JP2019089822A - New crystal form of topiroxostat, and preparation method therefor - Google Patents

Abstract

To provide a new crystal form of 5-(2-cyan-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, and a preparation method therefor.SOLUTION: The present invention provides a crystal form A of a compound represented by the following formula (I) having characteristic peaks at 2θ values of 10.2°±0.2°, 17.0°±0.2°, 27.3°±0.2° in a powder X-ray diffraction pattern.SELECTED DRAWING: Figure 1

Description

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

Topyroxostat has a chemical name of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole, and is a xanthine oxide developed by Fuji Chemical Co., Ltd. in Japan It is a reductase (XOR) inhibitor. Topiroxostat is approved and 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 existence of two or more different crystalline forms of a substance in a drug. Crystalline polymorphism is widespread in drugs. Even with the same drug, the solubility, melting point, density, stability, etc. differ greatly depending on the crystal form, and thus affect the stability, uniformity, bioavailability, efficacy and safety of the drug to various extents. Therefore, it is one of the important research contents that can not be neglected to conduct the screening of crystal polymorphs entirely and systematically in drug development and to select the crystal form most suitable for development.

Studies have shown that crystal polymorphism also exists in topiroxostat. The original manufacturer entrusts three crystal forms of topiroxostat with type I crystal, type II crystal and hydrate crystal in the patent WO2010017515A1, but the patent discloses hygroscopicity, stability, etc. of the three crystal forms. There is no mention of physicochemical properties, and it is only mentioned that Form I crystals have good water solubility. However, in drug development, it is one of the important research contents that can not be neglected to perform screening of crystal polymorphisms systematically and systematically and select the crystal form most suitable for development. Therefore, in order to provide more and better options for future drug development, screening of crystal polymorphism of the compound represented by the formula (I) is further performed, and the stability is good and the hygroscopicity is low, There is a need to find an anhydrous crystalline form that is suitable for industrial production.

As a result of intensive studies, the inventors of the present invention have found a new crystalline form of a compound represented by the formula (1) which has good stability, solubility and hygroscopicity suitable for pharmaceutical use.

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

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

Furthermore, the crystalline form A provided by the present invention is also one of the 2θ values of 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 ° Alternatively, it is characterized by having a characteristic peak in a powder X-ray diffraction pattern at two or three places.

In addition, the crystalline form A provided by the present invention may also be powdered X-ray to a 2θ value of 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 °. It is characterized by having a feature peak in a diffraction pattern.

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

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

Preferably, the crystalline form A provided by the present invention is at 10.2 ° ± 0.2 °, 17.0 ° ± 0.2 °, 27.3 ° ± 0.2 °, 15.7 ° ± 0. Powder X-ray at a 2θ value of 2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 °, 15.5 ° ± 0.2 °, 20.6 ° ± 0.2 ° It has a feature 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, crystalline form A provided by the present invention is characterized by an endothermic peak when heated to around 326 ° C. in differential scanning calorimetry and having a differential scanning calorimetry pattern substantially as shown in FIG. I assume.

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

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

Furthermore, the ketone-based solvent is more preferably 1-methyl pyrrolidone, 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 the compound of formula (I) and a pharmaceutical excipient. Generally, a therapeutically effective amount of crystalline form A of the compound of formula (I) is mixed or contacted with one or more pharmaceutically acceptable excipients and is well known in the pharmaceutical art A pharmaceutical composition or formulation is produced by the method of

The above 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, vaginal be able to. Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, and, if necessary, an immediate preparation of the pharmaceutically active ingredient. It can be release, delayed release or controlled 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, 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 according to the invention have a surprisingly low hygroscopicity and stability in water or in aqueous ethanol, in particular tablets, suspensions, capsules, disintegrating tablets, immediate release, sustained release and controlled release. It is preferable to use tablets of the type, more preferably tablets, suspensions, and capsules.

