HK1210080B - Sulfate of 5-hydroxy-1h-imidazole-4-carboxamide - Google Patents

Description

5-Hydroxy-1H-imidazole-4-carboxamide sulfate

Technical Field

The present invention relates to the sulfate salt of 5-hydroxy-1H-imidazole-4-carboxamide.

Background Art

5-Hydroxy-1H-imidazole-4-carboxamide (hereinafter also referred to as "Compound A") is a compound useful as a cancer suppressor (Patent Document 1). In order to provide a stable Compound A, it has been proposed to convert Compound A into an organic sulfonate (Patent Document 2).

Prior art literature

Patent Literature

Patent Document 1: Japanese Patent Application Laid-Open No. 53-32124

Patent Document 2: International Publication No. 2009/035168 Pamphlet

Summary of the Invention

Problems to be solved by the invention

Compound A is easily oxidized and discolored blue, and its storage stability is not sufficient. On the other hand, it is extremely important for the pharmaceutical precursor to be high-purity, stable at room temperature or above while maintaining quality and having low hygroscopicity.

An object of the present invention is to provide a salt of Compound A in which blue coloration is suppressed, the salt has high purity, low hygroscopicity, and excellent storage stability.

Solutions to Problems

Under such circumstances, the present inventors conducted intensive research and found that the sulfate of Compound A has suppressed blue coloration, high purity, low hygroscopicity, and excellent storage stability. Based on these findings, the present invention was completed. Specific solutions for solving the above problems are as follows.

[1] Sulfate salt of compound A.

[2] A crystal of a sulfate salt of Compound A, having diffraction peaks at diffraction angles of 5.0°, 20.3°, and 29.6° expressed in 2θ in a powder X-ray diffraction pattern.

A crystal of a sulfate salt of Compound A having diffraction peaks at diffraction angles of 5.0°, 10.1°, 13.6°, 14.3°, 14.7°, 20.3°, and 29.6° expressed in 2θ in a powder X-ray diffraction pattern.

[3] A crystal of a sulfate salt of compound A (hereinafter also referred to as "β-type crystal") having diffraction peaks at diffraction angles of 5.0°, 10.1°, 13.6°, 14.3°, 14.7°, 20.3°, 27.4°, 28.0°, 28.8° and 29.6° expressed in 2θ in a powder X-ray diffraction pattern.

In addition, β-type crystals can be distinguished from other crystalline forms by the diffraction peaks at diffraction angles of 5.0°, 20.3°, and 29.6° expressed in 2θ, or the diffraction peaks at diffraction angles of 5.0°, 10.1°, 13.6°, 14.3°, 14.7°, 20.3°, and 29.6° expressed in 2θ. These values are unique to the crystalline form.

[4] A pharmaceutical composition comprising: crystals of a sulfate salt of Compound A having diffraction peaks at diffraction angles of 5.0°, 20.3°, and 29.6° in terms of 2θ in a powder X-ray diffraction pattern; crystals of a sulfate salt of Compound A having diffraction peaks at diffraction angles of 5.0°, 10.1°, 13.6°, 14.3°, 14.7°, 20.3°, and 29.6° in terms of 2θ in a powder X-ray diffraction pattern; or crystals of a sulfate salt of Compound A having diffraction peaks at diffraction angles of 5.0°, 10.1°, 13.6°, 14.3°, 14.7°, 20.3°, 27.4°, 28.0°, 28.8°, and 29.6° in terms of 2θ in a powder X-ray diffraction pattern.

[5] A crystal of a sulfate salt of Compound A, which has diffraction peaks at diffraction angles of 13.7°, 17.0°, 18.0°, and 20.1° expressed in 2θ in a powder X-ray diffraction pattern.

A crystal of a sulfate salt of Compound A having diffraction peaks at diffraction angles expressed in 2θ of 10.0°, 13.7°, 14.6°, 17.0°, 18.0°, 20.1°, 24.4°, and 25.2° in a powder X-ray diffraction pattern.

[6] A crystal of a sulfate salt of compound A (hereinafter also referred to as "α-type crystal") having diffraction peaks at diffraction angles of 10.0°, 13.7°, 14.6°, 17.0°, 18.0°, 20.1°, 24.4°, 25.2° and 28.1° expressed in 2θ in a powder X-ray diffraction pattern.

