Method for preparing crystalline particles of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and pharmaceutical compositions containing the same

Abstract

The present invention relates to a pharmaceutical composition comprising crystalline particles containing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof, which contains 0.2 wt % or less of a compound of Chemical Formula 2 below: The crystalline particles according to the present invention are not only optimized in size, shape, and distribution for use in the drug manufacturing process, but also improve uniformity and flowability, thereby increasing the content uniformity generated in the drug manufacturing process and minimizing breakage during tableting, making them suitable for use as a raw drug substance in the drug manufacturing process.

Description

[Technical field]

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2020-0145750 filed on November 4, 2020, and all contents disclosed in the documents of said Korean patent application are incorporated herein by reference.

[0002] The present invention relates to a pharmaceutical composition comprising crystalline particles of a compound of the following formula 2 (1-(3-cyano-1-isopropyl-indol-5-yl)-pyrazole-4-carboxylic acid) or a pharma- ceutically acceptable salt thereof, the compound being 0.2% by weight or less of the compound of the following formula 2 (1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-methyl ester). [ka] [ka] [Background technology]

[0003] Xanthine oxidase is an enzyme that converts hypoxanthine to xanthine and then converts the resulting xanthine to uric acid. If there is an excessive amount of uric acid in the body, it can cause various diseases, including gout.

[0004] Gout is a condition in which uric acid crystals accumulate in joint cartilage, ligaments and surrounding tissues, causing severe inflammation and pain. The incidence of gout has been steadily increasing over the past 40 years.

[0005] Therefore, substances that inhibit the activity of xanthine oxidase can effectively treat xanthine oxidase-related diseases such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and joint disease, inflammatory bowel disease, etc.

[0006] Meanwhile, Korean Patent Publication No. 1751325 (Patent Document 1) provides a compound of Chemical Formula 1 (1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) and a method for preparing the compound as a substance that inhibits the activity of xanthine oxidase, and Korean Patent Publication No. 1424013 (Patent Document 2) provides various types of crystal forms obtained using various solvents and methods for preparing the same.

[0007] However, the crystalline particles of Chemical Formula 1 produced by the conventional manufacturing method of Patent Document 1 have a problem of poor fluidity, making it difficult to develop a stable and reproducible drug manufacturing process. In the case of Patent Document 2, the analysis is related to each crystal form itself, and no analysis has been conducted on the fluidity, etc.

[0008] Therefore, there is a need for further development of crystalline particles of Formula 1 in which the size, shape, and distribution of the crystalline particles are optimized for use in a complete manufacturing process and in which flowability is improved. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Korean Patent Publication No. 1751325 (2017.06.21.), Novel compound effective as a xanthine oxidase inhibitor, its preparation method and pharmaceutical composition containing the same [Patent Document 2] Korean Patent Publication No. 1424013 (2014.07.22.), Crystalline form of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and its manufacturing method Summary of the Invention [Problem to be solved by the invention]

[0010] In response to this, the present inventors have conducted extensive research to solve the above problems, and have confirmed that compounds of Chemical Formula 2 and Chemical Formula 3 can be produced during the manufacturing process of the compound of Chemical Formula 1 below. They have also confirmed that crystalline particles optimized for use in a pharmaceutical final manufacturing process can be obtained by adjusting the content of the compound of Chemical Formula 2 within a specific range, thereby completing the present invention.

[0011] Accordingly, an object of the present invention is to provide crystalline particles of a compound of Chemical Formula 1, or a pharma- ceutically acceptable salt thereof, containing 0.2 wt. % or less of a compound of Chemical Formula 2, which are optimized for pharmaceutical complete manufacturing processes, and a pharmaceutical composition comprising the same. [ka] [ka] [ka] [Means for solving the problem]

[0012] The present invention provides crystalline particles of a compound of Chemical Formula 1 or a pharma- ceutically acceptable salt thereof, comprising a compound of Chemical Formula 2 below at 0.2% by weight or less. [ka] [ka]

[0013] The crystalline particles of the present invention may further contain a compound represented by the following chemical formula 3. [ka]

[0014] The present invention provides a method for preparing crystalline particles of Chemical Formula 1 containing 0.2 wt % or less of the compound of Chemical Formula 2, and crystalline particles prepared by the method.

