Preparation of crystalline drug products

Abstract

The present invention relates to crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a molecular weight of about 8 to about 16 m 2 / g, preferably about 10 to about 15m 2 The present invention relates to a particle having a specific surface area (SSA) in the range of 1000 nm / g and a method for preparing the particle. Compound (I) is a potent androgen receptor (AR) modulator, which can be used as a drug, for example, a drug for treating prostate cancer.

Description

Field of the Invention

[0001] The present invention relates to crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a specific surface area (SSA) ranging from about 8 to about 16 m 2 / g, preferably about 10 to about 15m 2 / g, and a method for preparing the particles. Background of the Invention

[0003] Compound N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) and its preparation are disclosed in WO 2011 / 051540. Compound (I) is a potent androgen receptor (AR) modulator that can be used to treat cancer, particularly AR-dependent cancers such as prostate cancer and other diseases requiring AR antagonism. The structure of compound (I) is shown below:

[0004]

[0005] Since the hydrogen atoms of the pyrazole ring can exist in tautomeric equilibrium between the 1- and 2-positions, it is determined by the skilled person that the above structure and chemical name "N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I)" as referred to herein include the tautomers of compound (I), namely N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide.

[0006] Compound (I) has poor water solubility. Poorly soluble compounds generally have low oral bioavailability. Micronization is routinely attempted to improve the bioavailability of drugs with poor solubility. Micronization, i.e., reducing the particle size to a range of only a few microns, generally increases the dissolution rate of poorly soluble drugs by increasing the specific surface area (SSA). However, micronized particles generally have poor flowability and dispersibility, leading to defects in subsequent drug processing.

[0007] WO 2016 / 120530 discloses a stable crystalline form of compound (I) and a method for preparing the same by crystallization from a mixture of acetonitrile and water. This method produces small, irregular particles with sharp edges. Such particles are also not optimal for pharmaceutical processing purposes, for example due to poor powder flowability or difficulty in separation. Therefore, there is a need for crystalline particles of compound (I) that are better suited for pharmaceutical processing. SUMMARY OF THE INVENTION

[0009] It has now been found that compound (I) can be obtained as crystalline particles from the crystallization solvent, which have better subsequent pharmaceutical processing properties. In one aspect, the particles obtained have a consistent and relatively high specific surface area (SSA), which is in the range of 8-16 m 2 / g, preferably 10–15m 2 / g range, a large volume median diameter, for example in the range of 100-1000 μm, and a narrow particle size distribution. On the other hand, the particles have a round particle shape. The particles having a round particle shape are characterized by being substantially free of sharp edges. The particles of the present invention are easy to separate, free-flowing and exhibit reduced viscosity. In addition, it was found that even if the volume median diameter of the particles is reduced to the range of 10-100 μm (for example by grinding), in the range of about 8 to about 16 μm, the particles have a small volume median diameter, for example in the range of 100-1000 μm. 2 / g, preferably about 10 to about 15m 2 The specific surface area (SSA) of the particles did not change significantly over the range of 1000 μg / g, which confirmed the consistent bioavailability regardless of how the particle size was varied.

[0010] The particles according to the invention are therefore particularly suitable for pharmaceutical processing.

[0011] Thus, according to one aspect, the present invention provides crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a molecular weight of about 8 to about 16 m 2 / g, preferably about 10 to about 15m 2 The specific surface area (SSA) is in the range of 1000 nm / g.

[0012] According to another aspect, the present invention provides crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a molecular weight of about 8 to about 16 m 2 / g, preferably about 10 to about 15m 2The present invention has a specific surface area (SSA) in the range of 100 μm / g and a volume median diameter (Dv50) of ≥10 μm, preferably ≥15 μm, more preferably ≥20 μm.

[0013] According to another aspect, the present invention provides crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a molecular weight of about 8 to about 16 m 2 / g, preferably about 10 to about 15m 2 The present invention has a specific surface area (SSA) in the range of 1000 μm / g and a volume median diameter (Dv50) of 10-1000 μm, preferably 15-800 μm, more preferably 20-750 μm.

[0014] According to another aspect, the present invention provides crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a molecular weight of about 8 to about 16 m 2 / g, preferably about 10 to about 15m 2 / g and a volume median diameter (Dv50) of 100-1000 μm, preferably 120-800 μm, more preferably 150-750 μm. According to a specific aspect of the above embodiment of the present invention, the crystalline particles have a round particle shape.

[0015] According to yet another aspect, the present invention provides crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a volume median diameter (Dv50) of 100–1000 μm, preferably 120–800 μm, more preferably 150–750 μm and a round particle shape.

[0016] According to yet another aspect, the present invention provides a pharmaceutical dosage form comprising N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) as an active ingredient, wherein the active ingredient is in the form of crystalline particles according to any of the above embodiments.

[0017] According to a further aspect, the present invention provides a pharmaceutical dosage form, wherein the active ingredient is prepared from crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a volume median diameter (Dv50) of 100–1000 μm and a round particle shape, for example by milling the particles to provide a volume median diameter (Dv50) of 10–100 μm.

[0018] According to yet another aspect, the present invention provides a pharmaceutical dosage form wherein the active ingredient is prepared from crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a molecular weight of about 8 to about 16 m 2 / g, preferably about 10 to about 15m 2 The particles may have a specific surface area (SSA) in the range of 100-1000 μm / g, a volume median diameter (Dv50) of 100-1000 μm, and a rounded particle shape, for example by milling the particles to provide a volume median diameter (Dv50) of 10-100 μm.

