Process for the preparation of crystalline particles of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and pharmaceutical compositions comprising the same

Abstract

The present invention relates to a pharmaceutical composition comprising crystalline particles comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and comprising an amount of 0.2 wt% or less of a compound of formula 2. The crystalline particles according to the present invention have optimized size, shape and distribution to be inputted into the process of preparation of the final formulation, enhanced uniformity and flowability to improve the content uniformity in the process of preparation of the final pharmaceutical formulation and to minimize breakage in the process of compression into tablets, and thus can be used as a raw pharmaceutical material suitable for the process of preparation of the final pharmaceutical formulation.

Description

Technical Field

[0001] This application claims priority to Korean Patent Application No. 10-2020-0145750, filed on November 4, 2020, the entire contents of which are incorporated herein by reference.

[0002] This invention relates to a pharmaceutical composition comprising crystalline particles of a compound of formula 1 (1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) or a pharmaceutically acceptable salt thereof, said crystalline particles comprising less than 0.2% by weight of a compound of formula 2 (1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-methyl ester):

[0003] [Formula 1]

[0004]

[0005] [Equation 2]

[0006] Background Technology

[0007] Xanthine oxidase is an enzyme that converts hypoxanthine into xanthine and then converts the resulting xanthine into uric acid. When there is too much uric acid in the body, it can lead to various diseases, including gout.

[0008] Gout is a condition caused by the accumulation of uric acid crystals in the cartilage, ligaments, and surrounding tissues of joints, resulting in severe inflammation and pain. The incidence of gout has been steadily increasing over the past 40 years.

[0009] Therefore, substances that inhibit xanthine oxidase activity can effectively treat xanthine oxidase-related diseases, such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, joint diseases, and inflammatory bowel disease.

[0010] On the other hand, as a substance that inhibits xanthine oxidase activity, Korean Patent No. 1751325 (Patent Document 1) provides a compound of Formula 1 (1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) and a method for preparing said compound, and Korean Patent No. 1424013 (Patent Document 2) provides various types of crystalline forms obtained by using various solvents and methods for preparing them.

[0011] However, the crystalline particles of Formula 1 prepared according to the conventional preparation method of Patent Document 1 have poor fluidity, so there are difficulties in the preparation method of a stable and reproducible final product. In the case of Patent Document 2 (which involves the various crystalline forms themselves), their fluidity has not been analyzed.

[0012] Therefore, there is a need to further develop crystalline particles of Formula 1 with improved flowability, wherein the size, shape and distribution of the crystalline particles are optimized for inclusion in the preparation process of the final product.

[0013] [Existing Technical Documents]

[0014] [Patent Literature]

[0015] (Patent Document 1) Korean Patent No. 1751325 (June 21, 2017), Novel compounds effective asxanthine oxidase inhibitors, method for preparing the same and pharmaceutical composition containing the same.

[0016] (Patent Document 2) Korean Patent No. 1424013 (July 22, 2014), Crystal form of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and the producing method thereof. Summary of the Invention

[0017] Technical issues

[0018] Therefore, the inventors of this invention conducted various studies to solve the above-mentioned problems, and the results confirmed that compounds of formula 2 and formula 3 may be generated during the manufacturing process of the compound of formula 1. Moreover, by adjusting the content of compound of formula 2 to a specific range, crystalline particles optimized for input into the preparation process of the final pharmaceutical product can be obtained, thereby completing this invention.

[0019] Therefore, one object of the present invention is to provide crystalline particles of a compound of formula 1 or a pharmaceutically acceptable salt thereof, the crystalline particles comprising less than 0.2 wt% of a compound of formula 2, and the crystalline particles being optimized for use in the preparation of a final pharmaceutical product; and pharmaceutical compositions comprising the crystalline particles.

[0020] [Formula 1]

[0021]

[0022] [Equation 2]

[0023]

[0024] [Formula 3]

[0025]

[0026] Technical solution

[0027] The present invention provides crystalline particles of a compound of formula 1 or a pharmaceutically acceptable salt thereof, said crystalline particles comprising less than 0.2 wt% of a compound of formula 2 below.

[0028] [Formula 1]

[0029]

[0030] [Equation 2]

[0031]

[0032] The crystalline particles of the present invention may also contain compounds of formula 3.

[0033] [Formula 3]

[0034]

[0035] The present invention provides a method for preparing crystalline particles of Formula 1, wherein the crystalline particles contain less than 0.2 wt.% of a compound of Formula 2; and crystalline particles prepared by the above preparation method.

