JP2018510173A - Novel crystal form of topiroxostat and process for producing the same - Google Patents

Abstract

The present invention relates to a novel crystal form of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole and a production method thereof. The novel crystalline form provided by the present invention can be used to treat gout and hyperuricemia. The novel crystalline form provided by the present invention has good stability, a remarkable purification effect, and solubility and hygroscopicity are suitable for pharmaceutical use. Crystalline form A provided by the present invention has advantageous properties that contribute to industrial production and has important value in terms of future drug optimization and development. [Selection] Figure 1

Description

  The present invention relates to the field of chemical medicine, in particular, to crystal form A of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole and a process for producing the same.

  Topiroxostat is a xanthine oxide having a chemical name of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole and developed by Fuji Pharmaceutical Co., Ltd. in Japan. It is a reductase (XOR) inhibitor. Topiroxostat is marketed in Japan on June 28, 2013 as a treatment for gout and hyperuricemia. The chemical structure of this drug is represented by the following formula (I).

  Drug polymorphism refers to the presence of two or more different crystalline forms of a substance in a drug. Crystal polymorphism is widespread in drugs. Even for the same drug, solubility, melting point, density, stability, etc. vary greatly depending on the crystal form, thus affecting the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, it is one of the important research contents that cannot be ignored to conduct the screening of crystal polymorphs in drug development completely and systematically and to select the most suitable crystal form for development.

  Studies have shown that polymorphism also exists in topiroxostat. In the patent WO20141717515A1, the pioneer manufacturer has licensed the three crystal forms of topiroxostat I-type crystal, II-type crystal, and hydrate crystal, but the patent describes the hygroscopicity, stability, etc. of the three crystal forms. There is no description about the physicochemical properties, and there is only mention that type I crystals have good water solubility. However, in drug development, it is one of the important research contents that cannot be ignored to conduct crystal polymorphism screening in a full and systematic manner and select the most suitable crystal form for development. Therefore, in order to provide more and better options for future drug development, further screening of the crystalline polymorph of the compound represented by formula (I) is performed, the stability is good, the hygroscopicity is low, There is a need to find anhydrous crystal forms suitable for industrial production.

  As a result of intensive studies, the inventors of the present invention have found a new crystal form of the compound represented by the formula (I) having good stability, solubility and hygroscopicity suitable for pharmaceutical use.

  One of the objects of the present invention is to provide a new crystal form of the compound of formula (I), crystal form A.

  The crystalline form A provided by the present invention has a 2θ value of 10.2 ° ± 0.2 °, 17.0 ° ± 0.2 °, 27.3 ° ± 0.2 ° in the powder X-ray diffraction pattern. It has a characteristic peak.

  In addition, the crystalline form A provided by the present invention also has one of the 2θ values of 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 °. Or it has the characteristic peak in a powder X-ray diffraction pattern in two places or three places, It is characterized by the above-mentioned.

  Furthermore, the crystalline form A provided by the present invention also has a powder X-ray at 2θ values of 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 °. It has a characteristic peak in the diffraction pattern.

  Furthermore, the crystalline form A provided by the present invention also has a powder X-ray diffraction pattern at one or two of the 2θ values of 15.5 ° ± 0.2 °, 20.6 ° ± 0.2 °. It has the characteristic peak in.

  Furthermore, the crystalline form A provided by the present invention is also characterized by having a characteristic peak in the powder X-ray diffraction pattern at 2θ values of 15.5 ° ± 0.2 °, 20.6 ° ± 0.2 °. And

  Preferably, the crystalline form A provided by the present invention is 10.2 ° ± 0.2 °, 17.0 ° ± 0.2 °, 27.3 ° ± 0.2 °, 15.7 ° ± 0. Powder X-rays with 2θ values of 2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 °, 15.5 ° ± 0.2 °, 20.6 ° ± 0.2 ° It has a characteristic peak in the diffraction pattern.

  Furthermore, the crystalline form A provided by the present invention is also characterized by having a powder X-ray diffraction pattern substantially as shown in FIG.

