ddd, 1 H); 6.53 (dd, 1 H); 3.38-3.35 (m, 4H); 3.27 (dd, 4H); 2.35 (s, 3 H); 2.27 (s, 3 H)

Example 2: 1 - [2- (2,4- Dimethylphenylsulfanyl ) Phenyl] piperazine Formate  Manufacture of crystal form

20 g of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine was dissolved in 400 ml of t-butyl methyl ether and the temperature was raised to 40 to 45 ° C. 3.39 g of formic acid was added thereto for 5 minutes. And the mixture was crystallized with stirring for 1 to 2 hours while maintaining the temperature at 40 ° C to 45 ° C. The temperature of the mixed solution was cooled to 25 ° C to 30 ° C and agitated for 1 hour to aged crystals. The solid was filtered and washed with 100 ml of t-butyl methyl ether. And dried under vacuum at 30 캜 to obtain a crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate (22.4 g, 97.0%).

¹ H NMR (400 MHz, CD ₃ OD): 8.54 (s, 1 H); 7.30 (d, 1 H); 7.20 (bs, 1 H); 7.17-7. 11 (m, 2H); 7.07 (d, 1 H); 6.94 (ddd, 1 H); 6.53 (dd, 1 H); 3.36-3.33 (m, 4H); 3.27 (dd, 4H); 2.34 (s, 3 H); 2.28 (s, 3 H)

Comparative Example : 1- [2- (2,4- Dimethylphenylsulfanyl ) Phenyl] piperazine Hydrobromide  Produce

1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide was prepared according to the method described in Korean Patent No. 10-1627901.

Test Example  1: Stability test (acceleration)

The stability test of medicines confirms the stability under certain conditions in order to set the storage method and the period of use of the medicines.

The crystalline form of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinic acid salt of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] Piperazine salt of formate was compared with the stability of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide prepared in Comparative Example. Specifically, the stability test under accelerated conditions was conducted according to ICH guidelines and analyzed using high performance liquid chromatography (HPLC) analysis. The results are shown in Table 1 below.

Accelerated stability (temperature 40 ℃ ± 2 ℃, relative humidity 75% ± 5%, sealing) 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Hydrobromide 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Nicotinate 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Formate Initial 99.958% 99.996% 99.817% 3 days 99.954% 99.994% 99.798% 14 days 99.954% 99.994% 99.796% 20 days 99.957% 99.991% 99.787% 34 days 99.956% 99.989% 99.798%

Referring to Table 1, it was confirmed that the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinate, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] The result of the accelerated stability test for 34 days under the above accelerated conditions showed that the salt had a purity of 0.01% or less. Thus, the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nitric acid The crystalline form of the salt, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formic acid salt, was found to be very stable because of the large purity change under accelerated conditions. And can be stored for a long period of time.

Test Example  2: Hygroscopicity test

Non-hygroscopic is one of the most important factors for the processing and storage of pharmaceuticals. To confirm whether the compound can be used as a raw material for pharmaceuticals, 1- [2- (2,4-dimethyl Phenylsulfanyl) phenyl] piperazine nicotinic acid salt, and the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate was subjected to a hygroscopicity test. The results are shown in Table 2 below.

Hygroscopicity test (temperature 25 ° C ± 2 ° C, relative humidity 80% ± 5%, 24 hours, opened) 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Hydrobromide 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Nicotinate 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Formate Initial 0.27% 0.06% 0.10% 24 hours 0.30% 0.08% 0.08%

From the pharmaceutical point of view, it is desirable that the drug retains its initial moisture and morphology without absorbing moisture even in a high moisture environment.

Referring to Table 2, it was confirmed that the crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinate, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] All of the crystals of the salt showed a non-hygroscopic property at 25 ° C ± 2 ° C, relative humidity 80% ± 5% and water content (KF moisture%) for 24 hours.

Test Example  3: Solubility evaluation

Solubility is an important factor in the commercialization of drugs. Even if the effect is excellent, product development may be difficult due to low solubility. If the solubility is low, it precipitates and remains in a precipitated state, which is a large factor for reducing oral absorption. The crystalline form of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinic acid salt of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] The solubility of the crystalline form of piperazine formate was evaluated by pH. As the control group, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide prepared in Comparative Example was used. The results are shown in Table 3 below.

pH Solubility (mg / ml) 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Hydrobromide 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Nicotinate 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Formate 1.2 0.29 707 525 4.0 0.53 709 321 5.2 0.22 878 409 6.8 0.25 890 555 Purified water 0.51 860 418

The crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinate in purified water at pH 1.2, pH 4.0, pH 5.2 and pH 6.8 is 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide having a solubility of 1337 to 3990 times higher than that of 1- [2- (2,4-dimethylphenylsulfanyl) Was found to have a solubility of 605 to 2220 times higher than 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide. Therefore, the crystalline form of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt of the present invention and the crystalline form of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] Greatly improves the physicochemical properties of the drug, and is very advantageous for absorption and elution of the drug, which is advantageous for commercialization.

Test Example  4: X-ray Diffraction spectroscopy  analysis

The crystalline form of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinic acid salt of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] The crystalline form of the piperazine formate salt was analyzed using an X-ray diffractometer. The XRD measurement conditions were as follows. These results are shown in Fig. 1 (1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinic acid salt) - [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate).