[0036] The Karl index of the crystalline particles of the present invention is 25 or less, 20 or less, 10 or less, or 7 or less.

[0037] The present invention provides a pharmaceutical composition for treating or preventing xanthine oxidase-related diseases, wherein the xanthine oxidase-related diseases are selected from hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, joint disease, and inflammatory bowel disease, and the pharmaceutical composition comprises crystalline particles of a compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein the crystalline particles comprise less than 0.2 wt% of a compound of formula 2.

[0038] Beneficial effects

[0039] The size, shape, and distribution of crystalline particles of the compound of Formula 1 or a pharmaceutically acceptable salt thereof (the crystalline particles comprising less than 0.2 wt% of the compound of Formula 2) according to the present invention improve uniformity and flowability, and are optimized for input into the preparation process of the final pharmaceutical product, thereby improving the content uniformity in the preparation process of the final product and minimizing breakage during tableting, and thus can be used as a raw material pharmaceutical product suitable for the preparation process of the final pharmaceutical product. Attached Figure Description

[0040] Figure 1 Micrographs of the crystalline particles prepared in the examples and comparative examples are shown. Detailed Implementation

[0041] The present invention will now be described in detail with reference to the accompanying drawings, so that those skilled in the art can readily implement the invention.

[0042] Based on the principle that inventors can appropriately define the concepts of terms to describe their invention in the best possible way, the terms and words used in this specification and claims should not be regarded as limited to ordinary or dictionary terms, but should be interpreted as having meanings and concepts consistent with the technical ideas of the present invention.

[0043] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the invention. Unless the context clearly indicates otherwise, the singular forms “a” and “described” include plural indicators. It should be understood that terms such as “comprising” or “having” as used herein are intended to indicate the presence of said features, numbers, steps, operations, components, portions or combinations thereof, but do not preclude the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, portions or combinations thereof.

[0044] In this invention, the compound of Formula 1 is 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazol-4-carboxylic acid, which is known to inhibit xanthine oxidase and prevent uric acid deposition in the body. Furthermore, the compound of Formula 1 can treat or prevent diseases selected from hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, joint disease, and inflammatory bowel disease, said diseases being related to uric acid deposition in the body.

[0045] [Formula 1]

[0046]

[0047] Due to the structural characteristics resulting from the coupling reaction of pyrazole and indole, compounds of Formula 1 exhibit very low solubility in organic solvents and water, making it difficult to control the size, shape, and distribution of crystalline particles. In particular, the crystalline particles prepared by the conventional method described in Patent Document 1 suffer from poor flowability, making it difficult to stabilize and reproduce the final drug product. For the crystalline form of the compound in Patent Document 2, flowability was not analyzed, and difficulties exist in manufacturing large quantities of the drug product.

[0048] Therefore, the researchers of this invention continued to study the preparation of crystalline particles of Formula 1 with good flowability. As a result, it was found that the compounds prepared by conventional methods not only include the compound of Formula 1, but also the following compound of Formula 2 (i.e., the pyrazole of Formula 1 is methylated at the C4 position) and the following compound of Formula 3 (i.e., the amide compound in which the cyano group at the C3 position of indole is decomposed). It has been confirmed that the shape and flowability of the crystalline particles depend on the amount of the compounds of Formula 2 and Formula 3.

[0049] [Equation 2]

[0050]

[0051] [Formula 3]

[0052]

[0053] In this invention, in order to analyze the effect of compounds of formula 2 and formula 3 on the formation of crystalline particles of compound 1 (i.e., the active substance that has inhibitory activity against xanthine oxidase), crystalline particles are prepared by adding any amount of compound 2 or formula 3 to compound 1 with 100% purity. The Karl index and Hausner ratio, which are related to the flowability and cohesion of the crystalline particles, are analyzed by analyzing the shape and particle size, tap density and apparent density of the crystalline particles.

[0054] First, in the case of compound 2, there is a tendency for uneven crystal particle size and an increase in plate-like crystal particles as its content increases. However, in the case of compound 3, as its content increases, because the shape of the crystal particles is relatively close to that of a square hexahedron and their size is uniform, it can be seen that the shape and size of the crystal particles improve with increasing content of compound 3. Figure 1 Moreover, even in the case of particle size distribution, it can be seen that the particle size distribution becomes uneven with the increase of the content of compound 2, while the particle size distribution becomes more uniform with the increase of the content of compound 3 (Table 3).