As a pharmaceutically acceptable excipient in the above-mentioned pharmaceutical composition, 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; eg binders such as gum arabic, guar gum, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol etc .; eg starch, starch sodium glycolate, pregelatinized starch, Disintegrators 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; complexing agents such as, for example, each grade of cyclodextrin and resin; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, methyl methacrylate, wax, etc. Examples include, but are 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, etc. . If desired, a coating layer such as shellac coating, sugar coating or polymer coating can be formed into a tablet, and the polymer in the coating layer is, for example, hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl cellulose, methacrylic acid based polymer, hydroxypropyl Cellulose or starch may be mentioned, and may further contain silica, an antiblocking agent such as talc, an emulsifier such as titanium dioxide, and a colorant such as an iron oxide colorant. For liquid oral dosage forms, suitable excipients include water, oils, alcohols, glycols, flavoring agents, preservatives, stabilizers, coloring agents 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, xanthan gum, alginates, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. In the case of parenteral dosage forms, the excipients for aqueous or non-aqueous sterile injectable solutions typically include sterile water, saline or aqueous glucose solution, buffers, antioxidants, bacteriostats, and such It may also include a solute that can render the pharmaceutical composition isotonic with blood. Each excipient should be acceptable, compatible with the other ingredients in the formulation, and harmless to the patient.

The above pharmaceutical compositions can be prepared by methods known to those skilled in the art as conventional techniques. In preparing a pharmaceutical composition, 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, granules can be prepared by processes such as mixing, granulation, tableting or capsule filling. The powder is prepared by mixing the pharmaceutically active ingredient and the excipient ground to an appropriate grade. Solutions and syrups can be prepared by dissolving the pharmaceutically active ingredient in suitably flavored water or aqueous solution. Suspensions can be prepared by dispersing the pharmaceutically active ingredient in a pharmaceutically acceptable carrier.

In particular, when wet granulation of a solid preparation is described using wet granulation of tablets as an example, the manufacturing 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 wet solid into aggregates or granules, and continue wet granulation until desired uniform particle size is obtained Then, dry the granules. Next, the obtained dry granules are mixed with a disintegrant, a lubricant, an antiblocking agent and the like, and compressed with a tableting machine. If desired, coat with a suitable coating powder.

The crystalline form A of the compound of formula (I) provided by the present invention can be used as a xanthine oxidase inhibitor and the crystalline form of the present invention modulates the activity of xanthine oxidase by the amount of administration Can. Crystalline form A can be used to treat a xanthine oxidase related disease or condition in an individual (e.g., a patient), and has a therapeutically effective amount or a therapeutically effective dose of a crystalline form of the compound of the invention or a pharmaceutical composition thereof The treatment is carried out by administering the substance to an individual in need of such treatment. Crystalline form A of the compound of formula (I) provided by the present invention can also be used for the treatment of hyperuricemia and gout due to hyperuricemia.

The advantageous effects of the present invention are as follows.
The crystalline form A provided by the present invention is stable, has low hygroscopicity, and can reliably prevent the occurrence of crystal transition during storage and development of the drug, and thus changes in bioavailability and efficacy. Can be prevented.
Crystalline form A provided by the present invention has high solubility and meets the bioavailability and efficacy requirements.

In the method for producing crystal form A of the present invention, "patented crystal form" refers to the crystal form described in WO2010017515 which is the prior art.

The term "effective therapeutic amount" or "therapeutically effective amount" as referred to in the present invention means a biological response required by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. Refers to the amount of active compound or agent that causes a drug response.

In the present invention, "treatment" refers to one or more of the following. (1) Prevention of a disease that prevents the disease, symptoms or disorder, for example, in an individual who does not have the onset or appearance of the disease or symptoms of the disease even if the disease, symptoms or disorders tend to be afflicted. (2) Suppression of a disease that suppresses the disease, symptom or disorder, for example, in an individual who has developed or appeared a lesion or symptom of the disease, symptom or disorder. (3) For example, in an individual who has developed / appeared a lesion or symptom of this disease, symptom or disorder, ameliorate this disease, symptom or disorder (ie, reversing the lesion and / or symptom), for example, the severity of the disease Improvement of the disease that alleviates.