In addition, α-type crystals can be distinguished from other crystalline forms by the diffraction peaks at diffraction angles of 13.7°, 17.0°, 18.0°, and 20.1°, as described above, or the diffraction peaks at diffraction angles of 10.0°, 13.7°, 14.6°, 17.0°, 18.0°, 20.1°, 24.4°, and 25.2°, as described above. These values are unique to the crystalline form.

[7] A pharmaceutical composition comprising: crystals of a sulfate salt of Compound A having diffraction peaks at diffraction angles of 13.7°, 17.0°, 18.0°, and 20.1° in terms of 2θ in a powder X-ray diffraction pattern; crystals of a sulfate salt of Compound A having diffraction peaks at diffraction angles of 10.0°, 13.7°, 14.6°, 17.0°, 18.0°, 20.1°, 24.4°, and 25.2° in terms of 2θ in a powder X-ray diffraction pattern; or crystals of a sulfate salt of Compound A having diffraction peaks at diffraction angles of 10.0°, 13.7°, 14.6°, 17.0°, 18.0°, 20.1°, 24.4°, 25.2°, and 28.1° in terms of 2θ in a powder X-ray diffraction pattern.

[8] A crystal of a sulfate salt of Compound A, which has diffraction peaks at diffraction angles of 10.3°, 20.7°, 20.9°, and 31.2° expressed in 2θ in a powder X-ray diffraction pattern.

[9] A crystal of a sulfate salt of Compound A (hereinafter also referred to as a "γ-type crystal") having diffraction peaks at diffraction angles of 10.3°, 20.7°, 20.9°, 28.0°, and 31.2° expressed in 2θ in a powder X-ray diffraction pattern.

γ-type crystals can be distinguished from other crystalline forms by the diffraction peaks at diffraction angles of 10.3°, 20.7°, 20.9°, and 31.2° expressed in 2θ. These values are unique to this crystalline form.

[10] A pharmaceutical composition comprising: crystals of a sulfate salt of Compound A having diffraction peaks at diffraction angles of 10.3°, 20.7°, 20.9°, and 31.2° in terms of 2θ in a powder X-ray diffraction pattern; or crystals of a sulfate salt of Compound A having diffraction peaks at diffraction angles of 10.3°, 20.7°, 20.9°, 28.0°, and 31.2° in terms of 2θ in a powder X-ray diffraction pattern.

[11] A method for producing the crystals defined in [2] or [3], comprising the steps of adding an aqueous sulfuric acid solution to the crystals defined in [5] or [6] and suspending and stirring the crystals at 10°C to 65°C, preferably using less than 4 moles of sulfuric acid per 1 mole of compound A or its hydrate.

[12] A method for producing a crystal as defined in [5] or [6], comprising the steps of dissolving Compound A or a hydrate thereof in an aqueous sulfuric acid solution by heating and then slowly cooling the solution to allow crystallization.

[13] A method for producing the crystals defined in [8] or [9], which comprises adding an aqueous solution of sulfuric acid to the crystals defined in [5] or [6] and suspending and stirring the crystals at 10°C to 65°C, preferably using 4 moles or more of sulfuric acid per 1 mole of compound A or its hydrate.

Effects of the Invention

According to the present invention, a sulfate salt of compound A having excellent properties such as suppressed blue coloration, high purity and/or low hygroscopicity, and high storage stability can be provided.

Furthermore, according to the present invention, it is possible to provide a crystal of a sulfate salt of Compound A having excellent properties such as suppressed blue coloration, high purity and/or low hygroscopicity, and high storage stability.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing an example of an infrared absorption spectrum (ATR method) of a β-type crystal.

FIG. 2 is a diagram showing an example of a powder X-ray diffraction pattern of a β-type crystal.

FIG. 3 is a diagram showing an example of an infrared absorption spectrum (ATR method) of an α-type crystal.

FIG. 4 is a diagram showing an example of a powder X-ray diffraction pattern of an α-type crystal.

FIG. 5 is a diagram showing an example of an infrared absorption spectrum (ATR method) of a γ-type crystal.