[0015] The curl index of the crystalline particles of the present invention is 25 or less, 20 or less, 10 or less, or 7 or less.

[0016] The present invention provides a pharmaceutical composition for treating or preventing a xanthine oxidase-related disease selected from the group consisting of hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, joint disease and inflammatory bowel disease, comprising crystalline particles of a compound of Chemical Formula 1 containing 0.2% by weight or less of a compound of Chemical Formula 2, or a pharma- ceutical acceptable salt thereof. Effect of the Invention

[0017] The crystalline particles of the compound of Chemical Formula 1 or a pharma- ceutically acceptable salt thereof containing 0.2 wt % or less of the compound of Chemical Formula 2 according to the present invention are not only optimized in size, shape and distribution for use in a pharmaceutical final manufacturing process, but also improve uniformity and flowability to increase the content uniformity in the final manufacturing process and minimize breakage during tableting, making them suitable for use as a raw material pharmaceutical for the pharmaceutical final manufacturing process. [Brief description of the drawings]

[0018] [Figure 1] FIG. 2 is a micrograph showing crystalline particles produced in the examples and comparative examples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily embody the present invention.

[0020] The terms and words used in this specification and the claims should not be interpreted in accordance with their ordinary or dictionary meanings, but should be interpreted in accordance with the meanings and concepts that correspond to the technical ideas of the present invention, based on the principle that an inventor can appropriately define the concepts of terms in order to best describe his / her invention.

[0021] The terms used in the present invention are merely used to describe specific embodiments and are not intended to limit the present invention. A singular expression includes a plural expression unless the context clearly indicates a different meaning. In the present invention, the terms "include" or "have" are intended to specify the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, and should be understood not to preclude the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0022] In the present invention, the compound of formula 1 is It is known that 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid can inhibit xanthine oxidase and prevent uric acid deposition in the body. In addition, the compound of Formula 1 can treat or prevent diseases associated with uric acid deposition in the body, such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, joint disease, and inflammatory bowel disease. [ka]

[0023] The compound of formula 1 is a structural feature produced by the coupling reaction of pyrazole and indole, and has a very low solubility in organic solvents and water, which makes it very difficult to adjust the size, shape, and distribution of the crystalline particles. In particular, the crystalline particles produced by the conventional method of producing the compound of formula 1, the method of patent document 1, have poor fluidity, making it difficult to produce a stable and reproducible pharmaceutical complete manufacturing process, and the crystalline compound of patent document 2 has not only not been analyzed for fluidity, but also has process difficulties in producing it as a large amount of raw pharmaceutical material.

[0024] Therefore, the present researchers conducted extensive research to produce crystalline particles of the above-mentioned formula 1 with good fluidity, and found that compounds produced by conventional methods include not only formula 1, but also the compound of formula 2, which is a methyl ester of the compound of formula 1 at the C4 position of pyrazole, and the compound of formula 3, which is an amide compound decomposed by the cyano group at the C3 position of indole, as shown below, and confirmed that the shape and fluidity of the crystalline particles vary depending on the amount of the compounds of formula 2 and formula 3. [ka] [ka]

[0025] The compound of formula 1 is a structural feature produced by the coupling reaction of pyrazole and indole, and has a very low solubility in organic solvents and water, which makes it very difficult to control the size, shape, and distribution of the crystalline particles. In particular, the crystalline particles produced by the conventional method of producing the compound of formula 1, as described in Patent Document 1, have a problem of poor fluidity, making it difficult to produce a stable and reproducible pharmaceutical complete manufacturing process, and the crystalline compound of Patent Document 2 has not only not been analyzed for fluidity, but also has process difficulties in producing it as a large amount of raw pharmaceutical material.

[0026] Therefore, the present researchers conducted extensive research to produce crystalline particles of the above-mentioned formula 1 with good fluidity, and found that compounds produced by conventional methods include not only formula 1, but also the compound of formula 2, which is a methyl ester of the compound of formula 1 at the C4 position of pyrazole, and the compound of formula 3, which is an amide compound decomposed by the cyano group at the C3 position of indole, as shown below, and confirmed that the shape and fluidity of the crystalline particles vary depending on the amount of the compounds of formula 2 and formula 3. [Table 1]

[0027] Both bulk density and tap density are properties related to the Carr index, which can affect various dosage forms, especially the formulation uniformity. Specifically, the Carr index standard commonly used in pharmaceutical raw materials is 20% or less, and an index of 5-15% indicates excellent to good flowability. The Hausner ratio is the ratio of tap density to bulk density, and is an evaluation of friction between fine particles. A commonly used ratio is that a ratio of 1.2 or less is an indication of acceptable friction, i.e., good powder flow.