As used herein, "crystalline polymorph" refers to different crystalline forms of the same compound and includes, but is not limited to, hydrates and other solid molecular forms of solvates containing the same compound. The existence 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 crystal polymorphs are known to affect pharmacological activity, solubility, bioavailability and stability due to their different physicochemical properties . Therefore, when crystalline polymorphs exist in a compound useful as a drug, it is desirable to produce crystalline compounds with high utility from these crystalline polymorphs.

The "powder X-ray diffraction pattern" in the present invention refers to a diffraction pattern observed in an experiment or a parameter based thereon. Powder X-ray diffraction patterns are characterized by peak position and peak intensity.
As used herein, "crystalline" or "crystalline form" refers to those identified by the characteristics of the X-ray diffraction pattern shown. A person skilled in the art can understand that the physicochemical properties mentioned in the present invention are identifiable and the experimental error depends on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns generally vary with the conditions of the apparatus. In particular, the order of the peak intensities should not be considered as the sole or definitive factor, as the relative intensities of the X-ray diffraction patterns may also vary with the experimental conditions. Also, the experimental error of the peak angle is usually less than 5%, the errors of these angles have to be taken into account, and an error of ± 0.2 ° is usually tolerated. Furthermore, due to experimental factors such as sample height, an overall offset of the peak angle can occur, usually allowing some offset. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of one crystalline form in the present invention does not necessarily match the X-ray diffraction pattern of the example referred to herein. It is within the scope of the present invention if it is a crystalline form having the same or similar pattern as the feature peak in these spectra. A person skilled in the art can confirm, by comparing the spectrum of the present invention and the spectrum of an unknown crystal form, whether the two sets of spectra are the same or different crystal forms.

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

Hereinafter, the present invention will be further described by way of specific examples, but the present invention is not limited to the following examples. Those skilled in the art may improve the manufacturing method and the use apparatus within the scope of the claims, and these improvements are also included in the scope of the present invention. Accordingly, the scope of rights of the present invention patent is according to 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 H NMR: Proton nuclear magnetic resonance spectra

The powder X-ray diffraction pattern in the present invention is obtained by a Panalytical Empyrean 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
Kα 1 (Å): 1.540598; K α 2 (Å): 1.544426
Kα2 / Kα1 intensity ratio: 0.50
Voltage: 45 thousand volts (kV)
Current: 40mA (mA)
Scanning range: 3.0 to 40.0 degrees

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

Example 1
[Method for Producing Crystalline Form A of Compound Represented by Formula (I)]
Dissolve 7.4 mg of the free base of the compound of the formula (I) in 0.18 mL of 1-methylpyrrolidone and stir the solution, add 2.0 mL of acetonitrile dropwise to the above solution for an additional hour at room temperature Stir and filter. The obtained solid is in the crystal form A as a result of measurement.
The powder X-ray diffraction data of the crystalline form obtained in this example are as shown in Table 1. The XRPD pattern is as shown in FIG. Although the powder X-ray-diffraction data of the crystal form obtained by the present Example contain the data of Table 1, it is not limited to these. The DSC pattern is as shown in FIG. 2, and the ¹ H NMR pattern is as shown in FIG.

Example 2
[Method for Producing Crystalline Form A of Compound Represented by Formula (I)]
Dissolve 7.4 mg of the free base of the compound represented by the formula (I) in 0.18 mL of 1-methylpyrrolidone, add this solution dropwise to 2.0 mL of acetonitrile with stirring, and further stir at room temperature for 1 hour, filter did. The obtained solid is in the crystal form A as a result of measurement.
Powder X-ray diffraction data of crystal form A obtained in the present example are as shown in Table 2.

Example 3
[Hygroscopicity test of crystal form A of the compound represented by formula (I)]
About 10 mg of crystalline form A of the present invention was weighed at 25 ° C., and the hygroscopicity was measured by dynamic moisture adsorption measurement (DVS). The experimental results are as shown in Table 3. The DVS pattern of crystalline form A is as shown in FIG. The comparison of the XRPD patterns before DVS 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 medicinal season 2010 edition Appendix X IX J Pharmaceutical hygroscopicity guiding principle, experimental conditions: 25 ° C ± 1 ° C, 80% relative humidity)
Deliquescent: When it absorbs enough water, it becomes a liquid.
High hygroscopicity: The weight increase due to moisture absorption is 15% or more.
Hygroscopic: The weight gain due to moisture absorption is less than 15% and 2% or more.
Low hygroscopicity: The weight gain due to moisture absorption is less than 2% and 0.2% or more.
Non-hygroscopic or substantially non-hygroscopic: weight gain due to moisture absorption is less than 0.2%.