FIG. 6 is a diagram showing an example of a powder X-ray diffraction pattern of a γ-type crystal.

7 is a diagram showing an example of a powder X-ray diffraction pattern of a crystal of Compound A obtained in Comparative Example 1. FIG.

FIG8 is a photograph showing the state of α-form crystals of the sulfate salt of Compound A after storage for 2 weeks under conditions of 60° C. and 75% relative humidity.

FIG. 9 is a photograph showing the state of β-type crystals of the sulfate salt of Compound A after storage for 2 weeks under conditions of 60° C. and 75% relative humidity.

FIG10 is a photograph showing the state of crystals of Compound A after storage for 2 weeks under the conditions of 60° C. and 75% relative humidity.

DETAILED DESCRIPTION

The present invention is described in detail below. Numerical ranges expressed as "to" herein include the numerical values before and after the "to" as the minimum and maximum values, respectively. Furthermore, in the present invention, the amount of each component in a composition, when multiple substances corresponding to each component are present in the composition, refers to the total amount of the multiple substances present in the composition unless otherwise specified.

The salts of the present invention include anhydrates and hydrates.

The crystals of the present invention include crystals containing anhydrates, crystals containing hydrates, and crystals with attached water.

In the powder X-ray diffraction pattern of the crystal of the present invention, the term "diffraction angle of X° expressed in 2θ" for a diffraction angle having a peak means "diffraction angle of ((X-0.2) to (X+0.2))° expressed in 2θ" unless otherwise specified.

The salt and crystals of the present invention have any (preferably all) of the following characteristics: (1) suppressed blue coloration, (2) high purity, (3) low hygroscopicity, and (4) excellent storage stability, and are useful as pharmaceutical raw materials.

<Method for producing α-type crystal>

α-type crystals can be produced by dissolving Compound A or its hydrate in a sulfuric acid aqueous solution by heating and then slowly cooling to allow crystallization. Compound A or its hydrate can be produced, for example, by the method described in Japanese Patent Application Laid-Open No. 58-24569 or the method described in Preparation Example 1 described below.

The amount of sulfuric acid contained in the aqueous sulfuric acid solution can be 0.5 to 1.4 mol, more preferably 1.0 to 1.2 mol, relative to 1 mol of Compound A or its hydrate.

The amount of the sulfuric acid aqueous solution used to dissolve Compound A or its hydrate is not particularly limited. For example, it is preferably 20 to 100 times (v/w) the amount of Compound A or its hydrate, and more preferably 40 to 60 times (v/w).

The temperature for heating and dissolving Compound A or its hydrate in the aqueous sulfuric acid solution is not particularly limited, but can be, for example, 40°C to 60°C, preferably 50°C to 60°C, and more preferably 50°C to 55°C.

The crystallization temperature is not particularly limited, but can be, for example, 0°C to 40°C, preferably 0°C to 20°C, and more preferably 0°C to 10°C.

The time required for crystallization is not particularly limited, but is preferably 0.5 to 24 hours, and more preferably 0.5 to 6 hours.

<Method for producing β-type crystal>

The β-type crystal can be produced, for example, by adding an aqueous sulfuric acid solution to the α-type crystal and suspending and stirring the resulting mixture at 10° C. to 65° C. Furthermore, the yield of the crystal can be increased by crystallizing the resulting crystal.

The amount of sulfuric acid contained in the aqueous sulfuric acid solution is preferably 2 to 3 mol relative to 1 mol of Compound A in the α-type crystal.

The amount of the sulfuric acid aqueous solution used is not particularly limited, but is preferably 1 to 50 times (v/w) the amount of the α-type crystal, and more preferably 5 to 20 times (v/w).

The suspension stirring time is not particularly limited, but is preferably 0.5 to 5 hours, and more preferably 2 to 5 hours.

The time required for crystallization is not particularly limited, but is preferably 12 to 24 hours, for example.

<Method for producing γ-type crystal>

γ-type crystals can be produced, for example, by adding a sulfuric acid aqueous solution to α-type crystals and suspending and stirring the mixture at 10° C. to 65° C. Furthermore, the yield of the crystals can be increased by crystallizing the crystals.