[0055] Tap density and bulk density are analyzed to assess flowability and cohesion. Tap density refers to the change in volume when the container is tapped after the powder has been packed (intended to reduce voids between particles). Furthermore, porosity can be confirmed by examining the changes in bulk density (apparent density) and tap density. Typically, the Carr index (CI) (Carr, 1965) and the Hausner-Richter index (HR) (Hausner, 1967) are used to assess the flowability and cohesion of particulate powders.

[0056] The following table shows the classification of particulate powder flowability based on the Carr index and Hausner-Bill ratio.

[0057] Table 1:

[0058] <10 Excellent 1.00～1.11 11～15 good 1.12～1.18 16～20 medium 1.19～1.25 21～25 acceptable 1.26～1.34 26～31 Difference 1.35～1.45 32～38 Very bad 1.46～1.59 >38 Very, very bad >1.6

[0059] Bulk density and tap density are both properties related to the Karl Fischer index, and they affect various formulations, particularly the homogeneity of the formulation. Specifically, in the pharmaceutical industry, a Karl Fischer index of less than 20% is commonly used for raw materials, with 5% to 15% indicating excellent to good flowability. The Hausner ratio is the ratio of tap density to bulk density, and is an estimate of the interparticle friction. A commonly used ratio is below 1.2, which indicates acceptable friction for the powder, i.e., good flowability.

[0060] When compound 1 contains compound 2, if the content of compound 2 is 0.246%, the Karl index exceeds 20% and the Hausner ratio exceeds 1.25, but these are values ​​suitable for pharmaceutical formulations. However, if the content of compound 2 is 0.169%, the Karl index is 5.89% and the Hausner ratio is 1.06, showing very good results in both flowability and cohesiveness. However, if compound 3 is contained, regardless of the good shape of the crystalline particles, the Karl index and Hausner ratio are higher than the general values, and good results are shown with increasing content.

[0061] Therefore, it can be seen that although compounds of formula 2 and formula 3 can be generated together with compound 1 during the preparation of compound 1, as the content of compound 2 increases, the size and shape of the crystal particles become irregular and their fluidity deteriorates, while as the content of compound 3 increases, the size and shape of the crystal particles become uniform and their fluidity becomes better.

[0062] In general, to obtain crystalline particles with good flowability, the compound of Formula 1 preferably contains a amount of the compound of Formula 2 of less than 0.2 wt% based on all crystalline particles. When within the above-mentioned content range, the crystalline particles have good shape and size, uniform particle size distribution, and good flowability. However, when outside the above-mentioned content range, the crystalline particles become non-uniform in shape and size, and the particle size distribution and flowability deteriorate, thus making it unsuitable for use as a raw material pharmaceutical product.

[0063] The method for preparing the desired crystalline particles is as follows.

[0064] The method includes the following steps:

[0065] a) Add ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate, tetrahydrofuran, and methanol to the reactor, and then slowly add 10N NaOH;

[0066] b) Add purified water and ethyl acetate;

[0067] c) Crystallization by dropwise addition of HCl; and

[0068] d) Wash and dry the resulting crystals.

[0069] In addition, in the preparation method, the reaction temperature of step a) is maintained at 21°C to 27°C.

[0070] Furthermore, the step of adding HCl in step c) can be divided into two steps.

[0071] c-1) First, add HCl dropwise until the pH reaches 5 to 6 to generate nuclei; and

[0072] c-2) Next, add HCl dropwise until the pH reaches 2 to 3.

[0073] The content of compound 2 in the crystalline particles prepared by the above preparation method is less than 0.2 wt%, less than 0.1 wt%, and less than 0.05 wt%.

[0074] The size, shape, and distribution of the crystalline particles according to the present invention improve uniformity and flowability, and are optimized for input into the preparation process of the final pharmaceutical product, thereby improving the content uniformity in the preparation process of the final product and minimizing breakage during tableting. Therefore, it can be used as a raw material pharmaceutical product suitable for the preparation process of the final pharmaceutical product.

[0075] The crystalline particles of the present invention can be administered to human patients as an active pharmaceutical ingredient (API), or together with other active pharmaceutical ingredients, such as in combination therapy, or as a pharmaceutical composition in the form of an admixture with a suitable carrier or excipient.

