TWI754605B - Salts of indole derivatives and their crystals - Google Patents

Abstract

The subject of the present invention is to provide a 4-(3-cyanoindol-1-yl)- Different forms of 2-hydroxybenzoic acid. The present invention provides a 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid which has excellent solubility and other physical properties, is useful as a raw material for pharmaceuticals, and is suitable for industrial production of pharmaceuticals ． Sodium salt and method for producing the same.

Description

Salts of indole derivatives and their crystals

The present invention relates to a formula that has Xanthine oxidase inhibitory activity and is useful as a preventive or therapeutic drug for diseases caused by abnormal serum uric acid level:

The represented compound (chemical name: 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. sodium salt; hereinafter referred to as compound (A)) and a method for producing the same.

In Patent Document 1, there is disclosed a kind of formula that has xanthine oxidase inhibitory activity and is useful as a preventive or therapeutic drug for a disease caused by abnormal serum uric acid level:

The represented compound (hereinafter, referred to as compound (B)). However, with regard to its sodium salt, only It is described as a common salt, and the properties of the compound (A) are not reported at all.

Patent Document 1: International Publication No. 2008/126898

Crystallization is generally expected as a drug substance. However, as a result of intensive research conducted by the present inventors, the crystal of the compound (B) described in Patent Document 1 has a problem in water solubility as described in the following Test Example 1 (solubility test). When the solubility in water is poor, the drug absorption becomes a problem in many cases. In addition, in order to use it as a pharmaceutical, there are cases where a preparation means is required. Therefore, in order to use the compound (B) as a drug substance, improvement in solubility is required.

An object of the present invention is to provide a different form of the above-mentioned compound (B) which has high solubility and is suitable for use as a drug substance.

In view of the above problems, the inventors of the present invention conducted intensive research and found that 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. The sodium salt has extremely excellent solubility, and also has excellent crystallinity and storage stability, so it is a compound suitable as a drug substance, and the present invention has been completed.

That is, means for solving the above-mentioned problems are as follows.

(1) A compound represented by the following formula,

(2) The compound according to (1) above, which is crystalline.

(3) The compound according to the above ( ² ), which is 120.0±0.2, 116.9±0.2 and 120.0±0.2, 116.9±0.2 and Form A crystal with a peak at 109.4±0.2.

(4) The compound according to (2) or (3) above, which is an A-type crystal characterized by 1 to 3 physical properties selected from the group consisting of the following (a1) to (a3): (a1) Powder X-ray diffraction pattern including peaks at diffraction angles (2θ(°)) of 6.8±0.2, 13.2±0.2 and 16.2±0.2; (a2) including 2228±1, 1535±1 and 1516±1 Fourier Transform (FT, Fourier Transform)-Raman spectrum of the peak at a wavenumber (cm ⁻¹ ) of 1; and (a3) Differential calorimetry spectrum with the onset temperature of the endothermic peak around 316°C.

(5) The compound according to the above (2), which has B peaks at 162.4±0.2, 135.2±0.2 and 116.2±0.2 as chemical shift values (δ (ppm)) in the ¹³ C solid-state NMR spectrum form crystals.

(6) The compound according to the above (2) or (5), which is a B-shaped crystal characterized by 1 to 3 physical properties selected from the group consisting of the following (b1) to (b3): (b1) Powder X-ray diffraction pattern including peaks at diffraction angles (2θ(°)) of 6.2±0.2 and 12.4±0.2; (b2) including 2238±1, 1601±1, 1540±1 and 1516±1 FT-Raman spectrum of the peak at the wavenumber (cm ⁻¹ ) of 1; and (b3) Differential thermal analysis spectrum with the onset temperature of the endothermic peak around 60°C and 284°C.

(7) The compound of (2) above, which has C peaks at 140.1±0.2, 134.3±0.2 and 122.0±0.2 as chemical shift values (δ (ppm)) in the ¹³ C solid-state NMR spectrum form crystals.

(8) The compound according to (7) above, which is a C-shaped crystal characterized by 1 to 3 physical properties selected from the group consisting of (c1) to (c3) below: (c1) containing Powder X-ray diffraction patterns of peaks at diffraction angles (2θ(°)) of 5.4±0.2, 11.9±0.2 and 14.2±0.2; (c2) include wave numbers of 2235±1, 1535±1 and 1509±1 (cm ^-1 ) FT-Raman spectrum of the peak; and (c3) differential thermal analysis spectrum with the onset temperature of the endothermic peak around 285°C.

(9) The compound of (2) above, which has D peaks at 127.3±0.2, 118.0±0.2 and 112.3±0.2 as chemical shift values (δ (ppm)) in the ¹³ C solid-state NMR spectrum form crystals.

(10) The compound of (9) above, which is a D-shaped crystal characterized by 1 to 3 physical properties selected from the group consisting of (d1) to (d3) below: (d1) contains Powder X-ray diffraction pattern of peaks at diffraction angles (2θ(°)) of 5.5±0.2, 13.7±0.2 and 14.2±0.2; (d2) includes wave numbers of 2230±1, 1532±1 and 1508±1 (cm ⁻¹ ) FT-Raman spectrum of the peak; and (d3) differential thermal analysis spectrum with the onset temperature of the endothermic peak around 279°C.

(11) The compound according to the above (2), which is 176.4±0.2, 163.3±0.2, 141.2±0.2, ^136.5 ±0.2, 176.4±0.2, 163.3±0.2, 141.2±0.2, 136.5±0.2, A-shaped crystals with peaks at 132.4±0.2, 126.8±0.2, 123.5±0.2, 120.0±0.2, 116.9±0.2, 111.4±0.2, 109.4±0.2 and 85.5±0.2.

(12) The compound according to the above ( ² ), which is 176.6±0.2, 174.4±0.2, 163.6±0.2, 162.4±0.2, 176.6±0.2, 174.4±0.2, 163.6±0.2, 162.4±0.2, B-shaped crystals with peaks at 141.0±0.2, 135.2±0.2, 132.5±0.2, 128.6±0.2, 126.5±0.2, 123.6±0.2, 121.5±0.2, 118.6±0.2, 116.2±0.2, 109.7±0.2 and 86.7±0.2 .

( ¹³ ) The compound according to the above (2), which is 176.5±0.2, 163.4±0.2, 139.4±0.2, 133.0±0.2, 176.5±0.2, 163.4±0.2, 139.4±0.2, 133.0±0.2, D-shaped crystals with peaks at 127.3±0.2, 123.1±0.2, 121.4±0.2, 118.0±0.2, 112.3±0.2, 109.9±0.2 and 88.9±0.2.