[0028] When the compound of Chemical Formula 1 contains the compound of Chemical Formula 2, the Carr index exceeds 20% and the Hausner ratio exceeds 1.25 when the compound of Chemical Formula 2 is contained at 0.246%, which are values ​​that can be used in pharmaceutical preparations. However, when the compound of Chemical Formula 2 is contained at 0.169%, the Carr index is 5.89% and the Hausner ratio is 1.06, showing both significantly good fluidity and cohesiveness. However, when the compound of Chemical Formula 3 is contained, in addition to the good morphology of the crystalline particles, the Carr index and Hausner ratio are not only higher than the generally accepted values, but also show better results as the content increases.

[0029] Therefore, the compounds of Chemical Formula 2 and Chemical Formula 3 can both be produced in the same manner as the compound of Chemical Formula 1 in the manufacturing process of the compound of Chemical Formula 1; however, as the content of the compound of Chemical Formula 2 increases, the size and shape of the crystalline particles become irregular and the fluidity becomes poor, whereas as the content of the compound of Chemical Formula 3 increases, the size and shape of the crystalline particles become uniform and the fluidity becomes better.

[0030] In summary, in order to obtain crystalline particles with good fluidity, it is preferable that the compound of Chemical Formula 2 is contained in an amount of 0.2% by weight or less based on the total amount of crystalline particles in the compound of Chemical Formula 1. When the amount is within the above range, the shape and size of the crystalline particles are good, the particle distribution is regular, and the fluidity is good, but when the amount is outside the above range, the shape and size of the crystalline particles become non-uniform, and the particle size distribution and fluidity become poor, making it unusable as a raw material drug.

[0031] The manufacturing method for producing the desired crystalline particles is as follows. a) adding 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester, tetrahydrofuran, and methanol to a reactor, and then slowly adding 10N NaOH; b) further introducing purified water and ethyl acetate; c) crystallization by dropwise addition of HCl; and d) washing and drying the produced crystals.

[0032] In addition, the reaction temperature in step a) of the preparation method is maintained at 21 to 27°C.

[0033] The step of adding HCl dropwise in the step c) may further include the steps of: c-1) adding HCl dropwise in the first step until the pH reaches 5-6 to generate nuclei; c-2) In the second step, HCl is added dropwise until the pH reaches 2-3.

[0034] The content of the compound of Chemical Formula 2 in the crystalline particles prepared by the above method is 0.2 wt % or less, 0.1 wt % or less, or 0.05 wt % or less.

[0035] The crystalline particles according to the present invention are not only optimized in size, shape and distribution for use in a pharmaceutical final manufacturing process, but also improve uniformity and flowability to increase the content uniformity in the final manufacturing process and minimize breakage during tableting, making them suitable for use as a raw drug for the final manufacturing process. In addition, an optimal raw drug can be manufactured by a simple method for detecting the content of Chemical Formula 2 in the tablet and crystallization process of the compound of Chemical Formula 1.

[0036] The crystalline particles of the present invention may be administered to a human patient as an active pharmaceutical ingredient (API) by itself, or together with other pharmacoactive ingredients, such as in a combination therapy, or as a pharmaceutical composition mixed with suitable carriers and excipients.

[0037] The pharmaceutical compositions of the present invention can be manufactured in a known manner, for example, by means of conventional mixing, dissolving, granulating, tableting, pulverizing, emulsifying, encapsulating, trapping, or lyophilizing processes.

[0038] Thus, the pharmaceutical compositions according to the invention can be prepared in a conventional manner using one or more pharma- ceutically acceptable carriers, which are comprised of excipients or auxiliaries that facilitate the processing of the active compounds into pharma- ceutically usable dosage forms. The appropriate dosage form depends on the selected route of administration. Any of the known techniques, known carriers and excipients, and known means in the art, e.g., Remingston's Pharmaceutical Sciences, can be suitably used.