[0076] The pharmaceutical compositions of the present invention can be prepared by known methods, such as conventional mixing, dissolving, granulation, tableting, pulverizing, emulsifying, encapsulating, retaining or lyophilizing.

[0077] Therefore, pharmaceutical compositions according to the invention can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, said carriers being intended to include excipients or adjuvants that facilitate the processing of the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the chosen route of administration. Where appropriate, any of the known techniques, known carriers and excipients, and known means in the art (e.g., at Remingston's Pharmaceutical Sciences) can be used.

[0078] For example, in this invention, the crystalline particles of this invention can be formulated into injectable formulations or oral tablets according to the desired purpose, preferably into oral tablets.

[0079] For injection, the components of the present invention can be prepared in a liquid solution, preferably in a pharmaceutically suitable buffer such as Hank's solution, Ringer's solution, or physiological saline. For administration via mucosal permeation, a suitable permeation adjuvant is used in the formulation. Such permeation adjuvants are generally known in the art.

[0080] For oral administration, the active compound can be readily formulated by combining it with a pharmaceutically acceptable carrier known in the art. Such carriers enable the compounds of the present invention to be formulated as tablets, powders, granules, sugar-coated pills, capsules, liquids, gels, syrups, pastes, suspensions, etc. Tablets are particularly useful, being used in the form of tablets, capsules, pills, powders, and granules. For example, oral tablets can be prepared as follows.

[0081] The oral formulation according to the invention contains crystalline particles of a compound of formula 1 as an API or a pharmaceutically acceptable salt thereof, the crystalline particles comprising less than 0.2% by weight of a compound of formula 2; and contains one or more excipients selected from diluents, disintegrants, binders, flow aids, stabilizers and lubricants.

[0082] For example, diluents may be selected from microcrystalline cellulose, lactose monohydrate, lactose anhydride, lactose, starch, mannitol, carboxymethyl cellulose, sorbitol, and combinations thereof, but are not limited thereto. Disintegrants may be selected from low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium glycolate starch, F-melt, and combinations thereof, but are not limited thereto. Binders may be selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate, povidone, polyvinylpyrrolidone, copovidone, polyethylene glycol, sodium lauryl sulfate, light anhydrous silicate, synthetic aluminum silicate, silicate derivatives such as calcium silicate or magnesium aluminosilicate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, pregelatinized starch, gums such as gum arabic, gelatin, cellulose derivatives such as ethyl cellulose, and mixtures thereof, but are not limited thereto. Gliders may be selected from colloidal silica, hydrated silica, and combinations thereof, but are not limited thereto. The lubricant may be selected from magnesium stearate, silica, talc, light anhydrous silica, sodium stearoyl fumarate and combinations thereof, but is not limited thereto.

[0083] The content of API contained in the oral tablets, based on the total weight of the oral tablets, may be about 20 wt% to 70 wt%, about 20 wt% to 60 wt%, about 20 wt% to 50 wt%, about 20 wt% to 45 wt%, about 30 wt% to 70 wt%, about 30 wt% to 60 wt%, or about 30 wt% to 50 wt%, about 30 wt% to 45 wt%, about 40 wt% to 70 wt%, about 40 wt% to 60 wt%, about 40 wt% to 50 wt%, or about 40 wt% to 45 wt%.

[0084] In addition, the content of API can be, for example, about 50 mg to 500 mg per unit dosage form, 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, and about 300 mg to 400 mg.

[0085] In addition, the API content can be 50mg, 100mg, 150mg, 200mg, 300mg, 400mg or 500mg per unit dosage form.

[0086] Furthermore, the content of the API compound of formula 2, based on the total content of API, can be less than 0.2 wt%.

[0087] The pharmaceutical composition according to the invention contains crystalline particles of a compound of formula 1 or a pharmaceutically acceptable salt thereof in an amount that effectively achieves its intended purpose, said crystalline particles comprising less than 0.2 wt% of a compound of formula 2.

[0088] Specifically, a therapeutically effective amount means the amount of a compound that is effective in prolonging the survival time of a subject to be treated or in preventing, alleviating, or improving disease symptoms. The determination of a therapeutically effective amount is within the capabilities of a person skilled in the art, particularly based on the detailed disclosure provided herein.

