JP6767382B2 - New crystal form of topiroxostat and its manufacturing method - Google Patents

Description

The present invention relates to the field of chemistry and pharmaceuticals, particularly crystal form A of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole and a method for producing the same.

Topiroxostat 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 Yakuhin Co., Ltd. in Japan. It is a reductase (XOR) inhibitor. Topiroxostat has been approved and marketed in Japan on June 28, 2013 for the treatment of gout and hyperuricemia. The chemical structure of this drug is represented by the following formula (I).

Drug polymorphism (drug polymorphism) means that a drug has two or more different crystalline state of matter. Crystal polymorphism is widespread in drugs. The solubility, melting point, density, stability, etc. of the same drug differ greatly depending on the crystal form, which affects the stability, uniformity, bioavailability, efficacy, and safety of the drug to various degrees. Therefore, comprehensive and systematic screening of polymorphs in drug development and selection of the most suitable crystal form for development is one of the important research contents that cannot be ignored.

Studies have shown that topiroxostat also has a crystalline polymorphism. In patent WO2014017515A1, the original manufacturer has granted the rights to three crystal forms of topyroxostat, type I crystal, type II crystal, and hydrate crystal, but the patent states that the three crystal forms have hygroscopicity, stability, etc. There is no description about physicochemical properties, and there is only mention that type I crystals have good water solubility. However, in drug development, screening for polymorphs in a comprehensive and systematic manner and selecting the most suitable crystal form for development is one of the important research contents that cannot be ignored. Therefore, in order to provide more and better options for future drug development, further screening of crystalline polymorphs of the compound represented by the formula (I) was carried out, and the stability was good and the hygroscopicity was low. It is necessary to find an anhydrous crystalline form suitable for industrial production.

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

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

The crystal form A provided by the present invention has 2θ values of 10.2 ° ± 0.2 °, 17.0 ° ± 0.2 °, and 27.3 ° ± 0.2 ° in the powder X-ray diffraction pattern. It is characterized by having a characteristic peak.

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

Further, the crystalline form A provided by the present invention also has a 2θ value of 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 °, and powder X-ray. It is characterized by having 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 ° and 20.6 ° ± 0.2 °. It is characterized by having a characteristic peak in.

Further, 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 a 2θ value of 15.5 ° ± 0.2 ° and 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-ray to 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.

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

Another object of the present invention is to dissolve the powder of the compound represented by the formula (I) in a mixed solvent system consisting of one or more kinds of solvents, and suspend stirring, cooling crystallization, concentrated crystallization, and reverse solvent order. The present invention provides a method for producing crystalline form A, which comprises obtaining crystals by a crystallization method of addition or reverse solvent addition.

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

Further, the ketone solvent is more preferably 1-methylpyrrolidone, and the alkylnitrile is more preferably acetonitrile.

Another object of the present invention is to provide a pharmaceutical composition containing a crystalline form A of a compound represented by the formula (I) in an effective therapeutic amount and a pharmaceutical excipient. Generally, 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 art. To prepare a pharmaceutical composition or preparation by the method of.

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), rectum, transdermal, nasal, and vaginal. be able to. Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, liquids, syrups or suspensions, and if necessary, immediate pharmaceutical active ingredients. It can be release, delayed release or regulated 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 intravaginal administration include suppositories, stoppers, gels, pastes or sprays. The crystalline form of the present invention has surprisingly low hygroscopicity and stability in water or in aqueous ethanol, especially tablets, suspensions, capsules, disintegrating tablets, immediate release, sustained release and controlled release. It is preferably a sex tablet, and more preferably a tablet, a suspension, or a capsule.

Examples of pharmaceutically acceptable excipients in the above pharmaceutical composition include starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, and phosphoric acid in the case of solid oral dosage form. Diluters such as tricalcium, mannitol, sorbitol, sugar; binders such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol; eg starch, sodium glycolicate, pregelatinized starch, Disintegrants such as crospovidone, croscarmellose sodium, colloidal silica; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate; flow promoters such as colloidal silica; eg each Complex-forming agents such as grade cyclodextrin and resins; release rate control agents such as, but not limited to, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, methyl methacrylate, wax and the like. Other pharmaceutically acceptable excipients that may be used include, but are not limited to, film forming agents, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like. .. If desired, a coating layer such as a shelac coating, sugar coating or polymer coating can be formed on the tablet, and the polymer in the coating layer includes, for example, hydroxypropylmethyl cellulose, polyvinyl alcohol, ethyl cellulose, methacrylic acid polymer, hydroxypropyl. Examples thereof include cellulose or starch, and further, antiblocking agents such as silica and talc, emulsifiers such as titanium dioxide, and colorants such as iron oxide-based colorants can 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 include antisettling agents and thickeners. Suitable excipients for aqueous suspending agents include, for example, natural or synthetic rubbers such as arabic rubber, xanthan gum, alginate, dextran, sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone or gelatin. In the case of parenteral dosage forms, the excipients for aqueous or non-aqueous sterile injections usually include sterile water, saline or aqueous glucose solutions, such as buffers, antioxidants, bacteriostatic agents, and the like. It may contain a solute capable of isotonizing the pharmaceutical composition with blood. Each excipient must be acceptable, compatible with the other ingredients in the formulation, and harmless to the patient.