According to the results, the crystalline form A of the present invention is low in hygroscopicity, with a weight gain of 1.00% when stored and equilibrated at 80% relative humidity. From this property, the crystal form is less likely to be affected by humidity or deliquescent, which is advantageous for long-term storage. In addition, since this crystalline form has low hygroscopicity, special drying conditions are not required at the time of production, and the process of production and post treatment can be simplified to some extent, and industrial production is facilitated. Since this crystal form hardly changes in moisture content under various humidity conditions, it does not require severe storage conditions, can significantly reduce the cost of product storage and quality control, and has high economic value.

Example 4
[Comparative Study of Solubility of Crystalline Form A of Compound Represented by Formula (I) and Patent II Crystalline]
SGF (simulated gastric fluid), pH 5.0 FeSSIF (simulated intestinal fluid in fed state), pH 6.5 FaSSIF (simulated intestinal fluid in fasted state), and a sample of crystalline Form A prepared in Example 1 respectively A saturated solution was prepared at room temperature with pure water, and the content of the sample in the saturated solution after 1 hour, 4 hours and 24 hours was measured by high performance liquid chromatography (HPLC). The experimental results are as 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, and SGF (simulated gastric fluid) and pH 5 .0 FeSSIF (simulated intestinal fluid in fed state), the solubility of crystalline form A is about 3 times that of patent type II crystal, and in pH 6.5 Fa SSIF (simulated intestinal fluid in fasted state), the solubility of crystalline form A is patent type II crystal Was found to be about 1.3 times that of Thus, the solubility is extremely high, which contributes to the improvement of the bioavailability.

Example 5
[Study on Stability and Purity of Crystalline Form A of Compound Represented by Formula (I)]
The new crystalline form A obtained in the present invention is stored at 5 ° C., 25 ° C./RH 60%, 40 ° C./RH 75% for 90 days, sampled once each on the 15th, 30th and 90th days The chemical purity was measured by HPLC while measuring the XRPD change of the crystalline form of the sample. The experimental results show that crystalline form A has good physical stability and high chemical purity. The results of the purity data are as shown in Table 5. Figures 6, 7 and 8 show the XRPD results after storage of crystalline form A at 5 ° C, 25 ° C / RH 60%, 40 ° C / RH 75% for 15 days, 30 days and 90 days, respectively. (In FIG. 6, XRPD patterns after storage for 15 days at 5 ° C., initial crystalline form A, storage for 15 days at 25 ° C./60% RH, and after storage for 15 days at 40 ° C./75% RH. 7 shows XRPD patterns after 30 days of initial crystalline form A, 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. 8 is the XRPD pattern after storage for 90 days at 25 ° C./60% RH after storage for 90 days at 5 ° C., after initial phase A, storage at 5 ° C. for 90 days, from the top.

According to the results, crystal form A of the compound represented by the formula (I) is subjected to conditions of 5 ° C., 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 crystal form A of the compound represented by formula (I) provided by the present invention has good stability and high purity.

Example 6
Measure the appropriate amount of crystal form A of the compound represented by the formula (I) and the patent type I crystal, add a suitable amount of methyl isobutyl ketone (MIBK) to prepare a suspension, and adjust to 5 ° C, 25 ° C, 50 ° C. Each was stored, equilibrated for 1 hour, and centrifuged. The liquid was measured for concentration 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 a solid in which crystal form A and crystal form I are equilibrated for 1 hour, respectively. (FIG. 9 shows the XRPD pattern of crystal form A before equilibration, the XRPD pattern after equilibration at 5 ° C., 25 ° C., 50 ° C. for 1 hour in order from the top. XRPD pattern of Form I crystal, XRPD pattern after equilibration at 5 ° C., 25 ° C., 50 ° C. for 1 hour)

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

Claims (11)

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