The amount of sulfuric acid contained in the aqueous sulfuric acid solution is preferably 4 to 10 mol relative to 1 mol of Compound A in the α-form crystal.

The amount of the sulfuric acid aqueous solution used is not particularly limited, but is preferably 5 to 20 times (v/w) the amount of the α-type crystals, and more preferably 10 to 15 times (v/w).

The suspension stirring time is not particularly limited, but is preferably 0.5 to 5 hours, and more preferably 2 to 5 hours.

The time required for crystallization is not particularly limited, but is preferably 12 to 24 hours, for example.

When producing α-type crystals, it is preferable to use seed crystals, as this allows for more uniform control of the crystal shape.

In addition, seed crystals obtained in the previous production may be used, or a part of the crystallized crystals may be filtered out in advance as seed crystals.

The temperature for collecting the α, β or γ-type crystals produced by crystallization or suspension stirring by filtration is not particularly limited, but is preferably 0 to 25°C.

The crystallization or suspension stirring operation can be performed in air or in an inert gas atmosphere, but is preferably performed in an inert gas atmosphere. Examples of the inert gas atmosphere include argon atmosphere and nitrogen atmosphere.

<Pharmaceutical Composition>

The pharmaceutical composition of the present invention comprises one or more crystals selected from α-, β-, and γ-type crystals. The pharmaceutical composition of the present invention has excellent storage stability due to the inclusion of α-, β-, and/or γ-type crystals.

When α, β and/or γ type crystals are used as pharmaceutical compositions, usually, the excipients, carriers and diluents used in the formulation can also be appropriately mixed. They can be administered orally or parenterally in the form of tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, liquids, powder preparations, suppositories, eye drops, nasal drops, ear drops, patches, ointments or injections according to conventional methods. In addition, the method of administration, dosage and number of administrations can be appropriately selected according to the patient's age, weight and symptoms. Usually, for adults, as long as oral or parenteral (for example, injection, drip and administration to rectal site, etc.) administration is performed, 0.01 mg/kg ~ 2000 mg/kg is divided into 1 ~ several administrations on the 1st day.

Hereinafter, the present invention will be described in more detail with reference to Production Examples, Examples, and Formulation Examples, but the present invention is not limited thereto. % refers to mass % unless otherwise specified.

The abbreviations used below have the following meanings.

HPLC: High Performance Liquid Chromatography

Powder X-ray diffraction was measured using Ultima IV (Rigaku Corporation) under the following conditions.

(Measurement conditions)

Cathode: Cu

Tube voltage: 40kV

Tube current: 40mA

Scan axis: 2θ

The infrared absorption spectrum was measured using Spectrum One (Perkin Elmer) in accordance with the Japanese Pharmacopoeia, General Test Methods, and infrared absorption spectrum total reflectance measurement method (ATR method).

The water content was measured using a Karl Fischer titrator.

The purity is expressed as HPLC area %. HPLC measurement was performed using Prominence (Shimadzu Corporation) under the following conditions.

(Measurement conditions)

Measurement wavelength: 210nm

Column: Hydrosphere C18, inner diameter 6.0 × length 250 mm, particle size 5 μm

Column temperature: 40°C

Flow rate: 0.8 mL/min

Mobile phase A: 950 mL of water and 50 mL of 0.4 mol/L phosphoric acid-triethylamine buffer (pH 3)

Mobile phase B: 50 mL of water, 900 mL of acetonitrile, and 50 mL of 0.4 mol/L phosphoric acid-triethylamine buffer (pH 3)

The mobile phase used was a mixture of mobile phase A and mobile phase B with the following linear gradient.

Table 1

Time (minutes) Mobile phase A volume ratio (%) Mobile phase B volume ratio (%) 0 98 2 10 98 2 20 90 10 30 90 10 45 0 100 55 0 100

(Production Example 1)

(1) Under a nitrogen atmosphere, 30 g of 2-aminomalonamide (Tateyama Chemical) and 115 mg of oxalic acid were added to 600 mL of 2-propanol. The mixture was heated to 82°C, and 106 mL of triethyl orthoformate (Nisho Chemical, purity: 99.5%) was added dropwise over 10 minutes. The reaction mixture was then stirred at 84°C for 7 hours and 30 minutes. After cooling to 57°C, 30 mL of water and 24 mL of concentrated hydrochloric acid were added to the reaction mixture in that order. The reaction mixture was cooled to 5°C, the crystals were collected by filtration, and washed with 120 mL of acetone to obtain 49 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloride dihydrate as pale yellow crystals.