(14) The compound according to any one of (1) to (13) above, which is used as a pharmaceutical agent.

(15) The compound according to any one of (1) to (13) above, which is used for the prevention or treatment of diseases caused by abnormal serum uric acid levels.

(16) A method for preventing or treating a disease caused by abnormal serum uric acid level, characterized in that an effective amount of the compound according to any one of (1) to (13) above is administered.

(17) A pharmaceutical composition comprising the compound according to any one of (1) to (15) above and a pharmacologically acceptable pharmaceutical additive.

Other aspects of the present invention relate to the following (18) to (27) and the like.

(18) The compound according to (2) above, which has characteristic peaks at 6.8, 13.2, 16.2, 26.2 and 27.8 as diffraction angles (2θ(°)) in a powder X-ray diffraction diagram.

(19) The compound of (2) above, wherein in the ¹³ C solid-state NMR spectrum, as chemical shift values (δ (ppm)), 176.37, 163.32, 141.18, 136.46, 132.42, 126.81, 123.47, 119.95, There are characteristic peaks at 116.88, 111.44, 109.43 and 85.54.

(20) The compound according to the above (2), which has an endothermic peak in the vicinity of 314°C in a differential thermogram.

(21) The compound according to the above (2), wherein in the powder X-ray diffraction pattern, as The diffraction angle (2θ(°)) has characteristic peaks at 6.2, 12.4, 14.4, 19.1 and 28.9.

(22) The compound according to (2) above, wherein in the ¹³ C solid-state NMR spectrum, as chemical shift values (δ (ppm)), 176.59, 174.36, 163.61, 162.42, 140.98, 135.24, 132.47, 128.64, There are characteristic peaks at 126.54, 123.55, 121.53, 118.55, 116.21, 109.73 and 86.73.

(23) The compound according to the above (2), which has endothermic peaks around 78°C and 292°C in a differential thermogram.

(24) The compound according to (2) above, which has characteristic peaks at 13.7, 24.1, 27.0, 27.5, and 28.9, which are diffraction angles (2θ(°)), in a powder X-ray diffraction diagram.

(25) The compound according to (2) above, wherein in the ¹³ C solid-state NMR spectrum, as chemical shift values (δ (ppm)), 176.54, 163.42, 139.43, 133.02, 127.27, 123.11, 121.41, 118.03, There are characteristic peaks at 112.30, 109.86 and 88.90.

(26) The compound according to the above (2), which has an endothermic peak in the vicinity of 290°C in a differential thermogram.

(27) A pharmaceutical composition containing the compound according to any one of the above (18) to (26) as an active ingredient.

The compound (A) of the present invention has excellent solubility, crystallinity and storage stability. In addition, the crystal of the compound (A) is excellent in fluidity, and is a crystal that is easy to handle during formulation, for example.

FIG. 1 is a powder X-ray diffraction pattern of the A-type crystal obtained in Example 1. FIG. The vertical axis represents the diffraction intensity of X-rays, and the horizontal axis represents the diffraction angle (2θ(°)).

FIG. 2 is a powder X-ray diffraction pattern of the B-shaped crystal obtained in Example 2. FIG. The vertical axis represents the diffraction intensity of X-rays, and the horizontal axis represents the diffraction angle (2θ(°)).

3 is a powder X-ray diffraction pattern of the D-shaped crystal obtained in Example 3. FIG. The vertical axis represents the diffraction intensity of X-rays, and the horizontal axis represents the diffraction angle (2θ(°)).

4 is a graph of TG-DTA measurement of the A-type crystal obtained in Example 1. FIG. The vertical axis (left) represents the weight (%) in the thermogravimetric (TG) curve, the vertical axis (right) represents the heat flux (μV) in the differential thermal analysis (DTA) curve, and the horizontal axis represents the temperature (°C).

5 is a graph of TG-DTA measurement of the B-type crystal obtained in Example 2. FIG. The vertical axis (left) represents the weight (%) in the thermogravimetric (TG) curve, the vertical axis (right) represents the heat flux (μV) in the differential thermal analysis (DTA) curve, and the horizontal axis represents the temperature (°C).

6 is a graph of TG-DTA measurement of the D-shaped crystal obtained in Example 3. FIG. The vertical axis (left) represents the weight (%) in the thermogravimetric (TG) curve, the vertical axis (right) represents the heat flux (μV) in the differential thermal analysis (DTA) curve, and the horizontal axis represents the temperature (°C).

7 is a ¹³ C solid-state NMR spectrum of the A-type crystal obtained in Example 1. FIG. The vertical axis represents the intensity, and the horizontal axis represents the chemical shift value (δ (ppm)).

8 is a ¹³ C solid state NMR spectrum of the B-type crystal obtained in Example 2. FIG. The vertical axis represents the intensity, and the horizontal axis represents the chemical shift value (δ (ppm)).

9 is a ¹³ C solid-state NMR spectrum of the D-shaped crystal obtained in Example 3. FIG. The vertical axis represents the intensity, and the horizontal axis represents the chemical shift value (δ (ppm)).

10 is a powder X-ray diffraction pattern of the C-shaped crystal obtained in Example 4. FIG. The vertical axis represents the diffraction intensity of X-rays, and the horizontal axis represents the diffraction angle (2θ(°)).

11 is a graph of TG-DTA measurement of the C-shaped crystal obtained in Example 4. FIG. The vertical axis (left) represents the weight (%) in the thermogravimetric (TG) curve, the vertical axis (right) represents the heat flux (μV) in the differential thermal analysis (DTA) curve, and the horizontal axis represents the temperature (°C).

12 is a ¹³ C solid state NMR spectrum of the C-shaped crystal obtained in Example 4. FIG. The vertical axis represents the intensity, and the horizontal axis represents the chemical shift value (δ (ppm)).

13 is an FT-Raman spectrum diagram of the A-type crystal obtained in Example 1. FIG. The vertical axis represents the intensity, and the horizontal axis represents the wave number (cm ^-1 ).

14 is an FT-Raman spectrum diagram of the B-shaped crystal obtained in Example 2. FIG. The vertical axis represents the intensity, and the horizontal axis represents the wave number (cm ^-1 ).

15 is an FT-Raman spectrum chart of the C-shaped crystal obtained in Example 4. FIG. The vertical axis represents the intensity, and the horizontal axis represents the wave number (cm ^-1 ).

16 is an FT-Raman spectrum diagram of the D-shaped crystal obtained in Example 3. FIG. The vertical axis represents the intensity, and the horizontal axis represents the wave number (cm ^-1 ).