  Furthermore, the crystalline form A provided by the present invention is characterized in that in differential scanning calorimetry, an endothermic peak appears when heated to around 326 ° C., and has a differential scanning calorimetry pattern substantially as shown in FIG. And

  Another object of the present invention is to dissolve the powder of the compound represented by formula (I) in a mixed solvent system composed of one or more solvents, and perform suspension stirring, cooling crystallization, concentrated crystallization, and antisolvent order. It is to provide a method for producing crystal form A, characterized in that crystals are obtained by a crystallization method of addition or reverse solvent reverse addition.

  Further, the solvent system is preferably a ketone solvent or a mixed solvent system of a ketone solvent and an alkyl nitrile.

  Furthermore, the ketone solvent is more preferably 1-methylpyrrolidone, and the alkyl nitrile is more preferably acetonitrile.

  Another object of the present invention is to provide a pharmaceutical composition comprising an effective therapeutic amount of crystalline form A of a compound of formula (I) and a pharmaceutical excipient. In general, a therapeutically effective amount of crystalline form A of a compound of formula (I) is mixed or contacted with one or more pharmaceutically acceptable excipients and is well known in the pharmaceutical arts. A pharmaceutical composition or formulation is prepared by the method described above.

  The pharmaceutical composition is formulated into a dosage form for administration by an appropriate route such as oral, parenteral (including subcutaneous, intramuscular, intravenous or intradermal), rectal, transdermal, nasal, and vagina. be able to. Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, liquids, syrups or suspensions, if necessary, immediate delivery of the pharmaceutically active ingredient. It can be release, delayed release or modified release. Dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions. Dosage forms suitable for rectal administration include suppositories or enemas. Dosage forms suitable for transdermal administration include ointments, creams and patches. Dosage forms suitable for nasal administration include aerosols, sprays and nasal drops. Dosage forms suitable for vaginal administration include suppositories, stoppers, gels, pastes or sprays. The crystalline forms of the present invention have surprisingly low hygroscopicity and stability in water or aqueous ethanol so that they are especially tablets, suspensions, capsules, disintegrating tablets, immediate release, sustained release and controlled release. Of these, it is preferable to use tablets, suspensions, and capsules among them.

  Examples of the pharmaceutically acceptable excipient in the above pharmaceutical composition include, in the case of a solid oral dosage form, for example, starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, phosphoric acid. Diluents such as tricalcium, mannitol, sorbitol, sugar; binders such as gum arabic, guar gum, gelatin, polyvinyl pyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol; for example starch, starch sodium glycolate, pregelatinized starch, Disintegrants such as crospovidone, croscarmellose sodium, colloidal silica; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate; Glidants such as colloidal silica; complex forming agents such as cyclodextrins and resins of various grades; release rate control agents such as hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, methylmethacrylate, wax, etc. For example, but not limited to. Other pharmaceutically acceptable excipients that may be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like. . If desired, a coating layer such as shellac coating, sugar coating or polymer coating can be formed on the tablet. Examples of the polymer in the coating layer include hydroxypropylmethylcellulose, polyvinyl alcohol, ethylcellulose, methacrylic acid-based polymer, hydroxypropyl A cellulose or starch is mentioned, Furthermore, anti-blocking agents, such as a silica and a talc, emulsifiers, such as titanium dioxide, and coloring agents, such as an iron oxide type coloring agent, can also be included. In the case of liquid oral dosage forms, suitable excipients include water, oil-based, alcohol-based, glycol-based, flavoring agents, preservatives, stabilizers, colorants and the like. Aqueous or non-aqueous sterile suspensions may contain anti-settling agents and thickeners. Suitable excipients for aqueous suspensions include, for example, natural or synthetic gums such as gum arabic and xanthan gum, alginates, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. In the case of parenteral dosage forms, aqueous or non-aqueous sterile injection excipients typically include sterile water, saline or aqueous glucose solutions, including buffers, antioxidants, bacteriostatic agents, and such The pharmaceutical composition may include a solute that is isotonic with blood. Each excipient must be acceptable, compatible with the other ingredients in the formulation and not injurious to the patient.

  The above pharmaceutical composition can be prepared by a method well known to those skilled in the art as conventional techniques. In preparing the pharmaceutical composition, the crystalline form A of the present invention and one or more pharmaceutically acceptable excipients are mixed and optionally further mixed with one or more other pharmaceutically active ingredients. For example, tablets, capsules and granules can be prepared by processes such as mixing, granulation, tableting or capsule filling. Powders are prepared by mixing pharmaceutically active ingredients and excipients ground to the appropriate grade. Solutions and syrups can be prepared by dissolving the pharmaceutically active ingredient in appropriately flavored water or an aqueous solution. Suspensions can be prepared by dispersing pharmaceutically active ingredients in a pharmaceutically acceptable carrier.