[0039] For example, in the present invention, the crystalline particles of the present invention can be formulated into injection preparations and oral tablets, etc., depending on the purpose, and can be preferably formulated into oral tablets.

[0040] For injection, the components of the present invention can be formulated in a liquid solution, preferably in a pharma- ceutical suitable buffer such as Hank's solution, Ringer's solution, or physiological saline. For administration through mucous membranes, a suitable penetration enhancer is used in the formulation. Such penetration enhancers are generally known in the art.

[0041] For oral administration, the active compound can be easily formulated by combining with a pharmaceutically acceptable carrier known in the art. Such carrier allows the compound of the present invention to be formulated into tablets, powders, granules, sugar pills, capsules, liquids, gels, syrups, slurries, or suspensions. Preferably, tablets, capsules, rings, powders, or granules are used, and tablets are particularly useful. Oral tablets can be prepared, for example, as follows:

[0042] The oral formulation according to the present invention comprises, as an API, crystalline particles of the compound of Chemical Formula 1, or a pharma- ceutically acceptable salt thereof, containing 0.2% by weight or less of the compound of Chemical Formula 2, mixed with one or more excipients selected from a diluent, a disintegrant, a binder, a flow agent, a stabilizer, and an activator.

[0043] For example, the diluent may be selected from the group consisting of, but is not limited to, microcrystalline cellulose, lactose monohydrate, lactose anhydrous, lactose, starch, mannitol, carboxymethylcellulose, sorbitol, and combinations thereof. The disintegrant may be selected from the group consisting of, but is not limited to, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, F-melt™, and combinations thereof. The binder may be selected from the group consisting of, but is not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, polyvinyl acetate, povidone, polyvinylpyrrolidone, copovidone, macrogol, sodium lauryl sulfate, light anhydrous silicic acid, synthetic aluminum silicate, silicate derivatives such as calcium or magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, pregelatinized starch, gums such as gum acacia, gelatin, cellulose derivatives such as ethylcellulose, and mixtures thereof. The flow agent may be selected from the group consisting of, but is not limited to, colloidal silicon dioxide, hydrated silicon dioxide, and combinations thereof. The lubricant may be selected from the group consisting of, but is not limited to, magnesium stearate, silicon dioxide, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof.

[0044] The content of the API contained in the oral tablet may be about 20 to 70% by weight, about 20 to 60% by weight, about 20 to 50% by weight, about 20 to 45% by weight, about 30 to 70% by weight, about 30 to 60% by weight, about 30 to 50% by weight, about 30 to 45% by weight, about 40 to 70% by weight, about 40 to 60% by weight, about 40 to 50% by weight, or about 40 to 45% by weight, based on the total weight of the oral tablet.

[0045] Also, the API can comprise, for example, about 50 mg to 500 mg, about 50 mg to 400 mg, about 50 mg to 300 mg, about 50 mg to 200 mg, about 50 mg to 100 mg, about 100 mg to 500 mg, about 100 mg to 400 mg, about 100 mg to 300 mg, about 100 mg to 200 mg, about 200 mg to 500 mg, about 200 mg to 400 mg, about 200 mg to 300 mg, about 300 mg to 500 mg, or about 300 mg to 400 mg per unit dosage form.

[0046] The API may also be present in an amount of 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, or 500 mg per unit dosage form.

[0047] In addition, the compound of Formula 2 among the APIs may be included in an amount of 0.2 wt % or less based on the total content of the API.

[0048] The pharmaceutical composition according to the present invention contains crystalline particles of the compound of formula 1, or a pharma- ceutically acceptable salt thereof, containing 0.2% by weight or less of the compound of formula 2, in an amount effective to achieve its intended purpose. Specifically, a therapeutically effective amount refers to an amount of compound effective to prolong the survival of the subject being treated or to prevent, reduce or alleviate symptoms of disease. Determination of a therapeutically effective amount is within the capabilities of one of ordinary skill in the art, especially in light of the detailed disclosure provided herein.

[0049] When formulated into a unit dosage form, the compound of formula 1 or its pharma- ceutically acceptable salt, which contains 0.2% by weight or less of the compound of formula 2 as an active ingredient, is preferably contained in a unit dose of about 0.1 to 1,000 mg based on crystalline particles. The dosage is prescribed by a physician based on factors such as the patient's weight, age, and the specific nature and symptoms of the disease. However, the dosage required for treatment of an adult is usually in the range of about 1 to 1,000 mg per day, depending on the frequency and strength of administration. When administered intramuscularly, intravenously, or orally to an adult, a total dosage of about 1 to 500 mg per day, divided into a single dose, is sufficient, although a higher daily dosage may be preferred for some patients.