[0089] When formulated into unit dosage forms, each unit dosage form preferably contains about 0.1 to 1,000 mg of crystalline particles of a compound of formula 1 or a pharmaceutically acceptable salt thereof as the active ingredient, said crystalline particles comprising less than 0.2 wt% of a compound of formula 2. Dosage depends on the physician's prescription based on factors such as the patient's weight, age, and the specific nature and symptoms of the disease. However, depending on the frequency and intensity of administration, the dose required to treat adults is generally in the range of about 1 to 1000 mg per day. When administered intramuscularly, intravenously, or orally to adults, a total daily dose of about 1 to 500 mg is usually sufficient as a single dose. However, higher daily doses may be desirable for some patients.

[0090] The present invention also provides a method for treating or preventing human xanthine oxidase-related diseases by using crystalline particles of a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein the crystalline particles contain less than 0.2 wt% of a compound of formula 2.

[0091] The term "human xanthine oxidase-related diseases" refers to diseases that can be treated or prevented by inhibiting human xanthine oxidase. These diseases can include, but are not limited to, hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, diabetes-related complications, kidney disease, inflammation, joint disease, and inflammatory bowel disease. Examples of diabetes-related complications include hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, and kidney failure (Circulation Research, 2006, 98, 169–171; Hypertension 2003, 41, 1183–90).

[0092] The term “treatment” means to terminate or delay disease progression when used on subjects exhibiting symptoms of disease onset, while the term “prevention” means to terminate or delay disease onset when used on subjects who do not exhibit symptoms of disease onset but are at high risk of developing the disease.

[0093] The present invention will be described in more detail based on the following embodiments and experimental examples. However, these embodiments and experimental examples are only for the purpose of helping to understand the present invention, and the scope of the present invention is not limited in any way to these embodiments and experimental examples.

[0094] Example

[0095] Synthesis Example 1: Synthesis of Compound 1

[0096] Synthetic Example 1-1: Synthesis of ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate

[0097] The title compound was obtained through the following procedures (1), (2) and (3).

[0098] (1) Synthesis of ethyl 1-(3-formyl-1H-indol-5-yl)pyrazole-4-carboxylate

[0099]

[0100] Oxaloyl chloride (0.56 ml) was added to 50 ml of anhydrous dichloromethane, followed by the addition of N,N-dimethylformamide (0.51 ml) at 0 °C, and then stirred at 0 °C for 30 minutes. A mixture of compound 1-(1H-indol-5-yl)pyrazole-4-carboxylate (1.40 g) and 50 ml of dichloromethane was added to the reaction solution, and the mixture was stirred at room temperature under reflux for 1 hour, then the solvent was removed. 100 ml of tetrahydrofuran and 100 ml of 20% ammonium acetate aqueous solution were added, and the mixture was stirred under reflux for 30 minutes while heating. After the reaction was complete, the reaction solution was cooled, ethyl acetate was added, and the mixture was washed with an aqueous sodium bicarbonate solution. The organic layer was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound.

[0101] (2) Synthesis of ethyl 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylate

[0102]

[0103] The ethyl 1-(3-formyl-1H-indol-5-yl)pyrazole-4-carboxylate obtained in step (1) was dissolved in 150 ml of pyridine, and ammonium hydroxide (499 mg) was added to it. The mixture was stirred under reflux for 5 hours while heating. After the reaction was complete, the solvent was concentrated under reduced pressure and filtered through silica gel using acetone as the solvent to obtain the title compound.

[0104] (3) Synthesis of ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate

[0105]

[0106] The ethyl 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylate obtained in step (2) was dissolved in 94 mL of anhydrous tetrahydrofuran, and di(imidazol-1-yl)methylthione (90%, 2.79 g) was added. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, 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.

[0107] Synthetic Examples 1-2: Synthesis of ethyl 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylate

[0108]

[0109] Ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate (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 stirred under reflux for 5 hours while heating. After the reaction was complete, 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.

[0110] Synthetic Examples 1-3: Synthesis and crystallization of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (Formula 1) Preparation of the seeds

[0111]

[0112] Ethyl 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (16.09 kg), tetrahydrofuran (22.21 kg), and methanol (19.7 kg) obtained in Synthesis Examples 1-2 were added to the reactor, and 10N NaOH (33.11 kg) was slowly added at approximately 8°C to allow the reaction to proceed. After the reaction was complete, purified water (24.95 L) and concentrated HCl (25.99 kg) were slowly added dropwise while maintaining the temperature at 0 to 10°C, and the mixture was aged before filtration. The filtered solid was washed with purified water and then dried under vacuum to obtain a final product (14.83 kg) in the form of crystalline particles of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid (Formula 1). The results of component analysis of the final product confirmed that the product mainly consisted of the compound of Formula 1 shown below, but also included certain amounts of compounds of Formula 2 and Formula 3 shown below, specifically, the content of compound of Formula 2 was measured to be 0.24%.