The pharmaceutical composition can be prepared by a method well known to those skilled in the art as a conventional technique. When preparing the pharmaceutical composition, the crystalline form A of the present invention is mixed with one or more pharmaceutically acceptable excipients and, if desired, further mixed with one or more other pharmaceutically active ingredients. For example, tablets, capsules and granules can be prepared by steps such as mixing, granulation, tableting or capsule filling. Powders are prepared by mixing the pharmaceutically active ingredient and excipients ground to the appropriate grade. Liquids and syrups can be prepared by dissolving the pharmaceutically active ingredient in appropriately seasoned water or aqueous solutions. Suspensions can be prepared by dispersing the pharmaceutically active ingredient in a pharmaceutically acceptable carrier.

In particular, if the wet granulation method for solid preparations is described by taking wet granulation of tablets as an example, the manufacturing process is as follows. Dry solids such as active ingredients, fillers and binders are mixed and moistened with a wetting agent such as water or alcohol to agglomerate or granule the wet solid and continue wet granulation until the desired uniform particle size is achieved. , Then the granules are dried. Next, the obtained dried granules are mixed with a disintegrant, a lubricant, an anti-blocking agent and the like, and tableted with a tableting machine. If desired, it is coated 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 depending on the dose of administration. Can be done. Crystal form A can be used to treat xanthine oxidase-related diseases or conditions in individuals (eg, patients) and is the crystalline form or pharmaceutical composition of a therapeutically effective amount or dose of a compound of the invention. Treatment is performed by administering the substance 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.

The 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 surely prevent the occurrence of crystal transition during storage and development of a drug, so that changes in bioavailability and efficacy can be achieved. Can be prevented.
The crystalline form A provided by the present invention has high solubility and satisfies the requirements for bioavailability and efficacy.

In the method for producing the crystal form A of the present invention, the "patented crystal form" refers to the crystal form described in WO20144017515, which is a prior art.

The "effective therapeutic amount" or "therapeutically effective amount" as used in the present invention is a biological response or 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 drug that provokes a drug response.

The term "treatment" as used in the present invention refers to one or more of the following. (1) Prevention of a disease in which, for example, an individual who has a tendency to suffer from a disease, symptom or disorder but does not develop or develop a lesion or symptom of the disease prevents the disease, symptom or disorder. (2) For example, suppression of a disease that suppresses this disease, symptom or disorder in an individual in which a lesion or symptom of this disease, symptom or disorder develops or appears. (3) For example, in an individual in which a lesion or symptom of this disease, symptom or disorder develops or appears, the disease, symptom or disorder is improved (that is, the lesion and / or symptom is reversed), for example, the severity of the disease. Improvement of the disease to alleviate.

The term "polymorph" as used in the present invention refers to different crystalline forms of the same compound, including, but not limited to, other solid molecular forms of hydrates and solvates containing the same compound. The existence of many crystal forms in the same drug molecule is called a drug crystal polymorph. Drug crystal polymorphism is a common phenomenon in solid drugs. Pharmaceutical compounds with such polymorphs are known to affect pharmacological activity, solubility, bioavailability and stability due to their different physicochemical properties. .. Therefore, when crystalline polymorphs are present in compounds useful as drugs, it is desired to produce highly useful crystalline compounds from these polymorphs.

The "powder X-ray diffraction pattern" as used in the present invention refers to a diffraction pattern observed in an experiment or a parameter based on the diffraction pattern. The powder X-ray diffraction pattern is characterized by peak position and peak intensity.