[0050] The present invention also provides a method for treating or preventing a human xanthine oxidase-related disease using a therapeutically effective amount of crystalline particles of a compound of formula 1 or a pharma- ceutically acceptable salt thereof, containing 0.2% by weight or less of a compound of formula 2. The term "human xanthine oxidase-related disease" refers to a disease that can be treated or prevented by inhibiting human xanthine oxidase, and includes, but is not limited to, hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, diabetes-related complications, kidney disease, inflammation and joint disease, or inflammatory bowel disease. Examples of the uric acid-related complications include hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, and renal failure (Circulation Research, 2006, 98, 169-171; Hypertension 2003, 41, 1183-90).

[0051] The term "treatment" means to halt or delay the progression of a disease when applied to an object that exhibits symptoms of the disease, and the term "prevention" means to halt or delay the onset of the disease when applied to an object that does not exhibit symptoms of the disease but is at high risk of becoming so.

[0052] The present invention will be described in more detail with reference to the following examples and test examples. However, these examples and test examples are only intended to aid in the understanding of the present invention, and are not intended to limit the scope of the present invention in any way.

[0053] Synthesis Example 1: Synthesis of compound of formula 1 Synthesis Example 1-1: Synthesis of 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester The title compound was obtained through the following steps (1), (2), and (3).

[0054] (1) Synthesis of 1-(3-formyl-1H-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester [ka] Add oxalyl chloride (0.56ml) to 50ml of anhydrous dichloromethane, add N,N-dimethylformamide (0.51ml) at 0°C, and stir at 0°C for 30 minutes. Add a mixture of compound 1-(1H-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester (1.40ml) and 50ml of dichloromethane to the reaction solution, stir under reflux at room temperature for 1 hour, and then remove the solvent. Add 100ml of tetrahydrofuran and 100ml of 20% aqueous ammonium acetate solution, and heat and stir under reflux for 30 minutes. After the reaction is completed, the reaction solution is cooled, ethyl acetate is added, and the solution is washed with an aqueous sodium hydrogen carbonate solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound.

[0055] (2) Synthesis of 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylic acid ethyl ester [ka] The 1-(3-formyl-1H-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester obtained in step (1) was dissolved in 150 ml of pyridine, and hydroxyammonium chloride (499 mg) was added. The mixture was heated and stirred under reflux for 5 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the title compound was obtained by filtration through silica gel using acetone as a solvent.

[0056] (3) Synthesis of 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester [ka] The 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylic acid ethyl ester obtained in step (2) was dissolved in 94 ml of anhydrous tetrahydrofuran, and di(imidazol-1-yl)methanethione (90%, 2.79 g) was added and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting solid compound was separated by column chromatography to obtain 1.32 g (86% yield) of the title compound.

[0057] Synthesis Example 1-2: Synthesis of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester [ka] 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester (13.84 g) obtained in Preparation Example 1-1 was dissolved in 200 ml of acetonitrile. Cesium carbonate (32.17 g) and 2-iodopropane (19.7 ml) were added, and the mixture was heated and stirred under reflux for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting solid compound was separated by column chromatography to obtain 13.87 g (87% yield) of the title compound.

[0058] Synthesis Example 1-3: Synthesis of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (formula 1) and preparation of crystalline particles [ka] 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester (16.09 kg) obtained in Synthesis Example 1-2 was added to a reactor together with tetrahydrofuran (22.21 kg) and methanol (19.7 kg), and then 10 N NaOH (33.11 kg) was slowly added at about 8°C to carry out the reaction. After the reaction was completed, purified water (24.95 L) and conc. HCl (25.99 kg) were slowly added dropwise while maintaining the temperature at 0-10°C, and the mixture was aged and then filtered. The filtered solid was washed with purified water and dried in vacuum to obtain the final product (14.83 kg) in the form of crystalline particles of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (chemical formula 1). As a result of the component analysis of the final product, it was confirmed that the final product mostly contained the compound of Chemical Formula 1 as shown below, but also contained some compounds of Chemical Formula 2 and Chemical Formula 3 as shown below. In particular, the content of the compound of Chemical Formula 2 was measured to be 0.24%. [ka] [ka] [ka]