[0113] [Formula 1]

[0114]

[0115] [Equation 2]

[0116]

[0117] [Formula 3]

[0118]

[0119] Preparation Example 1: Preparation of crystalline particles of Formula 1 containing different concentrations of additive compounds (compounds of Formula 2)

[0120] In order to analyze the role of Formula 2 contained in the crystalline particles of the Formula 1 compounds prepared in the above-described synthetic Examples 1-3, the Formula 1 compounds were mixed with a specific amount of Formula 2 compounds by the following method to prepare crystalline particles (Examples 1 to 3).

[0121] Compounds of Formula 1 and Formula 2 were mixed in the proportions shown in Table 2. 90 ml of acetone and 9.9 ml of EtOAc were added, followed by slow dropwise addition of 105 ml of 1N NaOH over 1 hour with stirring to remove solid impurities. 0.15 ml of 6N HCl was added to the filtrate to lower the pH to pH 7-8, and the mixture was then heated to 50 ± 5 °C. While maintaining this temperature, 16.2 ml of 6N HCl was slowly added. After the addition was complete, the pH of the reaction mixture was confirmed to be 5 ± 0.5. Cooling was then initiated to lower the temperature of the reaction mixture to 25 °C, followed by filtration. The filtered solid was washed with purified water and then dried to obtain crystalline particles, i.e., the target compound. The content of Formula 2 compound in the obtained crystalline particles, as determined by HPLC, was confirmed to be 0.169% (Example 1), 0.246% (Example 2), and 1.646% (Example 3).

[0122] Preparation Example 2: Preparation of crystalline particles of Formula 1 containing different concentrations of additive compounds (compounds of Formula 3)

[0123] In order to analyze the role of Formula 3 contained in the crystalline particles of the Formula 1 compounds prepared in the above-mentioned synthetic examples 1-3, the Formula 1 compounds were mixed with a specific amount of Formula 3 compounds by the following method to prepare crystalline particles (Comparative Example 1 and Comparative Example 2).

[0124] 40 g of compound 1, 1.25 g of compound 3, 120 ml of acetone, and 140 ml of 1N NaOH were slowly added dropwise over 1 hour. After stirring the mixture, solid impurities were removed. 0.2 ml of 6N HCl was added to the filtrate to lower the pH to pH 7-8, and then the mixture was heated to 50 ± 5 °C. While maintaining this temperature, 21.6 ml of 6N HCl was slowly added. After the addition was complete, the pH of the reaction mixture was confirmed to be 5 ± 0.5. Cooling was then initiated to lower the temperature of the reaction mixture to 25 °C, followed by filtration. The filtered solid was washed with purified water and then dried to obtain crystalline particles, i.e., the target compound. The content of compound 3 in the obtained crystalline particles, as determined by HPLC, was confirmed to be 0.153% (Comparative Example 1).

[0125] Over a period of 1 hour, 25 g of compound 1, 35 g of compound 3, 90 ml of acetone, 9.9 ml of EtOAc, and 105 ml of 1N NaOH were slowly added dropwise. After stirring the mixture, solid impurities were removed. 0.15 ml of 6N HCl was added to the filtrate to lower the pH to pH 7-8, and then the mixture was heated to 50 ± 5 °C. While maintaining this temperature, 16.2 ml of 6N HCl was slowly added. After the addition was complete, the pH of the reaction mixture was confirmed to be 5 ± 0.5. Cooling was then initiated to lower the temperature of the reaction mixture to 25 °C, followed by filtration. The filtered solid was washed with purified water and then dried to obtain crystalline particles, i.e., the target compound. The content of compound 3 in the obtained crystalline particles, as determined by HPLC, was confirmed to be 1.243% (Comparative Example 2).

[0126] Table 2 below shows the content of additive compounds contained in the crystalline particles prepared in each embodiment and comparative example.

[0127] Table 2:

[0128]

[0129] Experimental Example 1. Analysis of the characteristics of individual crystal particles (analysis of crystal particle shape)

[0130] The shape of the crystalline particles prepared in the examples and comparative examples was observed and measured using a scanning electron microscope (SEM).