  In particular, regarding the wet granulation method for solid preparations, if the wet granulation of tablets is described as an example, the production process is as follows. Mix dry solids such as active ingredients, fillers, binders, etc., wet with a wetting agent such as water or alcohol, make the wet solids into aggregates or granules, and continue wet granulation until the desired uniform particle size is achieved Subsequently, the granules are dried. Next, the obtained dried granule is mixed with a disintegrant, a lubricant, an antiblocking agent and the like, and tableted with a tableting machine. If desired, coat with a suitable coating powder.

  The crystalline form A of the compound represented by the formula (I) provided by the present invention can be used as a xanthine oxidase inhibitor, and the crystalline form of the present invention regulates the activity of xanthine oxidase according to the amount of administration. Can do. Crystalline form A can be used to treat a xanthine oxidase-related disease or condition in an individual (eg, a patient), a therapeutically effective amount or a therapeutically effective dose of a crystalline form of a compound of the invention or a pharmaceutical composition thereof Treatment is performed by administering the product to an individual in need of such treatment. The crystalline form A of the compound represented by the formula (I) provided by the present invention can also be used for the treatment of hyperuricemia and gout caused by hyperuricemia.

Advantageous effects of the present invention are as follows.
The crystalline form A provided by the present invention has good stability, low hygroscopicity, and can reliably prevent the occurrence of crystal transition during storage and development of the drug. Can be prevented.
Crystalline form A provided by the present invention has high solubility and satisfies bioavailability and efficacy requirements.

  In the method for producing crystal form A of the present invention, “patent crystal form” refers to a crystal form described in WO201417515, which is a prior art.

  As used herein, an “effective therapeutic amount” or “therapeutically effective amount” refers to a biological response desired by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human or Refers to the amount of active compound or drug that causes a drug response.

  As used herein, “treatment” refers to one or more of the following. (1) Prevention of a disease by preventing the disease, symptom or disorder in an individual who has a tendency to suffer from the disease, symptom or disorder, but has not developed or developed a lesion or symptom of the disease. (2) For example, suppression of a disease that suppresses the disease, symptom, or disorder in an individual who develops or appears as a lesion or symptom of the disease, symptom, or disorder. (3) Improve the disease, symptom or disorder (ie, reverse the lesion and / or symptom), for example, in an individual who develops or appears the lesion or symptom of the disease, symptom or disorder, for example, the severity of the disease The improvement of the disease that reduces.

  As used herein, “crystal polymorph” refers to different crystal forms of the same compound, including but not limited to other solid molecular forms of hydrates and solvates containing the same compound. The presence of many crystal forms in the same drug molecule is called drug crystal polymorphism. Drug crystal polymorphism is a common phenomenon in solid drugs. Pharmaceutical compounds having such crystalline polymorphs are known to affect pharmacological activity, solubility, bioavailability and stability due to their different physicochemical properties . Therefore, in the case where a crystal polymorph exists in a compound useful as a drug, it is desired to produce a highly useful crystalline compound from these crystal polymorphs.

  The “powder X-ray diffraction pattern” referred to in the present invention refers to a diffraction pattern observed in an experiment or a parameter based thereon. The powder X-ray diffraction pattern is characterized by peak position and peak intensity.

  The term “crystal” or “crystal form” as used in the present invention refers to what is confirmed by the characteristics of the X-ray diffraction pattern shown. One skilled in the art can appreciate that the physicochemical properties referred to in the present invention are identifiable and that the experimental error depends on instrument conditions, sample preparation and sample purity. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern generally varies depending on the conditions of the apparatus. In particular, since the relative intensities of the X-ray diffraction patterns can also vary with experimental conditions, the order of peak intensities should not be considered as the only or decisive factor. Also, the experimental error of the peak angle is usually 5% or less, and the error of these angles must be taken into consideration, and an error of ± 0.2 ° is usually allowed. Furthermore, due to experimental factors such as sample height, an overall offset of the peak angle can occur, usually allowing some offset. Accordingly, it can be understood by those skilled in the art that the X-ray diffraction pattern of one crystal form in the present invention does not necessarily match the X-ray diffraction pattern of the examples referred to in this specification. Crystal forms having the same or similar pattern as the characteristic peaks in these spectra are within the scope of the present invention. One skilled in the art can confirm whether the two sets of spectra are the same crystal form or different crystal forms by comparing the spectrum of the present invention with the spectrum of the unknown crystal form.