[0059] Preparation Example 1: Preparation of crystalline particles of formula 1 containing various concentrations of additive compound (compound of formula 2) In order to analyze the role of Chemical Formula 2 contained in the crystalline particles of Chemical Formula 1 prepared in Synthesis Examples 1-3, a specific amount of the compound of Chemical Formula 2 was mixed with the compound of Chemical Formula 1 to prepare crystalline particles by the following method (Examples 1-3).

[0060] The compounds of formula 1 and formula 2 were mixed in the content ratios shown in Table 2, and then 90 ml of acetone and 9.9 ml of EtOAc were added, and 105 ml of IN NaOH was slowly added dropwise for 1 hour and stirred, and solid impurities were removed. 0.15 ml of 6N HCl was added to the filtered liquid to lower the pH to 7-8, and then heated to 50±5°C, and while maintaining this temperature, 16.2 ml of 6N HCl was slowly added. After the dropwise addition was completed, the pH of the reaction mixture was confirmed to be 5±0.5, and cooling was started to lower the temperature of the reaction mixture to 25°C, and then filtration was performed. The filtered solid was washed with purified water and dried to obtain crystalline particles, which are the target compound. The content of the compound of formula 2 in the obtained crystalline particles was measured by HPLC and confirmed to be 0.169% (Example 1), 0.246% (Example 2), and 1.646% (Example 3).

[0061] Preparation Example 2: Preparation of crystalline particles of formula 1 containing various concentrations of additive compound (compound of formula 3) In order to analyze the role of Chemical Formula 3 contained in the crystalline particles of Chemical Formula 1 prepared in Synthesis Examples 1-3, a specific amount of the compound of Chemical Formula 3 was mixed with the compound of Chemical Formula 1 to prepare crystalline particles by the following methods (Comparative Examples 1-2).

[0062] 40g of the compound of formula 1, 1.25g of the compound of formula 3, 120ml of acetone, and 140ml of 1N NaOH were slowly added dropwise for 1 hour. After stirring, solid impurities were removed. 0.2ml of 6N HCl was added to the filtered liquid to lower the pH to 7-8, and then heated to 50±5°C. While maintaining this temperature, 21.6ml of 6N HCl was slowly added. After completion of the dropwise addition, the pH of the reaction mixture was confirmed to be 5±0.5, and cooling was started to lower the temperature of the reaction mixture to 25°C, after which filtration was performed. The filtered solid was washed with purified water and dried to obtain crystalline particles, which are the target compound. The content of the compound of formula 3 in the obtained crystalline particles was measured and confirmed to be 0.153% (Comparative Example 1).

[0063] 25g of the compound of formula 1, 5g of the compound of formula 3, 90ml of acetone, 9.9ml of EtOAc, and 105ml of 1N NaOH were slowly added dropwise for 1 hour. After stirring, solid impurities were removed. 0.15ml of 6N HCl was added to the filtered liquid to lower the pH to 7-8, and then heated to 50±5°C. While maintaining this temperature, 16.2ml of 6N HCl was slowly added. After confirming that the pH of the reaction mixture after the dropwise addition was 5±0.5, cooling was started and the temperature of the reaction mixture was lowered to 25°C, and then filtration was performed. The filtered solid was washed with purified water and dried to obtain crystalline particles, which are the target compound. The content of the compound of formula 3 in the obtained crystalline particles was measured and confirmed to be 1.243% (Comparative Example 2).

[0064] Table 2 below shows the content of the additive compound contained in the crystalline particles produced in each of the Examples and Comparative Examples. [Table 2]

[0065] Experimental Example 1. Analysis of the characteristics of each crystalline particle (crystal shape analysis) The crystalline particles produced in the examples and comparative examples were observed and measured for particle shape using a scanning electron microscope (SEM). As a result of the analysis, as shown in Figure 1, the crystalline particles of Examples 1 to 3 tend to have a square hexahedral shape but the particle size is not uniform (Example 2) and there is a tendency for non-uniform plate-like particles and fine powder to increase as the content of the compound of Chemical Formula 2 increases (Example 3). Therefore, even when the compound of Chemical Formula 2 is added at 0.246% to the compound of Chemical Formula 1, some non-uniform particles are included, but the particles have a relatively uniform square hexahedral shape.