The "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. Those skilled in the art can understand that the physicochemical properties referred to in the present invention are identifiable and that 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 the X-ray diffraction pattern generally changes depending on the conditions of the apparatus. In particular, the order of peak intensities should not be considered as the only or decisive factor, as the relative intensities of the X-ray diffraction patterns can also vary with experimental conditions. In addition, 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. In addition, experimental factors such as sample height can result in an overall offset of the peak angle, which usually allows some offset. Therefore, it can be understood by those skilled in the art that one crystalline X-ray diffraction pattern in the present invention does not necessarily match the X-ray diffraction pattern of the example referred to herein. Any crystal form having the same or similar pattern as the characteristic peaks in these spectra belongs to the scope of the present invention. One of ordinary skill in the art can confirm whether the two sets of spectra represent the same crystal form or different crystal forms by comparing the spectrum of the present invention with the spectrum of an 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 a comparison of the XRPD patterns of the crystal form A before DVS and after DVS. FIG. 6 shows the XRPD overlay of crystalline form A, stored at 5 ° C. for 15 days, stored at 25 ° C./60% RH for 15 days, and then stored at 40 ° C./75% RH for 15 days (from top to bottom). Initial crystal form A is an XRPD pattern 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). FIG. 7 shows the XRPD overlay of crystalline form A, stored at 5 ° C. for 30 days, stored at 25 ° C./60% RH for 30 days, and stored at 40 ° C./75% RH for 30 days (from top to bottom). Initial crystal form A is an XRPD pattern 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). FIG. 8 shows the XRPD overlay of crystalline form A, stored at 5 ° C. for 90 days, stored at 25 ° C./60% RH for 90 days, and stored at 40 ° C./75% RH for 90 days (from top to bottom). Initial crystal form A, 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 a solid XRPD pattern in which crystal form A is equilibrated for 1 hour (in order from the top, initial crystal form A is an XRPD pattern after equilibration at 5 ° C., 25 ° C., and 50 ° C. for 1 hour). FIG. 10 is a solid XRPD pattern in which patented type I crystals are equilibrated for 1 hour (from top to bottom, initial type I crystals, XRPD pattern after equilibration at 5 ° C., 25 ° C., and 50 ° C. for 1 hour). FIG. 11 shows the transition relationship between the patented type I crystal and the crystal form A.

Hereinafter, the present invention will be further described with reference to 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 equipment used within the scope of the claims, and these improvements also belong to the scope of the present invention. Therefore, the scope of rights of the patent of the present invention is based on the attached 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 PANalytical Empyrene powder X-ray diffractometer. The measurement conditions for powder X-ray diffraction in the present invention are as follows.
X-ray diffraction conditions: Cu, Kα
Kα1 (Å): 1.540598; Kα2 (Å): 1.5444426
Kα2 / Kα1 intensity ratio: 0.50
Voltage: 45,000 volts (kV)
Current: 40mA (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 for 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 Crystal 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, 2.0 mL of acetonitrile is added dropwise to the above solution, and the mixture is added dropwise at room temperature for another 1 hour. Stirred and filtered. As a result of measurement, the obtained solid has a crystal form A.
The crystalline powder X-ray diffraction data obtained in this example is as shown in Table 1. The XRPD pattern is as shown in FIG. The crystalline powder X-ray diffraction data obtained in this example includes, but is not limited to, the data in Table 1. The DSC pattern is shown in FIG. 2, and the ¹ HNMR pattern is shown in FIG.

Example 2
[Method for Producing Crystal 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, this solution is added dropwise to 2.0 mL of acetonitrile with stirring, and the mixture is further stirred at room temperature for 1 hour and filtered. did. As a result of measurement, the obtained solid has a crystal form A.
The powder X-ray diffraction data of the crystal form A obtained in this example is as shown in Table 2.

Example 3
[Hygroscopicity test of crystalline 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 shown in Table 3. The DVS pattern of crystal form A is as shown in FIG. The comparison of the XRPD patterns 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 Pharmaceutical Code 2010 Appendix XIX J Pharmaceuticals Hygroscopic Test Guidance Principle, Experimental Conditions: 25 ° C ± 1 ° C, 80% Relative Humidity)
Deliquescent: When it absorbs enough water, it becomes a liquid.
High hygroscopicity: Weight increase due to hygroscopicity is 15% or more.
Hygroscopicity: Weight increase due to hygroscopicity is less than 15% and more than 2%.
Low hygroscopicity: Weight increase due to moisture absorption is less than 2% and 0.2% or more.
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 has a weight increase of 1.00% when stored at 80% relative humidity and equilibrated, and has low hygroscopicity. From this characteristic, it can be said that 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 during production, the production and post-treatment processes can be simplified to some extent, and industrial production is facilitated. Since this crystalline form has almost no change in water content under various humidity conditions, it does not require strict storage conditions, and the cost of product storage and quality control can be significantly reduced, and has high economic value.