[0131] As a result of the analysis, such as Figure 1 As shown, with the increase of the content of compound 2, the crystalline particles of Examples 1 to 3 have a square hexahedral shape, but there is a tendency for uneven particle size (Example 2) and an increase in uneven plate-like particles and fine powder (Example 3). Therefore, it can be seen that even if compound 1 contains 0.246% of compound 2, it contains some uneven particles, but exhibits a relatively uniform square hexahedral shape.

[0132] However, Comparative Examples 1 and 2 show aspects that differ from Examples 1 to 3. The crystalline particles in Comparative Example 1 not only had an uneven shape but also produced a large amount of fine powder, making them difficult to incorporate into the final product preparation process. However, in the case of Comparative Example 2, the crystalline particles had a shape relatively close to a square hexahedron, and the particle size was uniform. Furthermore, in the case of the compound of Formula 3, the shape and size of the crystalline particles improved with increasing content.

[0133] Therefore, unlike Formula 2, as can be seen from the compound of Formula 2, the compound of Formula 3 exhibits crystalline particles with a uniform square hexahedral shape that can be incorporated into the preparation process of the final product as its content increases. It is evident that the compounds of Formula 2 and Formula 3 produced in the preparation process of the compound of Formula 1 have completely different properties from each other.

[0134] Experimental Example 2. Analysis of the characteristics of crystalline particles (analysis of particle size distribution)

[0135] The volume average particle size distribution and particle size distribution of crystalline particles prepared in the preparation examples, examples, and comparative examples were measured by using a wet method with a laser diffraction particle size analyzer.

[0136] It can be said that the larger the values ​​of DV10 / DV50 and DV50 / DV90 used as indicators, the better the particle size distribution. Here, DV10, DV50 and DV90 refer to the particle sizes of 10%, 50% and 90% of the total number of particles, respectively, when the measured particles are arranged in order from smallest to largest.

[0137] As shown in Table 1 below, it can be seen that compared to the comparative examples, the crystalline particles of Examples 1 and 2 have a relatively uniform particle size distribution, but the particle size is smaller. However, it can be seen that Example 3, as well as Comparative Examples 1 and 2, have an uneven particle size distribution.

[0138] Table 3:

[0139]

[0140] Experimental Example 3. Analysis of the packing density and tap density of crystal particles (analysis of flowability)

[0141] The bulk density and tap density of the crystalline particles prepared according to the preparation examples, embodiments, and comparative examples were measured. Bulk density is the volume of approximately 50g of granular powder placed in a graduated cylinder, while tap density is the volume of the graduated cylinder after it has been tapped at a constant height on the floor 100 times without any change in volume. Bulk density refers to the volume occupied by a certain mass of powder, which is the sum of the volume of the powder and the volume of the voids between the particles as the total volume.

[0142] According to the method of Jinapong et al. (2008), the flowability and cohesion of the particulate powder were calculated using the bulk density and tap density measured above via the Karl index of equation (3) and the Hauss-Nabi of equation (4).

[0143] Equation (3):

[0144] Equation (4):

[0145] Table 4:

[0146]

[0147]

[0148] The Carr index is a measure of powder compressibility, defined as the percentage of (tap density - bulk density) / tap density. As the index increases, the powder becomes more compressible and less flowable. The Hausner ratio is the ratio of tap density to bulk density and is an estimate of the interparticle friction.

[0149] The crystalline particles of Example 1 had a Karl quotient of 5.89% and a Hausner ratio of 1.06, showing very good (excellent) results in both flowability and cohesion. The values ​​for Example 2 were not as good as those for Example 1, but overall, they exhibited acceptable flowability and cohesion for pharmaceutical formulations. However, although the crystalline particles of Example 3 showed the same good particle size distribution as Example 1 in the particle size distribution analyzed above, they possessed properties unsuitable for general formulations because their Karl quotient was approximately 30% and their Hausner ratio was 1.42.

[0150] The Carr index of the crystalline particles in Comparative Example 1 was 35.58%, and the Hausner ratio was 1.56. The effect was worse than that of the crystalline particles in Example 3 (poor flowability and high cohesiveness). However, compared with the crystalline particles in Comparative Example 1, the crystalline particles in Comparative Example 2 had improved values, similar to Example 2 above.