(2) Under a nitrogen atmosphere, 20.0 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloride dihydrate was added to 240 mL of 0.45 mol/L hydrochloric acid and heated to 50°C to dissolve the mixture. A solution of 14.3 g of sodium formate in 40 mL of water was added dropwise to the solution over 33 minutes. The reaction mixture was cooled to 5°C, and the crystals were collected by filtration and washed with a mixture of 20 mL of acetone and 40 mL of water, and then with 60 mL of acetone to obtain 12.8 g of 5-hydroxy-1H-imidazole-4-carboxamide 3/4 hydrate as pale yellow crystals.

(Example 1)

30 mL of water and 625 μL of concentrated sulfuric acid were added to 1.5 g of 5-hydroxy-1H-imidazole-4-carboxamide 3/4 hydrate, heated to 50-55 ° C, and then 45 mL of water was added to dissolve the mixture. The mixture was stirred at this temperature for 30 minutes. The reaction solution was slowly cooled to room temperature, and after confirming the precipitation of crystals, ice-cooled and filtered to collect the crystals. Washed with water and air-dried to obtain 1.8 g of α-type crystals.

The α-type crystal shows characteristic peaks at diffraction angles of 10.0, 13.7, 14.6, 17.0, 18.0, 20.1, 24.4, 25.2, and 28.1° in a powder X-ray diffraction pattern expressed in 2θ.

Furthermore, the α-type crystal shows characteristic peaks at 1563 cm ^-1 , 1504 cm ^-1 , 1456 cm ^-1 , 1390 cm ^-1 , 1050 cm ^-1 , and 863 cm ^-1 in the infrared absorption spectrum.

The infrared absorption spectrum (ATR method) of the α-type crystal is shown in FIG3 , and the powder X-ray diffraction pattern is shown in FIG4 and Table 2.

The moisture content of the α-type crystals was 9.1%.

[Table 2]

(Example 2)

To 4.0 g of α-form crystals produced according to the method described in Example 1, 40 mL of a 1 mol/L aqueous sulfuric acid solution was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and 45 minutes. 20 mL of a 1 mol/L aqueous sulfuric acid solution was added to the reaction mixture, and after standing overnight, the mixture was further stirred for 1 hour and 30 minutes, and the crystals were collected by filtration. The crystals were washed with a 1 mol/L aqueous sulfuric acid solution and acetone, and air-dried to obtain 3.7 g of β-form crystals.

The β-type crystal shows characteristic peaks at diffraction angles of 5.0, 10.1, 13.6, 14.3, 14.7, 20.3, 27.4, 28.0, 28.8, and 29.6° in a powder X-ray diffraction pattern expressed in 2θ.

Furthermore, the β-type crystal shows characteristic peaks at 1560 cm ^-1 , 1508 cm ^-1 , 1459 cm ^-1 , and 1059 cm ^-1 in the infrared absorption spectrum.

The infrared absorption spectrum (ATR method) of the β-type crystal is shown in FIG1 , and the powder X-ray diffraction pattern is shown in FIG2 and Table 3.

The moisture content of the β-type crystals was 8.1%.

[Table 3]

(Example 3)

To 0.5 g of α-form crystals produced according to the method described in Example 1, 5 mL of a 2 mol/L aqueous sulfuric acid solution was added. The mixture was stirred at room temperature for 3 hours and 20 minutes. Then, 1 mL of concentrated sulfuric acid was added and stirred for 4 hours and 40 minutes. After standing overnight, the crystals were collected by filtration, washed with acetone, and air-dried to obtain 0.5 g of γ-form crystals.

The γ-type crystal shows characteristic peaks at diffraction angles of 10.3, 20.7, 20.9, 28.0, and 31.2° in terms of 2θ in a powder X-ray diffraction pattern.