[0066] However, Comparative Examples 1 and 2 show different aspects from Examples 1 to 3, and Comparative Example 1 has not only an uneven shape of crystalline particles, but also a large amount of differential generation is observed, making it difficult to introduce it into a complete manufacturing process. However, Comparative Example 2 has a crystal shape relatively close to a square hexahedron, and the particle size is uniform, and it can be seen that the shape and size of the crystalline particles become better as the content of the compound of Chemical Formula 3 increases.

[0067] Therefore, unlike Chemical Formula 2, the compound of Chemical Formula 3 exhibits uniform square hexahedral crystals that can be introduced into a complete manufacturing process as its content increases, and therefore the compounds of Chemical Formulas 2 and 3 produced in the manufacturing process of Chemical Formula 1 have completely different properties.

[0068] Experimental Example 2. Analysis of the characteristics of crystalline particles (particle size distribution analysis) ) The volume average particle distribution and particle size distribution of the crystalline particles produced in the Preparation Examples, Examples, and Comparative Examples were measured by a wet method using a laser diffraction particle size analyzer.

[0069] The particle size distribution is used as an indicator of DV 10 / DV 50 and domestic violence 50 / DV 90 The larger the value, the better. Here, DV 10 , DV 50 , DV 90 The particle sizes indicate the particle sizes of the particles that make up 10%, 50%, and 90% of the total number of particles when the measured particles are arranged in order from smallest to largest particle size.

[0070] As shown in Table 1 below, the crystalline particles of Examples 1 and 2 have a relatively uniform particle size distribution compared to the comparative examples, but the particle size is smaller. However, Example 3 and Comparative Examples 1 and 2 have non-uniform particle size distributions. [Table 3]

[0071] Experimental Example 3. Analysis of volume density and tap density of crystalline particles (fluidity analysis) The bulk density and tapped density of the crystalline particles produced in the Preparation Examples, Examples, and Comparative Examples were measured. The bulk density was the volume of about 50 g of granular powder placed in a graduated cylinder, and the tapped density was the volume measured when the graduated cylinder was lightly tapped against the bottom at a certain height 100 times and no further volume change occurred. The volume density means the volume occupied by a certain mass of powder, and the total volume means the combined volume of the powder volume and the volume of the voids between the particles.

[0072] The flowability and cohesiveness of the granular powder were calculated using the volume density and tapped density measured above according to the method of Jinapong et al. (2008) using the Carr index (equation (3)) and the Hausner ratio (equation (4)).

number

[0073] The Carr index is a measure of the compressibility of a powder and is defined as (tapped density - bulk density) / percentage of tapped density. The higher the index, the more compressible and less flowable the powder is. The Hausner ratio is the ratio of tapped density to bulk density and is an assessment of interparticulate friction.

[0074] The crystalline particles of Example 1 have a Carr index of 5.89% and a Hausner ratio of 1.06, showing remarkably good results in both fluidity and cohesion (Excellent), and although the values ​​of Example 2 are not better than those of Example 1, they generally have acceptable fluidity and cohesion for pharmaceutical dosage forms. However, the crystalline particles of Example 3 have a Carr index of about 30% and a Hausner ratio of 1.42, which means that they cannot be used in general dosage forms, although they show a good particle size distribution in the particle size distribution analyzed above, similar to that of Example 1.

[0075] The crystalline particles of Comparative Example 1 have a curl index of 35.58% and a Hausner ratio of 1.56, which are inferior to the crystalline particles of Example 3 (poor fluidity and high cohesiveness). However, the crystalline particles of Comparative Example 2 have improved values ​​compared to Comparative Example 1 and are similar to the values ​​of Example 2.

[0076] Therefore, in order to obtain crystalline particles containing the compound of Chemical Formula 1 with good fluidity, the compound of Chemical Formula 2 may be contained at 0.246%, and when the compound of Chemical Formula 2 is contained at a content of 0.2% or less, crystalline particles with remarkably excellent fluidity can be obtained.