17 is a powder X-ray diffraction pattern of a crystal of Compound (B) obtained in Comparative Example 1. FIG. The vertical axis represents the diffraction intensity of X-rays, and the horizontal axis represents the diffraction angle (2θ(°)).

18 is a powder X-ray diffraction pattern of the crystal of benzathine salt obtained in Comparative Example 2. FIG. The vertical axis represents the diffraction intensity of X-rays, and the horizontal axis represents the diffraction angle (2θ(°)).

Fig. 19 shows the water adsorption and desorption isotherms of the A-form crystals. Solid lines represent adsorption isotherms and dashed lines represent desorption isotherms. The vertical axis represents mass change (%), and the horizontal axis represents relative humidity (%RH).

Fig. 20 shows the moisture adsorption and desorption isotherms of crystals of compound (B). Solid lines represent adsorption isotherms and dashed lines represent desorption isotherms. The vertical axis represents mass change (%), and the horizontal axis represents relative humidity (%RH).

The compound (A) of the present invention can be produced, for example, by the following method.

烷之混合液並加熱溶解，進行熱過濾(hot filtration)而獲得溶液，將所獲得之溶液冷凍乾燥後，對所獲得之固體添加乙腈並加以混合，自混合物中取出固體，並進行乾燥。 For example, compound (B) in a free state, which can be produced according to the method described in Patent Document 1 or according to the method, is mixed with an equal amount (1.0 equivalent) or a slight excess of a base in an organic solvent/water mixed solvent and Heated, and the solid precipitated after cooling was collected by filtration. The obtained solid is dried by air drying, heating, or (and) reduced pressure in a laboratory environment (about 25°C/50% relative humidity) as needed, and stored under humidified conditions after drying as needed. , whereby compound (A) can be produced. As a base, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate etc. are mentioned, Preferably it is sodium hydroxide. As an organic solvent, methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile, tetrahydrofuran, etc. are mentioned. In the mixed solvent of organic solvent and water, in the case of obtaining A-type crystals, it is preferable to increase the ratio of the organic solvent, and in the case of obtaining B-type crystals, it is preferable to increase the ratio of water. As the drying conditions for crystals, in the case of obtaining B-shaped crystals, it is preferable to air-dry or dry in a laboratory environment (about 25°C/50% relative humidity), and then store them under humidified conditions. In addition, D-type crystals can also be produced, for example, by adding water and 1,4-di-

The mixed solution of alkane was heated and dissolved, and hot filtration was performed to obtain a solution. After the obtained solution was freeze-dried, acetonitrile was added to the obtained solid and mixed, and the solid was taken out from the mixture and dried.

The compound (A) of the present invention also includes a solvate with a hydrate or a solvent acceptable for pharmaceuticals.

The compound (A) of the present invention has a uric acid production inhibitory effect, and is useful as a preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels.

A solid pharmaceutical composition can be prepared by mixing the compound (A) of the present invention with a conventional formulation carrier.

These pharmaceutical compositions can be produced by mixing appropriate pharmaceutical additives such as excipients, disintegrants, binders, lubricants, etc. according to the dosage form according to the usual preparation method, and according to the Regularly adjust.

For example, a powder is prepared by adding appropriate excipients, lubricants, etc. to the active ingredient as necessary, and mixing well to obtain a powder. For example, lozenges are made by adding appropriate excipients, disintegrants, binders, lubricants, etc. to the active ingredients, and tableting according to conventional methods to prepare lozenges, and further coating as appropriate to prepare lozenges. Film-coated tablets, sugar-coated tablets, enteric-coated tablets, etc. For example, capsules are prepared by adding appropriate excipients, lubricants, etc. to the active ingredients, mixing them thoroughly, or forming granules or fine granules according to conventional methods, and filling them into appropriate capsules to prepare capsules. Furthermore, when such a preparation is orally administered, it can also be prepared as an immediate-release or sustained-release preparation according to a preventive or therapeutic method.

When the pharmaceutical composition of the present invention is used for actual prevention or treatment, the dose of compound (A) as its active ingredient is appropriately determined according to the patient's age, sex, body weight, disease, and the degree of treatment. It is determined that, for example, in the case of oral administration, adults can be administered in the range of about 1 to 2000 mg per day, which can be administered in one or several divided doses.

[Example]

The contents of the present invention will be described in more detail using the following examples and test examples, but the present invention is not limited to these contents.

(Example 1) Form A crystal

Compound (B) (1168.9 mg) was mixed with ethanol (17.5 mL) and water (1.6 mL), and heated at 80°C. A 1 mol/L sodium hydroxide aqueous solution (4.2 mL) was added to the mixture, and the mixture was stirred at the same temperature for about 1 hour and at room temperature for 3 days. The solid was taken out from the mixture and washed with a mixed solution of ethanol and water (a solution in which 3 volumes of ethanol and 1 volume of water were mixed) (500 μL). The obtained solid was dried under reduced pressure at 70° C. for 3 hours to obtain a type A crystal (yield: 1179 mg).

¹ H-NMR (DMSO-d ₆ ) (δ(ppm)): 6.79-6.85(2H,m), 7.33-7.41(2H,m), 7.65-7.67(1H,m), 7.72-7.74(1H, m),7.82-7.86(1H,m),8.57(1H,s)

(Example 2) B-shaped crystal

Compound (B) (2035 mg) was mixed with 7.31 mL of 1 mol/L aqueous sodium hydroxide solution, and a mixed solution of ethanol and water (a solution of 1 volume of ethanol and 1 volume of water) (120 mL), and carried out at 70° C. Heat to dissolve. The solution was filtered hot and the resulting solution was stirred at room temperature for about 2 hours. The precipitated solid was collected by filtration, and washed twice with a mixed solution of ethanol and water (a solution containing 1 volume of ethanol and 1 volume of water) (1 mL). The obtained solid was air-dried in a laboratory environment (about 25°C/50% relative humidity) for about 3 hours to obtain form B crystals (yield 1.85 g). In addition, the B-type crystal is a hydrate.