Furthermore, the γ-type crystal shows characteristic peaks at 1560 cm ^-1 , 1503 cm ^-1 , 1459 cm ^-1 , 1304 cm ^-1 , 1061 cm ^-1 , and 892 cm ^-1 in the infrared absorption spectrum.

The infrared absorption spectrum (ATR method) of the γ-type crystal is shown in FIG5 , and the powder X-ray diffraction pattern is shown in FIG6 and Table 4.

The moisture content of the γ-type crystals was 4.1%.

[Table 4]

(Comparative Example 1)

According to the method described in Example 6 of International Publication No. 2009/035168, 5-hydroxy-1H-imidazole-4-carboxamide was obtained as a pale yellow powder.

Analysis by high performance liquid chromatography revealed that the obtained 5-hydroxy-1H-imidazole-4-carboxamide contained approximately 0.15% of benzoic acid.

The powder X-ray diffraction pattern is shown in FIG7 and Table 5.

[Table 5]

(Comparative Example 2)

With reference to the method described in Example 3 of International Publication No. 2009/035168, methanesulfonate of 5-hydroxy-1H-imidazole-4-carboxamide was produced as follows.

To 1.4 g of 5-hydroxy-1H-imidazole-4-carboxamide 3/4 hydrate, 30 mL of water and 1.0 g of methanesulfonic acid were added, heated at 50°C to dissolve, and then stirred at the same temperature for 30 minutes. After cooling the reaction solution to room temperature, toluene was added, and the water was azeotropically distilled off under reduced pressure. The precipitated solid was collected by filtration, washed with ethyl acetate, and air-dried to obtain 1.7 g of 5-hydroxy-1H-imidazole-4-carboxamide methanesulfonate.

The water content of the methanesulfonate of 5-hydroxy-1H-imidazole-4-carboxamide was 7.8%.

(Test Example 1) Storage stability test at 60°C and 75% relative humidity (1)

As test substances, the crystals obtained in Examples 1 and 2 and Comparative Example 1 were selected.

About 0.3 g of the test substance was placed in each glass bottle and stored at 60° C. and 75% relative humidity for 2 weeks.

The state of the crystal of Example 1 after the test is shown in Fig. 8 , and the state of the crystal of Example 2 is shown in Fig. 9 . Furthermore, the state of the crystal of Comparative Example 1 after the test is shown in Fig. 10 .

The crystals obtained in Examples 1 and 2 were significantly less colored than the crystals obtained in Comparative Example 1 and were excellent in storage stability.

(Test Example 2) Storage stability test at 60°C and 75% relative humidity (2)

As a test substance, the crystals obtained in Example 1 were selected.

Approximately 0.3 g of the test substance was placed in a glass bottle and stored at 60°C and 75% relative humidity for 2 weeks. After the test, the purity was measured by HPLC. The result showed that the purity of the test substance was 99.97%.

The crystals obtained in Example 1 had high purity even after storage for 2 weeks and were excellent in storage stability.

Furthermore, the crystals obtained in Example 2 were evaluated in the same manner as in Test Example 2. The crystals had high purity even after storage for 2 weeks and were excellent in storage stability.

(Test Example 3) Storage stability test at 60°C and 75% relative humidity (3)

As test substances, the crystals obtained in Example 2 and Comparative Example 2 were selected.

About 0.3 g of the test substance was placed in a glass bottle and stored at 60°C and 75% relative humidity for 2 weeks. The mass change rate of the test substance was determined according to the following formula.

Mass change rate (%) = {(A ₁ - _{A 0} )/A ₀ } × 100

_A0 : Mass of the test substance before the test (g)

_A1 : Mass of the test substance after the test (g)

Furthermore, changes in the appearance color of the test substances were visually evaluated.

The results are shown in Table 6.

Table 6

The crystals obtained in Example 2 had lower hygroscopicity than the crystals obtained in Comparative Example 2, and did not change in appearance color.

Furthermore, when these crystals were stored at 25° C. and a relative humidity of 97% for 2 weeks, the crystals obtained in Example 2 did not change in appearance and were stable, but the crystals obtained in Comparative Example 2 deliquesced and were unstable.