[0151] Therefore, in order to obtain crystalline particles containing the compound of formula 1 with good flowability, the content of the compound of formula 2 can be 0.246%. When the content is less than 0.2%, crystalline particles with very good flowability can be obtained.

[0152] Synthetic Examples 1-4: Synthesis of Improved 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic Acid (Formula 1) and Preparation of crystalline particles

[0153] As confirmed by the above experimental examples, when a small amount, especially less than 0.2%, of compound 2 is incorporated into the crystalline particles of compound 1, crystalline particles with uniformity and excellent flowability can be obtained. Therefore, based on this, a method for preparing compound 1 containing less than 0.2% of compound 2 is obtained.

[0154] Ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate (312 kg), tetrahydrofuran (554 kg), and methanol (624 L) obtained in Synthesis Example 1-2 were added to the reactor, followed by the slow addition of 10N NaOH (386 kg). Because the reaction is exothermic, the addition was carried out over approximately one hour, taking care not to exceed the internal temperature of 27°C. After the addition was complete, the reaction was maintained between 21°C and 27°C. After the reaction was complete, purified water (624 L) and ethyl acetate (197 kg) were added, and 3N HCl (1048 kg) was slowly added dropwise while maintaining the temperature at 30°C to 35°C. The 3N HCl was added in two stages: a first addition to achieve the first nucleation of the solid, continuing until the pH reached 5 to 6. The reaction mixture producing the solid was stirred for 30 minutes, followed by the second addition, continuing until the pH reached 2 to 3. After the addition was complete, 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. Specifically, the content of compound 2 was measured to be 0.02 wt%.

[0155] Furthermore, the particle size distribution and flowability of the final product were confirmed to be excellent.

[0156] Therefore, it was confirmed that in the method of synthesizing Examples 1-3 (i.e., the existing method for manufacturing compound 1), when ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate, tetrahydrofuran, methanol and 10N NaOH are mixed and the reaction temperature is set to 27°C, ethyl acetate is added together with purified water after the reaction, and HCl is added dropwise in two steps, so the content of compound 2 can be adjusted to less than 0.2 wt%.

[0157] Experimental Example 4: Preparation of a compound comprising Formula 1 or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API). Oral tablet method

[0158] To prepare oral tablets containing a portion of the compound of formula 1 comprising formula 2 as an API, the excipients listed in the table below are mixed with the API, and then oral tablets are prepared using a tableting machine.

[0159] Table 5:

[0160] .

Claims

1. A pharmaceutical composition for treating or preventing xanthine oxidase-related diseases, said pharmaceutical composition comprising crystalline particles of a compound of formula 1 or a pharmaceutically acceptable salt thereof, said crystalline particles comprising >0 wt% to ≤0.2 wt% of a compound of formula 2; and a pharmaceutically acceptable excipient: [Formula 1] [Equation 2] 。 2. The pharmaceutical composition according to claim 1, wherein the content of said crystalline particles is from 20 wt% to 70 wt% based on a total of 100 wt% of said pharmaceutical composition.

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

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

5. The pharmaceutical composition according to claim 1, further comprising a compound of formula 3: [Formula 3] 。 6. A method for preparing crystalline particles of Formula 1, wherein the crystalline particles comprise >0 wt% to ≤0.2 wt% of a compound of Formula 2. ， ， The method includes the following steps: a) Mix ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate, tetrahydrofuran, and methanol into a reactor, then slowly add NaOH and allow it to react. b) Add purified water and ethyl acetate; c) Crystallization by dropwise addition of HCl; and d) Wash and dry the resulting crystals. In step a), the reaction temperature is maintained between 21°C and 27°C, and Step c) includes the following two steps: c-1) First, add HCl dropwise until the pH reaches 5 to 6 to generate nuclei; and c-2) Next, add HCl dropwise until the pH reaches 2 to 3.

7. A crystalline particle prepared by the method according to claim 6.

8. The crystalline particles according to claim 7, wherein the crystalline particles contain >0 wt% to ≤0.2 wt% of the compound of formula 2.

9. An oral tablet comprising the crystalline particles of claim 8 as an active pharmaceutical ingredient (API), wherein the API content is from 20 wt% to 70 wt% of a total of 100 wt% of the tablet.

10. The oral tablet of claim 9, wherein the content of said API is 30 wt% to 60 wt% based on a total of 100 wt% of said tablet.

11. The oral tablet of claim 10, wherein the content of said API is 40 wt% to 50 wt% based on a total of 100 wt% of said tablet.

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