¹ H-NMR (DMSO-d ₆ ) (δ(ppm)): 6.80-6.85(2H,m), 7.34-7.41(2H,m), 7.65-7.67(1H,m), 7.72-7.74(1H, m),7.83-7.87(1H,m),8.57(1H,s)

(Example 3) D-shaped crystal

烷混合液(體積比1：1)100mL混合，並於70℃下進行加熱溶解。一面利用水與1,4-二

烷混合液(體積比1：1)20mL充分清洗所獲得之溶液，一面利用玻璃過濾器進行過濾。利用乾冰-丙酮浴將所獲得之濾液急遽冷卻而製成固體。其後，取出所獲得之固體，對該固體進行約1天減壓乾燥(產量1956mg)。將所獲得之固體之一部分(1100mg)取出，於室溫下添加乙腈20mL，立即利用70℃之熱水浴加熱1分鐘，並於室溫下攪拌10分鐘。自混合物 中取出固體，利用乙腈1mL充分清洗，於室溫下進行約1小時減壓乾燥，而獲得D形結晶(產量923mg)。 Compound (A) (2000mg) and water were mixed with 1,4-di

100 mL of alkane mixed solution (volume ratio 1:1) was mixed and dissolved by heating at 70°C. One side utilizes water with 1,4-two

The obtained solution was sufficiently washed with 20 mL of an alkane mixed solution (volume ratio 1:1), and filtered with a glass filter. The obtained filtrate was rapidly cooled with a dry ice-acetone bath to obtain a solid. Thereafter, the obtained solid was taken out, and the solid was dried under reduced pressure for about 1 day (yield 1956 mg). A part (1100 mg) of the obtained solid was taken out, 20 mL of acetonitrile was added at room temperature, immediately heated with a hot water bath at 70° C. for 1 minute, and stirred at room temperature for 10 minutes. The solid was taken out from the mixture, washed well with 1 mL of acetonitrile, and dried under reduced pressure at room temperature for about 1 hour to obtain a D-type crystal (yield: 923 mg).

¹ H-NMR (DMSO-d ₆ ) (δ(ppm)): 6.81-6.83(2H,m), 7.34-7.41(2H,m), 7.65-7.67(1H,m), 7.73-7.75(1H, m),7.84-7.86(1H,m),8.57(1H,s)

About the obtained A, B and D type crystals, powder X-ray diffraction, thermal analysis and ¹³ C solid state NMR spectrum were measured under the following conditions, and each data was obtained.

Regarding powder X-ray diffraction, after lightly grinding the crystals in a mortar to pulverize the coarse particles, the powder X-ray diffractometer X' Pert Pro MPD (Spectris Co., Ltd. PANalytical Division) was used by reflection method. Determination.

Measurement conditions

Radiation source: CuKα rays

Tube voltage: 45kV

Tube current: 40mA

The diffraction patterns of the obtained A, B and D crystals are shown in Figures 1 to 3, respectively, and the diffraction angle (2θ(°)) of the representative diffraction peak and the relative intensity (%) of the diffraction peak are respectively shown. Shown in Tables 1 to 3.

The following peak groups can be used, for example, for identification of the A-type crystals. As a peak group, it was 6.8±0.2, 13.2±0.2, and 16.2±0.2. As another peak group, they were 6.8±0.2, 13.2±0.2, 16.2±0.2, 26.2±0.2, and 27.8±0.2. As yet another peak group, 6.8±0.2, 13.2±0.2, 16.2±0.2, 17.2±0.2, 23.7±0.2, 24.4±0.2, 25.0±0.2, 26.2±0.2, 27.6±0.2, 27.8±0.2, and 28.4±0.2 .

The following peak groups can be used for identification of the B-type crystal, for example. As a peak group, it was 6.2±0.2 and 12.4±0.2. As another peak group, they were 6.2±0.2, 12.4±0.2, 14.4±0.2, 19.1±0.2, and 28.9±0.2. As another peak group, they were 6.2±0.2, 12.4±0.2, 14.4±0.2, 14.8±0.2, 19.1±0.2, 20.2±0.2, 27.7±0.2, and 28.9±0.2.

For the identification of the D-form crystal, for example, the following peak groups can be used. As a peak group, it was 5.5±0.2, 13.7±0.2, and 14.2±0.2. As another peak group, they were 5.5±0.2, 13.7±0.2, 14.2±0.2, 24.1±0.2, 27.0±0.2, 27.5±0.2, and 28.9±0.2. As another peak group, 5.5±0.2, 13.7±0.2, 14.2±0.2, 16.9±0.2, 24.1±0.2, 25.0±0.2, 25.3±0.2, 26.4±0.2, 27.0±0.2, 27.5±0.2, and 28.9±0.2 . As another peak group, 4.3±0.2, 5.5±0.2, 13.0±0.2, 13.7±0.2, 14.2±0.2, 16.9±0.2, 17.3±0.2, 18.9±0.2, 20.2±0.2, 22.2±0.2, 24.1±0.2 , 25.0±0.2, 25.3±0.2, 26.4±0.2, 27.0±0.2, 27.5±0.2, 28.1±0.2, 28.9±0.2, 29.3±0.2, 30.0±0.2, 30.5±0.2, 30.9±0.2 and 32.5±0.2. Furthermore, as another peak group, they were 13.7±0.2, 24.1±0.2, 27.0±0.2, 27.5±0.2, and 28.9±0.2.

In general, it is known that the relative intensity of the X-ray diffraction pattern may vary depending on the sample conditions or measurement conditions. In addition, the 2θ value of the diffraction pattern obtained by powder X-ray diffraction may slightly vary depending on the sample conditions or measurement conditions. A typical variation in 2Θ values is about ±0.2(°).

The thermal analysis was measured in a nitrogen atmosphere using a differential type differential thermobalance TG-DTA TG8120 (Rigaku Co., Ltd.).

Measurement conditions

Heating rate: 10°C/min

Reference material: Alumina

The graphs of the obtained A, B and D crystals are shown in FIGS. 4 to 6 , respectively.

Endothermic peak of A-type crystal: around 314°C (temperature at the peak): around 316°C (initial temperature)

Endothermic peaks of B-type crystals: around 78°C and around 292°C (peak top temperature): around 60°C and around 284°C (initial temperature)

Weight loss of B-shaped crystals (around 50~100℃): about 9%

Endothermic peak of D-shaped crystal: around 290°C (temperature of peak top): around 279°C (initial temperature)

In addition, the weight change and endothermic change in thermal analysis may fluctuate depending on sample conditions or measurement conditions.

For ¹³ C solid-state NMR spectroscopy, the specimen was filled in a 4 mm rotor made of zirconia, and an Avance DRX500 (Bruker Corporation) was used, by Cross Polarization/Magic Angle Spinning (CP/MAS, Cross Polarization/Magic Angle Spinning) method to measure. Also, as an external standard, the carbonyl carbon of glycine was adjusted to 176.42 ppm.