FIG. 1 is an XRPD pattern of crystal form A. FIG. 2 is a DSC pattern of crystal form A. FIG. 3 is a ¹ H-NMR pattern of crystal form A. FIG. 4 is a DVS pattern of crystal form A. FIG. 5 shows the XRPD pattern comparison before DVS and after DVS of crystal form A. FIG. FIG. 6 shows the XRPD overlay after crystal form A after storage at 5 ° C. for 15 days, storage at 25 ° C./60% RH for 15 days, and storage at 40 ° C./75% RH for 15 days (in order from the top). Initial crystal form A is an XRPD pattern after 15 days storage at 5 ° C., 15 days storage at 25 ° C./60% RH, and 15 days storage at 40 ° C./75% RH). FIG. 7 shows the XRPD overlay after crystal form A after storage at 5 ° C. for 30 days, storage at 25 ° C./60% RH for 30 days, and storage at 40 ° C./75% RH for 30 days (in order from the top). Initial crystal form A is an XRPD pattern after 30 days storage at 5 ° C., 30 days storage at 25 ° C./60% RH, and 30 days storage at 40 ° C./75% RH). FIG. 8 shows XRPD overlay after crystal form A after 90 days storage at 5 ° C., 90 days storage at 25 ° C./60% RH, and 90 days storage at 40 ° C./75% RH (in order from the top). Initial crystal form A is an XRPD pattern after 90 days storage at 5 ° C., 90 days storage at 25 ° C./60% RH, and 90 days storage at 40 ° C./75% RH). FIG. 9 is an XRPD pattern of a solid obtained by equilibrating crystal form A for 1 hour (in order from the top, XRPD patterns after equilibration for 1 hour at 5 ° C., 25 ° C., and 50 ° C.). FIG. 10 is a solid XRPD pattern obtained by equilibrating the patent I crystal for 1 hour (from the top, the initial I crystal, and the XRPD pattern after equilibrating at 5 ° C., 25 ° C., and 50 ° C. for 1 hour). FIG. 11 shows the transition relationship between the patent type I crystal and the crystal form A.

  EXAMPLES Hereinafter, although this invention is further demonstrated by a specific Example, this invention is not limited to the following Example. Those skilled in the art may improve the manufacturing method and the apparatus used within the scope of the claims, and these improvements are also within the scope of the present invention. Accordingly, the scope of the patent of the present invention is as defined by the appended claims.

The meanings of the abbreviations used in the present invention are as follows.
XRPD: Powder X-ray diffraction DSC: Differential scanning calorimetry
¹ HNMR: proton nuclear magnetic resonance spectrum

The powder X-ray diffraction pattern in the present invention is obtained by a Panaxial Empirean powder X-ray diffractometer. The measurement conditions of powder X-ray diffraction in the present invention are as follows.
X-ray diffraction conditions: Cu, Kα
Kα1 (Å): 1.540598; Kα2 (Å): 1.544426
Kα2 / Kα1 intensity ratio: 0.50
Voltage: 45,000 volts (kV)
Current: 40 mA (mA)
Scanning range: 3.0-40.0 degrees

The differential scanning calorimetry (DSC) pattern in the present invention is acquired by TA Q2000. The measurement conditions of differential scanning calorimetry (DSC) in the present invention are as follows.
Scanning speed: 10 ° C / min
Shielding gas: Nitrogen gas

Example 1
[Method for Producing Crystalline Form A of Compound Represented by Formula (I)]
7.4 mg of the free base of the compound represented by the formula (I) is dissolved in 0.18 mL of 1-methylpyrrolidone, the solution is stirred, and 2.0 mL of acetonitrile is added dropwise to the above solution, and further at room temperature for 1 hour. Stir and filter. The obtained solid was measured to be crystalline form A.
Table 1 shows the powder X-ray diffraction data of the crystalline form obtained in this example. The XRPD pattern is as shown in FIG. The powder X-ray diffraction data of the crystal form obtained in this example includes the data of Table 1, but is not limited thereto. The DSC pattern is as shown in FIG. 2, and the ¹ HNMR pattern is as shown in FIG.