[0077] Synthesis Example 1-4: Synthesis of Improved 1-(3-Cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (Formula 1) and Preparation of Crystalline Particles In the above experimental examples, it was confirmed that the smaller the amount of the compound of Chemical Formula 2 in the crystalline particles of the compound of Chemical Formula 1, particularly 0.2% or less, the more uniform and highly fluid the crystalline particles obtained. Reflecting this, the present inventors have devised a method for producing the compound of Chemical Formula 1 containing 0.2% or less of the compound of Chemical Formula 2.

[0078] 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester (312 kg) obtained in Synthesis Example 1-2, tetrahydrofuran (554 kg), and methanol (624 L) were added to a reactor, and then 10N NaOH (386 kg) was slowly added. Since this was an exothermic reaction, the reaction was continued for about 1 hour while taking care not to allow the internal temperature to exceed 27°C. After the addition was completed, the reaction was carried out at a temperature of 21 to 27°C. After the reaction was completed, purified water (624 L) and ethyl acetate (197 kg) were added, and then 3N HCl (1048 kg) was slowly added dropwise while maintaining the temperature at 30 to 35°C. In the above process, 3N HCl was added dropwise in two separate steps, and the first addition was performed after 10 minutes of solids. stThe pH was adjusted to 5-6 for nucleation. The reaction mixture in which the solid was produced was stirred for 30 minutes, and then a second dropwise addition was performed until the pH was 2-3. After the dropwise addition was completed, the mixture was cooled to room temperature, aged at this temperature for 30 minutes, and then filtered. The filtered solid was washed with purified water (624 L) and dried under nitrogen and vacuum to obtain a final compound (273.2 kg) containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid, and the content of the compound of Formula 2 was measured to be 0.02 wt%.

[0079] In addition, the particle size distribution and flowability of the final product were found to be significantly excellent.

[0080] Therefore, in the method of Synthesis Example 1-3, which is a conventional method for preparing the compound of Chemical Formula 1, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester, tetrahydrofuran, methanol and 10N NaOH are mixed and reacted at a temperature of 27°C, and after the reaction, purified water is added together with ethyl acetate, and HCl is added dropwise in two portions, so that the content of Chemical Formula 2 can be controlled to 0.2 wt% or less.

[0081] Experimental Example 4: Method for preparing an oral tablet containing the compound of Formula 1 or a pharma- ceutically acceptable salt thereof as an active pharmaceutical ingredient (API) In order to prepare oral tablets containing the compound of Chemical Formula 1, which partially contains the compound of Chemical Formula 2, as an API, the compound was mixed with the API using the excipients shown in the table below, and then oral tablets were produced using a tablet press. [Table 5]

Claims

1. A pharmaceutical composition for treating or preventing a xanthine oxidase-related disease selected from the group consisting of hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, joint disease and inflammatory bowel disease, comprising crystalline particles of a compound of formula 1 or a pharma- ceutical acceptable salt thereof containing 0.2% by weight or less of a compound of formula 2 below, and a pharma- ceutical acceptable excipient. 【Chemistry 1】 【Chemistry 2】

2. The pharmaceutical composition according to claim 1, wherein the content of the crystalline particles is 20 to 70% by weight, based on 100% by weight of the total pharmaceutical composition.

3. The pharmaceutical composition according to claim 2, wherein the content of the crystalline particles is 30 to 60% by weight, based on 100% by weight of the total pharmaceutical composition.

4. The pharmaceutical composition according to claim 3, wherein the content of the crystalline particles is 40 to 50% by weight, based on 100% by weight of the total pharmaceutical composition.

5. The pharmaceutical composition of claim 1, further comprising a compound of the following formula 3: 【Chemistry 3】

6. a) mixing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester, tetrahydrofuran and methanol into a reactor, and then slowly adding NaOH to react; b) introducing purified water and ethyl acetate; c) crystallization by dropwise addition of HCl; and d) washing and drying the produced crystals; A method for producing crystalline particles of the following formula 1, containing a compound of the following formula 2 in an amount of 0.2 wt % or less, In the step a), the reaction temperature is maintained at 21 to 27° C.; and The step c) includes the steps of: c-1) firstly adding HCl dropwise until the pH reaches 5-6 to generate nuclei; and c-2) adding HCl dropwise until the pH reaches 2-3; The method includes: 【Chemistry 4】 【Chemistry 5】

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