(Preparation Example 1)

The pharmaceutical composition containing the salt of the present invention and its crystal can be produced by, for example, the following formulation.

tablet

(1), (2) and (3) are mixed, and the mixed powder is sprayed with (4) to form granules. Then, (5) and (6) are added and mixed, and tableting is performed.

Industrial applicability

The salt of the present invention and its crystals have the characteristics of (1) suppressed blue coloration, (2) high purity, (3) low hygroscopicity, and (4) excellent storage stability, and are useful as pharmaceutical raw materials.

Claims (9)

1. A crystal of a sulfate of 5-hydroxy-1H-imidazolium-4-carboxamide, which has diffraction peaks at diffraction angles of 5.0°, 20.3° and 29.6° (denoted by 2θ) in a powder X-ray diffraction pattern. 2. A crystal of a sulfate of 5-hydroxy-1H-imidazolium-4-carboxamide, which, in a powder X-ray diffraction pattern, exhibits diffraction peaks at diffraction angles of 5.0°, 10.1°, 13.6°, 14.3°, 14.7°, 20.3°, 27.4°, 28.0°, 28.8°, and 29.6° (denoted by 2θ). 3. A pharmaceutical composition comprising: crystals of a sulfate of 5-hydroxy-1H-imidazolium-4-carboxamide having diffraction peaks at diffraction angles of 5.0°, 20.3°, and 29.6° (represented by 2θ) in a powder X-ray diffraction pattern; or Crystals of 5-hydroxy-1H-imidazolium-4-carboxamide sulfate with diffraction peaks at diffraction angles of 5.0°, 10.1°, 13.6°, 14.3°, 14.7°, 20.3°, 27.4°, 28.0°, 28.8° and 29.6° (denoted by 2θ) in powder X-ray diffraction patterns. 4. A crystal of a sulfate of 5-hydroxy-1H-imidazolium-4-carboxamide, which has diffraction peaks at diffraction angles of 13.7°, 17.0°, 18.0° and 20.1° (denoted by 2θ) in a powder X-ray diffraction pattern. 5. A crystal of a sulfate of 5-hydroxy-1H-imidazolium-4-carboxamide, which, in a powder X-ray diffraction pattern, has diffraction peaks at diffraction angles of 10.0°, 13.7°, 14.6°, 17.0°, 18.0°, 20.1°, 24.4°, 25.2° and 28.1° (denoted by 2θ). 6. A pharmaceutical composition comprising: crystals of a sulfate of 5-hydroxy-1H-imidazolium-4-carboxamide having diffraction peaks at diffraction angles of 13.7°, 17.0°, 18.0°, and 20.1° (represented by 2θ) in a powder X-ray diffraction pattern; or Crystals of 5-hydroxy-1H-imidazolium-4-carboxamide sulfate with diffraction peaks at diffraction angles of 10.0°, 13.7°, 14.6°, 17.0°, 18.0°, 20.1°, 24.4°, 25.2° and 28.1° (denoted by 2θ) in powder X-ray diffraction patterns. 7. A crystal of a sulfate of 5-hydroxy-1H-imidazolium-4-carboxamide, which has diffraction peaks at diffraction angles of 10.3°, 20.7°, 20.9° and 31.2° (denoted by 2θ) in a powder X-ray diffraction pattern. 8. A crystal of a sulfate of 5-hydroxy-1H-imidazolium-4-carboxamide, which has diffraction peaks at diffraction angles of 10.3°, 20.7°, 20.9°, 28.0° and 31.2° (denoted by 2θ) in a powder X-ray diffraction pattern. 9. A pharmaceutical composition comprising: crystals of a sulfate of 5-hydroxy-1H-imidazolium-4-carboxamide having diffraction peaks at diffraction angles of 10.3°, 20.7°, 20.9°, and 31.2° (represented by 2θ) in a powder X-ray diffraction pattern; or Crystals of 5-hydroxy-1H-imidazolium-4-carboxamide sulfate with diffraction peaks at diffraction angles of 10.3°, 20.7°, 20.9°, 28.0° and 31.2° (denoted by 2θ) in powder X-ray diffraction patterns.