Example 2
[Method for Producing Crystalline Form A of Compound Represented by Formula (I)]
7.4 mg of the free base of the compound represented by the formula (I) is dissolved in 0.18 mL of 1-methylpyrrolidone, and this solution is added dropwise to 2.0 mL of acetonitrile with stirring. The mixture is further stirred at room temperature for 1 hour and filtered. did. The obtained solid was measured to be crystalline form A.
Table 2 shows the powder X-ray diffraction data of the crystal form A obtained in this example.

Example 3
[Hygroscopic Test of Crystal Form A of Compound Represented by Formula (I)]
Under the condition of 25 ° C., about 10 mg of the crystalline form A of the present invention was weighed, and the hygroscopicity was measured by dynamic moisture adsorption measurement (DVS). The experimental results are as shown in Table 3. The DVS pattern of crystal form A is as shown in FIG. The XRPD pattern comparison before and after DVS is as shown in FIG. 5. In the figure, the upper pattern is before DVS and the lower pattern is after DVS.

[Description of hygroscopic characteristics and definition of hygroscopic weight increase] (Chinese Pharmacy 2010 edition Appendix XIX J Pharmaceutical Hygroscopicity Test Guidance Principle, Experimental Conditions: 25 ° C ± 1 ° C, 80% Relative Humidity)
Deliquescent: Becomes liquid when it absorbs enough moisture.
High hygroscopicity: Weight increase due to moisture absorption is 15% or more.
Hygroscopicity: Weight increase due to moisture absorption is less than 15% and 2% or more.
Low hygroscopicity: Weight increase due to moisture absorption is less than 2% and 0.2% or more.
Non-hygroscopic or substantially non-hygroscopic: weight increase due to moisture absorption is less than 0.2%.

  According to the results, the crystal form A of the present invention has a weight increase of 1.00% when equilibrated by storage at 80% relative humidity, and has low hygroscopicity. From this characteristic, it can be said that the crystal form is less likely to be affected or deliquescent by humidity and is advantageous for long-term storage. In addition, since this crystal form has low hygroscopicity, no special drying conditions are required at the time of manufacture, and the manufacturing and post-treatment processes can be simplified to some extent, thereby facilitating industrial production. Since this crystal form has almost no change in moisture content under various humidity conditions, it does not require strict storage conditions, can greatly reduce the cost of product storage and quality control, and has high economic value.

Example 4
[Comparative Study of Solubility of Crystal Form A of Compound Represented by Formula (I) and Patent Type II Crystal]
Samples of crystal form A and patent type II crystal produced in Example 1 were SGF (simulated gastric fluid), pH 5.0 FeSSIF (simulated intestinal fluid in the fed state), pH 6.5 FaSSIF (simulated intestinal fluid in the fasted state) and A saturated solution was prepared at room temperature with pure water, and the content of the sample in the saturated solution after 1, 4 and 24 hours was measured by high performance liquid chromatography (HPLC). The experimental results are shown in Table 4.

  From the above comparison results, the novel crystalline form A of the present invention stored in SGF, FaSSIF and FeSSIF for 1 hour, 4 hours, and 24 hours has higher solubility compared to the patent type II crystal, SGF (simulated gastric fluid) and pH 5 In 0.0FeSSIF (simulated intestinal fluid in the fed state), the solubility of crystal form A is about three times that of the patent type II crystal, and in pH 6.5 FaSSIF (simulated intestinal fluid in the hungry state), the solubility of crystal form A is the patent type II crystal It was found to be about 1.3 times that. Thus, the solubility is remarkably increased and contributes to the improvement of bioavailability.