Measurement conditions

Rotation speed: 10kHz

Contact time (P15): 3.0m seconds

Repeat time (d1): 5.0 seconds

The spectra of the obtained A, B and D crystals are shown in Figures 7 to 9, respectively, and the chemical shift values (δ (ppm)) of the representative peaks to the first decimal place (to the decimal point) The chemical shift values (δ (ppm)) of the second position are shown in Tables 4 to 6, respectively.

The following peak groups can be used, for example, for identification of the A-type crystals. As a peak group, it was 120.0±0.2, 116.9±0.2, and 109.4±0.2. As another peak group, they were 163.3±0.2, 141.2±0.2, 136.5±0.2, 132.4±0.2, 126.8±0.2, 123.5±0.2, 120.0±0.2, 116.9±0.2, 111.4±0.2, and 109.4±0.2. As another peak group, 176.4±0.2, 163.3±0.2, 141.2±0.2, 136.5±0.2, 132.4±0.2, 126.8±0.2, 123.5±0.2, 120.0±0.2, 116.9±0.2, 111.4±0.2, 109.4±0.2 and 85.5±0.2.

[table 5]

The following peak groups can be used for identification of the B-type crystal, for example. As a peak group, it was 162.4±0.2, 135.2±0.2, and 116.2±0.2. As another peak group, 163.6±0.2, 162.4±0.2, 141.0±0.2, 135.2±0.2, 132.5±0.2, 128.6±0.2, 126.5±0.2, 123.6±0.2, 121.5±0.2, 118.6±0.2, 116.2±0.2 and 109.7±0.2. As another peak group, 176.6±0.2, 174.4±0.2, 163.6±0.2, 162.4±0.2, 141.0±0.2, 135.2±0.2, 132.5±0.2, 128.6±0.2, 126.5±0.2, 123.6±0.2, 121.5±0.2 , 118.6±0.2, 116.2±0.2, 109.7±0.2 and 86.7±0.2.

For the identification of the D-form crystal, for example, the following peak groups can be used. As a peak group, it was 127.3±0.2, 118.0±0.2, and 112.3±0.2. As another peak group, they were 163.4±0.2, 139.4±0.2, 133.0±0.2, 127.3±0.2, 123.1±0.2, 121.4±0.2, 118.0±0.2, 112.3±0.2, and 109.9±0.2. As another peak group, 176.5±0.2, 163.4±0.2, 139.4±0.2, 133.0±0.2, 127.3±0.2, 123.1±0.2, 121.4±0.2, 118.0±0.2, 112.3±0.2, 109.9±0.2, and 88.9±0.2 .

In addition, the chemical shift value obtained from the ¹³ C solid-state NMR spectrum may slightly vary depending on the sample conditions or measurement conditions. Typical chemical shift values vary by about ±0.2 ([delta] (ppm)).

(Example 4) C-shaped crystal

A part (1.006 g) of the B-type crystals obtained in Example 2 was dried under reduced pressure at 80°C overnight to obtain C-type crystals (yield: 0.8936 g).

Each data was obtained by measuring powder X-ray diffraction, thermal analysis and ¹³ C solid state NMR spectrum of the obtained C-type crystals by the same method as the A, B, and D-type crystals.

The diffraction angle (2θ(°)) of the obtained representative diffraction peaks and the relative intensity (%) of the diffraction peaks are shown in Table 7. The chemical shift values of the representative peaks to the first decimal place are shown in Table 7. (δ (ppm)) (chemical shift value to the second decimal place (δ (ppm))) is shown in Table 8, and each graph is shown in FIGS. 10 to 12, respectively.

Endothermic peak of C-shaped crystal: around 295°C (temperature of peak top): around 285°C (initial temperature)

[Table 7] C-shaped crystals

For the identification of the C-shaped crystal, the following peak groups can be used, for example. As a peak group, it was 5.4±0.2, 11.9±0.2, and 14.2±0.2. As another peak group, 5.4±0.2, 11.9±0.2, 12.7±0.2, 13.4±0.2, 13.7±0.2, 14.2±0.2, 16.6±0.2, 18.2±0.2, 19.6±0.2, 20.1±0.2, 27.0±0.2 and 27.5±0.2. As another peak group, 5.4±0.2, 11.9±0.2, 12.7±0.2, 13.4±0.2, 13.7±0.2, 14.2±0.2, 16.5±0.2, 16.6±0.2, 17.2±0.2, 18.2±0.2, 19.6±0.2 , 20.1±0.2, 27.0±0.2, 27.5±0.2, 28.1±0.2 and 31.5±0.2.

For the identification of the C-shaped crystal, the following peak groups can be used, for example. As a peak group, it was 140.1±0.2, 134.3±0.2, and 122.0±0.2. As another peak group, they were 163.3±0.2, 140.1±0.2, 134.3±0.2, 132.8±0.2, 127.2±0.2, 124.8±0.2, 122.0±0.2, 118.7±0.2, and 110.1±0.2. As another peak group, 176.6±0.2, 175.4±0.2, 163.3±0.2, 140.1±0.2, 134.3±0.2, 132.8±0.2, 127.2±0.2, 124.8±0.2, 122.0±0.2, 118.7±0.2, 110.1±0.2 , 89.0±0.2 and 87.2±0.2.

Fourier Transform - Determination of Raman Spectroscopy

For A, B, C and D crystals, a Vertex70 Fourier Transform Infrared spectroscopy (FT-IR, Fourier Transform Infrared spectroscopy) spectrometer (Bruker) with RAM II FT-Raman module was used, and a sample rotor (Ventacon, UK) to measure Fourier transform-Raman spectroscopy (FT-Raman).

Measurement conditions

Near infrared laser: 1064nm

Detector: Liquid nitrogen cooled germanium detector

Laser output: 200mW (A, B and C crystals): 100mW (D crystals)

The obtained representative peaks of the A, B, C, and D-type crystals are shown in Tables 9 to 12 below, respectively, and the spectrograms are shown in FIGS. 13 to 16, respectively. Regarding the intensity, the intensity of the strongest peak is set to 1, and it is expressed as s=strong (intensity 1~0.51), m=intermediate (intensity 0.5~0.25), and w=weak (intensity<0.25).

The following peak groups can be used, for example, for identification of the A-type crystals. As a peak group, it is 2228±1, 1535±1 and 1516±1.

The following peak groups can be used for identification of the B-type crystal, for example. As a peak group, it is 2238±1, 1601±1, 1540±1 and 1516±1.

For the identification of the C-shaped crystal, the following peak groups can be used, for example. As a peak group, it is 2235±1, 1535±1 and 1509±1.

For the identification of the D-form crystal, for example, the following peak groups can be used. As a peak group, it is 2230±1, 1532±1 and 1508±1.