Example 4
[Comparative study of solubility between crystal form A of compound represented by formula (I) and patented type II crystal]
Crystal form A produced in Example 1 and a sample of patented type II crystal were used as SGF (simulated gastric juice), pH 5.0 FeSSIF (simulated intestinal juice in a feeding state), pH 6.5 FaSSIF (simulated intestinal juice in a hungry state) and A saturated solution was prepared with pure water at room temperature, 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 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 than the patented type II crystal, and SGF (simulated gastric fluid) and pH 5 At 0.0 FeSSIF (simulated intestinal fluid in the feeding state), the solubility of crystalline form A is about three times that of the patented type II crystal, and in pH 6.5 FaSSIF (simulated intestinal fluid in the hungry state), the solubility of crystalline form A is the patented type II crystal. It was found to be about 1.3 times that of. In this way, the solubility is significantly increased, which 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 crystalline form A obtained by the present invention was stored at 5 ° C., 25 ° C./RH60%, and 40 ° C./RH75% for 90 days, and sampled once on the 15th, 30th, and 90th days, respectively. The change in XRPD of the crystal form of the sample was measured, and the chemical purity was measured by HPLC. From the experimental results, it was found that the crystal form A has good physical stability and high chemical purity. The results of the purity data are shown in Table 5. FIGS. 6, 7 and 8 show the XRPD results after storing the crystalline form A at 5 ° C., 25 ° C./RH60% and 40 ° C./RH75% for 15, 30, and 90 days, respectively. (FIG. 6 shows the XRPD pattern of the initial crystal form A, stored at 5 ° C. for 15 days, stored at 25 ° C./60% RH for 15 days, and stored at 40 ° C./75% RH for 15 days, in that order from the top. FIG. 7 is an XRPD pattern in which the initial crystal form A is stored at 5 ° C. for 30 days, stored at 25 ° C./60% RH for 30 days, and then stored at 40 ° C./75% RH for 30 days in order from the top. 8 is an XRPD pattern in which the initial crystal form A is stored at 5 ° C. for 90 days, stored at 25 ° C./60% RH for 90 days, and then stored at 40 ° C./75% RH for 90 days in order from the top.)

According to the results, the crystal form A of the compound represented by the formula (I) is at 5 ° C. under the conditions of a long-term stability test (25 ° C./60% RH) and an 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
Weigh the crystal form A and patented type I crystal of the compound represented by the formula (I) in an appropriate amount, add an appropriate amount of methyl isobutyl ketone (MIBK) to prepare a suspension, and 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 concentration of the solid was measured by XRPD. The results are shown in Table 6. 9 and 10 are solid XRPD patterns in which crystal type A and type I crystals are equilibrated 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 at 5 ° C., 25 ° C., and 50 ° C. for 1 hour. In FIG. 10, the XRPD pattern before equilibration is performed in order from the top. XRPD pattern of type I crystal, XRPD pattern after equilibration at 5 ° C, 25 ° C, and 50 ° C for 1 hour.)

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

Claims (7)

10.2 ° ± 0.2 °, 15.5 ° ± 0.2 °, 17.0 ° ± 0.2 °, 20.6 ° ± 0.2 °, 27.3 ° ± 0.2 ° A crystal of crystal form A of a compound represented by the following formula (I), which has a characteristic peak in a powder X-ray diffraction pattern at a value of 2θ.
Furthermore, powder X-rays are found at one, two, or three of the 2θ values of 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, and 24.5 ° ± 0.2 °. crystals of crystalline form a according to claim 1, characterized in that it has a characteristic peak in the diffraction pattern. Crystals of crystalline Form A according to claim 1 or 2 characterized by having a powder X-ray diffraction pattern as shown in FIG. The compound of formula (I), 1-methylpyrrolidine was dissolved in pyrrolidone, acetonitrile poor solvent, any one of the preceding claims, characterized in that to obtain crystals by sequentially adding or inverse addition 1 A method for producing a crystal of crystal form A of the compound represented by the formula (I) according to the above item. Crystalline and pharmaceutically acceptable pharmaceutical composition comprising a pharmaceutical excipient crystalline Form A according to any one of claims 1-3 effective amount. The pharmaceutical composition according to claim 5, wherein the crystals of the crystalline form A can be used in the manufacture of a therapeutic agent formulations of gout and hyperuricemia. Use of the crystal of crystalline form A according to any one of claims 1 to 3 for producing a pharmaceutical composition for treating gout and hyperuricemia.