Example 5
[Study on stability and purity of crystal form A of compound represented by formula (I)]
The new crystal form A obtained in the present invention was stored at 5 ° C., 25 ° C./RH 60%, 40 ° C./RH 75% for 90 days, and sampled once every 15 days, 30 days and 90 days. The XRPD change of the crystal form of the sample was measured, and the chemical purity was measured by HPLC. Experimental results show that crystal form A has good physical stability and high chemical purity. The results of the purity data are as shown in Table 5. FIGS. 6, 7 and 8 show the XRPD results after storage of Crystal Form A at 5 ° C., 25 ° C./RH 60%, 40 ° C./RH 75% for 15, 30, and 90 days, respectively. (FIG. 6 shows the XRPD pattern of the initial crystal form A in order from the top, after 15 days storage at 5 ° C., after 15 days storage at 25 ° C./60% RH, and after 15 days storage at 40 ° C./75% RH. 7 is an XRPD pattern of the initial crystal form A in order from the top, after 30 days storage at 5 ° C., 30 days storage at 25 ° C./60% RH, and 30 days storage at 40 ° C./75% RH. 8 is an XRPD pattern of the initial crystal form A in order from the top after 90 days storage at 5 ° C., 90 days storage at 25 ° C./60% RH, and 90 days storage at 40 ° C./75% RH.

  According to the results, the crystal form A of the compound represented by formula (I) is 5 ° C., under the conditions of long-term stability test (25 ° C./60% RH) and accelerated stability test (40 ° C./75% RH). The sample is stable during storage and there is almost no change in purity. From the above experimental results, it can be seen that the crystalline form A of the compound represented by the formula (I) provided by the present invention has good stability and high purity.

Example 6
Appropriate amounts of crystal form A and patent type I crystals of the compound represented by formula (I) are weighed, and an appropriate amount of methyl isobutyl ketone (MIBK) is added to prepare a suspension at 5 ° C, 25 ° C and 50 ° C. Each was stored, equilibrated for 1 hour, and centrifuged. The concentration of the liquid was measured by high performance liquid chromatography, and the solid was measured by XRPD. The results are as shown in Table 6. FIGS. 9 and 10 are XRPD patterns of solids obtained by equilibrating crystal forms A and I for 1 hour, respectively. (FIG. 9 shows the XRPD pattern of crystal form A before equilibration in order from the top, and the XRPD pattern after equilibration for 1 hour at 5 ° C., 25 ° C., and 50 ° C. In FIG. XRPD pattern of type I crystal is an XRPD pattern after equilibration at 5 ° C., 25 ° C. and 50 ° C. for 1 hour.

FIG. 11 shows a transition relationship diagram between the I-type crystal and the crystal form A drawn according to the Van Hove equation based on the solubility and temperature data of the I-type crystal and the crystal form A in the above table. As a result of studying the transition relation, it was found that the crystal form A is always more stable than the type I crystal under the condition of more than 5 ° C.

Claims (11)

A characteristic peak in the powder X-ray diffraction pattern has 2θ values of 10.2 ° ± 0.2 °, 17.0 ° ± 0.2 °, and 27.3 ° ± 0.2 °, which are described below. Crystal form A of the compound of formula (I).
  15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 ° of 2θ values, one or two or three places, powder X-ray diffraction pattern The crystalline form A of claim 1 having a characteristic peak in   2. A characteristic peak in a powder X-ray diffraction pattern is present at one or two of 2θ values of 15.5 ° ± 0.2 °, 20.6 ° ± 0.2 °. Or crystal form A according to 2.   The crystal form A according to any one of claims 1 to 3, which has a powder X-ray diffraction pattern substantially as shown in Fig. 1.   Dissolving the powder of the compound represented by formula (I) in a solvent system composed of one or more solvents, suspending stirring, cooling crystallization, concentration crystallization, reverse solvent sequential addition or reverse solvent reverse addition crystallization The method for producing the crystal form A of the compound represented by the formula (I) according to any one of claims 1 to 4, wherein the crystal is obtained by a method.   The production method according to claim 5, wherein the solvent system is a ketone solvent or a mixed solvent system of a ketone solvent and an alkyl nitrile.   The production method according to claim 6, wherein the ketone solvent is 1-methylpyrrolidone.   The production method according to claim 6, wherein the alkyl nitrile is acetonitrile.   A pharmaceutical composition comprising an effective amount of crystal form A according to any one of claims 1 to 4 and a pharmaceutically acceptable pharmaceutical excipient.   10. The pharmaceutical composition according to claim 9, wherein the crystalline form A can be used for the preparation of a therapeutic drug for gout and hyperuricemia. Use of the crystalline form A according to any one of claims 1 to 4 for treating gout and hyperuricemia.