In addition, the wavenumber obtained from the Fourier transform-Raman spectroscopy may slightly vary depending on the sample conditions or measurement conditions. A typical wavenumber variation is about ±1 (cm ^-1 ).

For example, the ¹³ C solid state NMR spectrum, powder X-ray diffraction and FT-Raman spectrum of each crystal form in the tablet can be measured by the same method as the above-mentioned method after pulverizing the tablet with a slight pressure.

(Comparative Example 1) Crystals of Compound (B)

Powder X-ray diffraction was measured for the crystals of compound (B) obtained by the method described in Example 188 of Patent Document 1 in the same manner as the crystals A, B, C and D. The obtained diffraction pattern is shown in FIG. 17 .

(Comparative Example 2) Crystal of benzathine salt of compound (B) (hereinafter referred to as crystal of benzathine salt)

100 mg of compound (B), 43.2 mg of N,N'-dibenzylethylenediamine, and 2 mL of a mixed solvent of ethanol/water (volume ratio 1/1) were mixed, heated to 80°C, and stirred for 1 hour. The mixture was left to cool at room temperature and stirred overnight. The solid was taken out from the mixture and washed twice with 100 μL of a mixed solvent of ethanol/water (volume ratio 1/1). The obtained solid was air-dried for 30 minutes, followed by drying under reduced pressure at 70° C. for 3 hours to obtain crystals of benzathine salt (yield 109.0 mg).

¹ H-NMR (DMSO-d ₆ ) (δ(ppm)): 3.04(2H,s), 4.05(2H,s), 6.95-6.98(2H,m), 7.35-7.46(7H,m), 7.67 -7.75(2H,m),7.88-7.90(1H,m),8.61(1H,s)

The crystals of the benzathine salt obtained in Comparative Example 2 were the same as those of A, B, C and D. The powder X-ray diffraction was measured in the same manner as the crystals. The obtained diffraction pattern is shown in FIG. 18 .

In the present invention, the A-form crystal of compound (A) can also be identified by combining the above-mentioned peaks of powder X-ray diffraction, ¹³ C solid-state NMR spectrum and FT-Raman spectroscopy.

As an aspect of identifying the A-type crystal of the compound (A), the following aspects (A-1) to (A-3) can be mentioned, for example.

(A-1) ¹³ C solid-state NMR spectrum comprising peaks at chemical shift values (δ (ppm)) of 120.0±0.2, 116.9±0.2, and 109.4±0.2; and 2228±1, 1535±1, and 1516±1 FT-Raman spectrum of the peak at the wavenumber (cm ^-1 ).

(A-2) ^13C solid-state NMR spectrum comprising peaks at chemical shift values (δ (ppm)) of 120.0±0.2, 116.9±0.2, and 109.4±0.2; and 6.8±0.2, 13.2±0.2, and 16.2±0.2 The powder X-ray diffraction pattern of the peak at the diffraction angle (2θ(°)).

(A-3) Powder X-ray diffraction pattern including peaks at diffraction angles (2θ(°)) of 6.8±0.2, 13.2±0.2 and 16.2±0.2; including 120.0±0.2, 116.9±0.2 and 109.4±0.2 The ¹³ C solid ^- state NMR spectrum of the peak at the chemical shift value (δ (ppm)) of the .

Examples of aspects for identifying the B-type crystal of the compound (A) include the following aspects (B-1) to (B-3).

(B-1) ^13C solid-state NMR spectrum comprising peaks at chemical shift values (δ (ppm)) of 162.4±0.2, 135.2±0.2, and 116.2±0.2; and 2238±1, 1601±1, 1540±1 And the FT-Raman spectrum of the peak at the wave number (cm ^-1 ) of 1516±1.

(B-2) ¹³ C solid-state NMR spectrum comprising peaks at chemical shift values (δ (ppm)) of 162.4±0.2, 135.2±0.2 and 116.2±0.2; and diffraction angles comprising 6.2±0.2 and 12.4±0.2 Powder X-ray diffraction pattern of the peak at (2θ(°)).

(B-3) Powder X-ray diffraction pattern including peaks at diffraction angles (2θ(°)) of 6.2±0.2 and 12.4±0.2; including chemical shift values of 162.4±0.2, 135.2±0.2 and 116.2±0.2 ¹³ C solid-state NMR spectrum of peaks at (δ (ppm)); and FT-Raman spectra of peaks at wavenumbers (cm ⁻¹ ) including 2238±1, 1601±1, 1540±1, and 1516±1 .

Examples of aspects for identifying the C-shaped crystal of the compound (A) include the following aspects (C-1) to (C-3).

(C-1) ^13C solid-state NMR spectrum comprising peaks at chemical shift values (δ (ppm)) of 140.1±0.2, 134.2±0.2, and 122.0±0.2; and 2235±1, 1535±1, and 1509±1 FT-Raman spectrum of the peak at the wavenumber (cm ^-1 ).

(C-2) ^13C solid-state NMR spectrum comprising peaks at chemical shift values (δ (ppm)) of 140.1±0.2, 134.2±0.2, and 122.0±0.2; and 5.4±0.2, 11.9±0.2, and 14.2±0.2 The powder X-ray diffraction pattern of the peak at the diffraction angle (2θ(°)).

(C-3) Powder X-ray diffraction pattern including peaks at diffraction angles (2θ(°)) of 5.4±0.2, 11.9±0.2 and 14.2±0.2; including 140.1±0.2, 134.2±0.2 and 122.0±0.2 The ¹³ C solid state NMR spectrum of the peak at the chemical shift value (δ ( ^ppm )) of .

As an aspect of identifying the D-form crystal of the compound (A), the following aspects (D-1) to (D-3) can be mentioned, for example.

(D-1) ¹³ C solid-state NMR spectrum comprising peaks at chemical shift values (δ (ppm)) of 127.3±0.2, 118.0±0.2, and 112.3±0.2; and 2230±1, 1532±1, and 1508±1 FT-Raman spectrum of the peak at the wavenumber (cm ^-1 ).

(D-2) ^13C solid-state NMR spectrum comprising peaks at chemical shift values (δ (ppm)) of 127.3±0.2, 118.0±0.2, and 112.3±0.2; and 5.5±0.2, 13.7±0.2, and 14.2±0.2 The powder X-ray diffraction pattern of the peak at the diffraction angle (2θ(°)).