One) Device: D8 Advance (Bruker)

2) Detector: Lynxeye

3) Wavelength of X-ray light source: 1.5405A

Test Example  5: differential scanning calorie ( DSC ) analysis

The crystalline form of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinic acid salt of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] The physical properties of the crystalline form of the piperazine formic acid salt were confirmed. The crystalline form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinate, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate was subjected to DSC analysis under nitrogen Respectively. The results are shown in Table 4 and FIG. 2 (1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt) and FIG. 5 (1- [2- (2,4- ) Phenyl] piperazine formate). The differential scanning calorimeter measurement conditions are as follows.

One) Device: DSC 823e (Mettler Toledo)

2) Measuring range: 25 to 350 ° C

3) Temperature rise interval: 5 ° C / min

1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Hydrobromide 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Nicotinate 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine
Formate Onset 229.5 133.3 144.3 Peak 230.8 134.0 144.9, 147.7

Test Example  6: Hydrogen Nuclear Magnetic Resonance Spectrum (NMR) Analysis

The crystalline form of the 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinic acid salt of the present invention prepared in Examples 1 and 2, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl ] Hydrogen Nuclear Magnetic Resonance Spectrum (NMR) analysis was performed on the crystal form of the piperazine formate salt. The results are shown in FIG. 3 (1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinicotinate) and FIG. 6 (1 - [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate).

One) Device: Bruker Model AVANCE II 400

2) Measuring range: -0.5 ~ 10ppm

3) Number of scans: 16

Claims (21)

1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate represented by the following formula (1):
[Chemical Formula 1]

. The 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt according to claim 1, which is crystalline. The pharmaceutical composition according to claim 2, wherein the crystalline 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazinic acid salt has the following composition: 8.5 ° ± 0.2 °, 13.7 ° ± 0.2 °, 16.5 ° ± 0.2 ° and 19.9 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate, which exhibits an XRD pattern with a peak at 2 [theta] of +0.2 [deg.]. The pharmaceutical composition according to claim 2, wherein the crystalline 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt has 8.5 ° ± 0.2 °, 11.6 ° ± 0.2 °, 13.4 ° ± 0.2 °, 13.7 20.0 +/- 0.2, 14.4 +/- 0.2, 16.5 +/- 0.2, 17.0 +/- 0.2, 18.0 +/- 0.2, 18.6 +/- 0.2, 19.6 +/- 0.2, 19.9 +/- 0.2, 0.2 °, 20.5 ° ± 0.2 °, 22.1 ° ± 0.2 °, 22.6 ° ± 0.2 °, 23.0 ° ± 0.2 °, 24.0 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.2 ° ± 0.2 °, 27.7 ° ± 0.2 ° And an XRD pattern having a peak at 2 [theta] of 29.0 [deg.] + - 0.2 [deg.]. The 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt according to claim 2, which has an endothermic peak at 134.0 ± 1.5 ° C in a differential scanning calorimetry (DSC) analysis. The 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate salt according to claim 1, which is an anhydride. reacting 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine with nicotinic acid in at least one organic solvent selected from the group consisting of t-butyl methyl ether and acetonitrile, Process for producing crystalline 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate represented by formula (1)
[Chemical Formula 1]

. 8. The method according to claim 7, wherein the amount of nicotinic acid is 0.8-2.0 equivalents based on 1 equivalent of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine. , 4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate crystal form. 8. The process according to claim 7, wherein the amount of the organic solvent is 1- to 30-fold by volume relative to 1 weight of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine. (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate crystal form. The process for producing 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate crystal form according to claim 7, wherein the reaction temperature is 0 to 70 ° C. 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate represented by the following formula 2:
(2)

. The 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate salt according to claim 11, which is crystalline. 13. The method according to claim 12, wherein the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate is 9.8 DEG +/- 0.2 DEG, 12.7 DEG +/- 0.2 DEG, 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate, which exhibits an XRD pattern having peaks at 2 [theta] of [theta] + 0.2 deg. And 22.7 deg. 13. The method according to claim 12, wherein the crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate is 9.8 DEG +/- 0.2 DEG, 12.7 DEG +/- 0.2 DEG, The peaks were measured in the range of ± 0.2 °, 18.5 ° ± 0.2 °, 19.7 ° ± 0.2 °, 21.9 ° ± 0.2 °, 22.7 ° ± 0.2 °, 23.5 ° ± 0.2 °, 24.5 ° ± 0.2 ° and 28.7 ° ± 0.2 ° 2θ 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate. The process according to claim 12, characterized by having an endothermic peak at 144.9 ± 1.5 ° C and 147.7 ± 1.5 ° C in a differential scanning calorimetry (DSC) analysis of 1- [2- (2,4- Rajin formate. The 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate salt according to claim 11, which is an anhydride. reacting 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine with formic acid in at least one organic solvent selected from the group consisting of t-butyl methyl ether and acetonitrile, Process for producing crystal form of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate represented by formula (2)
(2)

. 18. The compound according to claim 17, wherein the amount of formic acid is 0.9 to 3.0 equivalents based on 1 equivalent of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine. 4-dimethylphenylsulfanyl) phenyl] piperazine formate crystal form. 18. The process according to claim 17, wherein the amount of the organic solvent is 1- to 30-fold by volume relative to 1 weight of 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine. (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate crystal form. The process for producing 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine formate crystal form according to claim 17, wherein the reaction temperature is 0 to 70 ° C. A pharmaceutical composition comprising 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] piperazine nicotinate according to claim 1 or 1- [2- (2,4-dimethylphenylsulfanyl) phenyl] A pharmaceutical composition for the prevention or treatment of depression or anxiety, which comprises a salt of Rajin Formate.

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