(D-3) Powder X-ray diffraction pattern including peaks at diffraction angles (2θ(°)) of 5.5±0.2, 13.7±0.2 and 14.2±0.2; including 127.3±0.2, 118.0±0.2 and 112.3±0.2 The ¹³ C solid ^- state NMR spectrum of the peak at the chemical shift value (δ (ppm)) of the .

(Test Example 1) Solubility test

Form A, B, C and D crystals, compound (B) and benzathine salt crystals were respectively suspended in water and shaken at 37°C. At this time, 2 mL of water was added to 20 mg of each crystal, or 6 mL of water was added to 30 mg of each crystal to prepare a suspension. A part of each suspension was filtered, and the obtained filtrate was measured by a high performance liquid chromatography (HPLC, High Pressure Liquid Chromatograph). Under the same conditions, a separately prepared standard solution of known concentration was measured by HPLC, and a calibration curve was prepared according to the obtained area value. The solubility of each crystal was calculated from the obtained calibration curve and compared. The measurement conditions by HPLC are as follows.

As for the measurement conditions other than the crystals of the benzathine salt, the solubility test HPLC condition (1) was used, and as for the measurement conditions for the benzathine salt crystals, the solubility test HPLC condition (2) was used.

Solubility test HPLC conditions (1)

Detector: UV-Vis Absorption Spectrometer / Wavelength: 225nm

Column: L-column2 ODS, 3μm, 4.6×150mm (manufactured by the General Chemical Substance Evaluation Research Institute)

Column temperature: a certain temperature around 40°C

Flow: 1.0mL/min

Mobile phase A: a solution mixed with 10 mmol of potassium dihydrogen phosphate, 10 mmol of dipotassium hydrogen phosphate and 1000 mL of water

Mobile Phase B: Acetonitrile

current ratio

0~7.5 minutes: mobile phase A/mobile phase B=60/40

Solubility test HPLC conditions (2)

Detector: UV-Vis Absorption Spectrometer / Wavelength: 225nm

Column: L-column2 ODS, 3μm, 4.6×150mm (manufactured by the General Chemical Substance Evaluation Research Institute)

Column temperature: a certain temperature around 40°C

Flow: 1.0mL/min

Mobile phase A: a solution mixed with 10 mmol of potassium dihydrogen phosphate, 10 mmol of dipotassium hydrogen phosphate and 1000 mL of water

Mobile Phase B: Acetonitrile

current ratio

0~17 minutes: mobile phase A/mobile phase B=70/30

Table 13 shows the solubility values of A, B, C and D form crystals, compound (B) and benzathine salt crystals in water. The solubility of each crystal 2 hours after the start of the test was compared. The solubility of benzathine salt crystals is about 4 times higher than that of compound (B) crystals, and about 400 times higher than that of compound (B) crystals for crystals A, B, C and D, respectively. , about 100 times, about 135 times, about 434 times the solubility. Based on the above, the crystals of A, B, C, and D forms have a marked improvement in solubility with respect to the compound (B).

[Table 13]

(Test Example 2) Stability Test 1

The A, B and D crystals were stored under open conditions at 40°C and 75% relative humidity, and the physical and chemical stability of each crystal was investigated. The physical stability of the crystal form was confirmed by measuring the powder X-ray diffraction at the beginning of the test and after 2 months in the same manner as above, and by measuring the amount of analog using the following HPLC measurement conditions. chemical stability. The results are shown in Table 14. Under open storage at 40°C and 75% relative humidity, no change in crystal form was observed for any crystal. In addition, A, B, and D type crystals are all chemically stable.

HPLC conditions

Detector: UV-Vis Absorption Spectrometer / Wavelength: 225nm

Column: L-column2 ODS, 3μm, 4.6×150mm (manufactured by the General Chemical Substance Evaluation Research Institute)

Column temperature: a certain temperature around 40°C

Flow: 1.0mL/min

Mobile phase A: A solution prepared by adding 1 mol/L sodium hydroxide solution to 20 mmol/L potassium dihydrogen phosphate solution to adjust the pH to 6.0

Mobile Phase B: Acetonitrile

current ratio

0~10 minutes: mobile phase A/mobile phase B=70/30

10~20 minutes: mobile phase A/mobile phase B=70/30~25/75 (gradient)

20~30 minutes: mobile phase A/mobile phase B=25/75

Injection volume: 5μL

Sample solution: Add a mixture of mobile phase A and mobile phase B to the sample to prepare a solution of about 0.5 mg/mL.

Except for the peak derived from the blank sample, the area of each peak was measured by the automatic integration method, and the values were obtained by the area percentage method.

(Test Example 3) Stability Test 2

A, B, C and D crystals were stored at 40°C, and the physical and chemical stability of each crystal was investigated. Confirmation was carried out in the same manner as in Test Example 2. The results are shown in Table 15. When stored at 40°C, no change in crystal form was observed in any of the crystals. In addition, any crystal is chemically stable.

(Test Example 4) Moisture adsorption and desorption test

About the A-form crystal of compound (A) and compound (B), the measurement of moisture adsorption-desorption was performed under the following conditions. The results are shown in Table 16, and the water adsorption and desorption isotherms are shown in FIGS. 19 to 20 .

(use equipment)

Moisture adsorption and desorption measuring device IGAsorp (Hiden Isochema Co., Ltd.)

(operate) <Specimen and amount for measurement>

Crystalline of compound (B): about 5 mg

Form A crystal: about 17mg

<Pretreatment: Drying>

Each sample was placed in a moisture adsorption/desorption measuring device, and the temperature and humidity were set to 60°C/0% RH, and dried for 60 minutes or more. After drying, the temperature and humidity were set to 25°C/0%RH, and the mass was stabilized for 30 minutes or more.

<Measurement>

For the above-mentioned dried specimen, the mass of the specimen was continuously measured by the adsorption system while controlling the relative humidity every 10% RH from 10% RH to 90% RH, and the desorption system was The mass of the specimen was continuously measured while controlling the relative humidity every 10% RH from 90% RH to 0% RH. The measurement conditions of the moisture adsorption and desorption measurement device were set as follows.

<Measurement conditions>

Initial Conditions: begin with Adsorption scan

Initial Humidity: 10%RH

Flow rate: 250mL/min

Mode: F1

Min Time: 30 minutes

Timeout: 60 minutes

Wait Until: 99%

Furthermore, the weight % is based on the dry sample, and the mass change before and after adsorption (or desorption) is expressed as a mass percentage.

Under the above conditions, the A-type crystal of the compound (A) has a water content change of 1/3 compared to the crystal of the compound (B).

As described above, the compound (A) of the present invention exhibits extremely excellent solubility and stability. Furthermore, the water content of the A-type crystal is less fluctuating, and it is more preferable as a pharmaceutical raw material.

(Industrial Availability)

The compound (A) of the present invention has excellent solubility or other physical properties, is useful as a pharmaceutical raw material, and is suitable for industrial production of pharmaceuticals.

Claims (16)

A 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. The crystal of sodium salt, which has peaks at 120.0±0.2, 116.9±0.2 and 109.4±0.2 as chemical shift values (δ (ppm)) in the ¹³ C solid-state nuclear magnetic resonance (NMR, Nuclear Magnetic Resonance) spectrum The A-form crystal. A 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. Crystals of sodium salts, which are A-shaped crystals that are characterized by 1 to 3 physical properties selected from the group consisting of the following (a1) to (a3), and have at least the physical properties of (a1): (a1) Powder X-ray diffraction pattern including peaks at diffraction angles (2θ(°)) of 6.8±0.2, 13.2±0.2 and 16.2±0.2; (a2) including 2228±1, 1535±1 and 1516±1 Fourier Transform (FT, Fourier Transform)-Raman spectrum of the peak at a wavenumber (cm ⁻¹ ) of 1; and (a3) Differential calorimetry spectrum with the onset temperature of the endothermic peak around 316°C. For the crystal of claim 1, it is an A-type crystal characterized by 1 to 3 physical properties selected from the group consisting of (a1) to (a3) below: (a1) includes 6.8 Powder X-ray diffraction patterns of peaks at diffraction angles (2θ(°)) of ±0.2, 13.2±0.2 and 16.2±0.2; (a2) including wave numbers of 2228±1, 1535±1 and 1516±1 ( cm ⁻¹ ) Fourier transform-Raman spectrum of the peak; and (a3) differential thermal analysis spectrum with the onset temperature of the endothermic peak around 316°C. A 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. The hydrate of sodium salt is a B-type crystal with peaks at 162.4±0.2, 135.2±0.2 and 116.2±0.2 as chemical shift values (δ (ppm)) in the ¹³ C solid state NMR spectrum. A 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. A crystal of a hydrate of a sodium salt, which is a B-shaped crystal characterized by 1 to 3 physical properties selected from the group consisting of (b1) to (b3) below, and has at least one of (b1) Physical properties: (b1) Powder X-ray diffraction pattern including peaks at diffraction angles (2θ(°)) of 6.2±0.2 and 12.4±0.2; (b2) 2238±1, 1601±1, 1540±1 and the FT-Raman spectrum of the peak at the wave number (cm ^-1 ) of 1516±1; and (b3) the differential thermal analysis spectrum with the onset temperature of the endothermic peak around 60°C and 284°C. For the crystal of claim 4, it is a B-shaped crystal characterized by 1 to 3 physical properties selected from the group consisting of the following (b1) to (b3): (b1) includes 6.2 Powder X-ray diffraction patterns of peaks at diffraction angles (2θ(°)) of ±0.2 and 12.4±0.2; (b2) including wave numbers of 2238±1, 1601±1, 1540±1 and 1516±1 ( cm ⁻¹ ) the FT-Raman spectrum of the peak; and (b3) the differential thermal analysis spectrum with the onset temperature of the endothermic peak around 60°C and 284°C. A 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. The crystals of the sodium salt are C-shaped crystals with peaks at 140.1±0.2, 134.3±0.2 and 122.0±0.2 as chemical shift values (δ (ppm)) in the ¹³ C solid state NMR spectrum. For the crystal of claim 7, it is a C-shaped crystal characterized by 1 to 3 physical properties selected from the group consisting of the following (c1) to (c3): (c1) includes 5.4 Powder X-ray diffraction patterns of peaks at diffraction angles (2θ(°)) of ±0.2, 11.9±0.2 and 14.2±0.2; (c2) including wave numbers of 2235±1, 1535±1 and 1509±1 ( cm ⁻¹ ) the FT-Raman spectrum of the peak; and (c3) the differential thermal analysis spectrum with the onset temperature of the endothermic peak around 285°C. A 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. The crystal of the sodium salt is a D-shaped crystal with peaks at 127.3±0.2, 118.0±0.2 and 112.3±0.2 as chemical shift values (δ (ppm)) in the ¹³ C solid state NMR spectrum. For the crystal of claim 9, it is a D-shaped crystal characterized by 1 to 3 physical properties selected from the group consisting of the following (d1) to (d3): (d1) contains 5.5 Powder X-ray diffraction patterns of peaks at diffraction angles (2θ(°)) of ±0.2, 13.7±0.2 and 14.2±0.2; (d2) including wave numbers of 2230±1, 1532±1 and 1508±1 ( cm ⁻¹ ) FT-Raman spectrum of the peak; and (d3) differential thermal analysis spectrum with the onset temperature of the endothermic peak around 279°C. A 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. The crystals of sodium salt, which are in ¹³ C solid state NMR spectrum, at 176.4±0.2, 163.3±0.2, 141.2±0.2, 136.5±0.2, 132.4±0.2, 126.8± as chemical shift values (δ (ppm)) Form A crystals with peaks at 0.2, 123.5±0.2, 120.0±0.2, 116.9±0.2, 111.4±0.2, 109.4±0.2 and 85.5±0.2. A 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. Crystallization of hydrate of sodium salt, which is 176.6±0.2, 174.4±0.2, 163.6±0.2, 162.4±0.2, 141.0±0.2 as chemical shift value (δ (ppm)) ^in13C solid state NMR spectrum , 135.2±0.2, 132.5±0.2, 128.6±0.2, 126.5±0.2, 123.6±0.2, 121.5±0.2, 118.6±0.2, 116.2±0.2, 109.7±0.2, and 86.7±0.2 B-shaped crystals with peaks. A 4-(3-cyanoindol-1-yl)-2-hydroxybenzoic acid. Crystallization of sodium salt, which is 176.5±0.2, 163.4±0.2, 139.4±0.2, 133.0±0.2, 127.3±0.2, 123.1± as chemical shift value (δ(ppm)) ^in13C solid state NMR spectrum D-shaped crystals with peaks at 0.2, 121.4±0.2, 118.0±0.2, 112.3±0.2, 109.9±0.2 and 88.9±0.2. Such as the crystal of any one of items 1 to 13 of the scope of application, it is intended to be used as a medicine. The crystal according to any one of items 1 to 13 of the patent application scope is used for preventing or treating diseases caused by abnormal serum uric acid level. A pharmaceutical composition, which contains the crystal of any one of items 1 to 13 of the scope of the application and a pharmacologically acceptable pharmaceutical additive.

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