[0019] According to another aspect, the present invention provides a method for preparing crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I), the method comprising the following steps:

[0020] a) providing N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) in a solvent comprising ethanol and water, wherein the amount of water is 35-60%, preferably 40-58%, more preferably 42-55% by weight of the solvent;

[0021] b) heating the mixture to approximately reflux temperature until N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) dissolves;

[0022] c) cooling the mixture to about 20-35° C. over a period of at least 3 hours, preferably about 4 to about 8 hours, optionally with the addition of seed crystals;

[0023] d) adding water over a period of at least 1 hour, preferably from about 2 to about 10 hours, such that after step d), the amount of water in the solvent is 55-80%, preferably 58-78%, more preferably 60-75% by weight of the solvent, optionally simultaneously with step c);

[0024] e) separating the precipitate.

[0025] According to yet another aspect, the present invention provides crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a volume median diameter (Dv50) of 100–1000 μm, preferably 120–800 μm, more preferably 150–750 μm and having a round particle shape, the particles being obtainable by a method comprising the steps of:

[0026] a) providing N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) in a solvent comprising ethanol and water, wherein the amount of water is 35-60%, preferably 40-58%, more preferably 42-55% by weight of the solvent;

[0027] b) heating the mixture to approximately reflux temperature until N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) dissolves;

[0028] c) cooling the mixture to about 20-35° C. over a period of at least 3 hours, preferably about 4 to about 8 hours, optionally with the addition of seed crystals;

[0029] d) adding water over a period of at least 1 hour, preferably from about 2 to about 10 hours, such that after step d), the amount of water in the solvent is 55-80%, preferably 58-78%, more preferably 60-75% by weight of the solvent, optionally simultaneously with step c);

[0030] and

[0031] e) separating the precipitate.

[0032] According to a specific embodiment, the specific surface area (SSA) of the particles obtainable by the above method ranges from about 8 to about 16 m 2 / g, preferably about 10 to about 15m 2 / g. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The particle size distribution of the crystalline particles of Compound (I) prepared according to the present invention analyzed by laser diffraction is shown.

[0035] Figure 2 A scanning electron microscope image (50x magnification, bar length 500 μm) of crystalline particles of Compound (I) prepared according to the present invention is shown.

[0036] Figure 3 (Reference) shows a scanning electron microscope image (500x magnification) of particles of Compound (I) prepared according to Example 1 of WO 2016 / 120530. Detailed Description of the Invention

[0038] As used herein, the term "particles having a rounded particle shape" refers to particles according to the present invention having a substantially spherical, ellipsoidal or potato-like geometry with a curved surface substantially free of sharp or rough edges, such geometry and surface being uniform and distinct when the particles are examined under a scanning electron microscope, in particular at a magnification of 50-100 times. The rounded particles according to the present invention are further characterized by having an average aspect ratio greater than 0.8, preferably greater than 0.82, and / or an average HS (High Sensitivity) circularity greater than 0.89, preferably greater than 0.9.

[0039] As used herein, the term "aspect ratio" refers to the ratio of the shortest dimension to the longest dimension of a particle and ranges from 0 to 1.

[0040] As used herein, the term "high sensitivity (HS) circularity" refers to a parameter equal to the square of circularity, where circularity is equal to the ratio of the circumference of a circle equal to the projected area of ​​a particle to the actual circumference (perimeter) of the particle. Thus, high sensitivity (HS) circularity is calculated as (4π×area) / (perimeter) 2 ).

[0041] The average aspect ratio and average high sensitivity (HS) circularity of the particles can be determined on dry dispersions by optical microscopy-based methods, such as the Morphologi G3 TM Particle size and shape analyzer (Malvern Instruments). TM The samples were prepared using an integrated dry powder disperser (Malvern Instruments), for example using a 7 mm 3 The sample volume and dispersion pressure are 1.0 bar. Automated image analysis is suitable for use without filters. The applied magnification depends on the particle size of the powder being analyzed and is typically 10x.

[0042] As used herein, the term "crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I)" refers to particles of compound (I) wherein compound (I) is at least partially in crystalline form, including microcrystalline form. For example, the term includes particles of compound (I) wherein compound (I) is at least partially in crystalline Form I disclosed in WO 2016 / 120530. The X-ray powder diffraction (XRPD) pattern of crystalline Form I has characteristic peaks at approximately 8.5, 10.4, 16.6, 16.9, and 24.3 degrees 2-θ. Thus, the term includes particles that exhibit characteristic XRPD peaks at approximately 8.5, 10.4, 16.6, 16.9, and 24.3 degrees 2-θ.

[0043] The particle size distribution of the crystalline particles of compound (I) can be analyzed by laser diffraction, for example, using a Beckman Coulter LS13320 laser diffraction particle size analyzer equipped with a Tornado dry powder system, using air as the dispersion medium, a measuring pressure of 24"H2O±2"H2O, a sample volume of 10 ml, a system control target of 5% in terms of turbidity and applying a Fraunhofer optical model.

[0044] The parameters considered are the volume diameters (μm) of the 10th, 50th and 90th percentiles of the particles, denoted respectively as Dv10, Dv50 and Dv90, which are determined by assuming that the particles have a geometry equal to that of a sphere.

[0045] The specific surface area (SSA) of the crystalline particles of Compound (I) can be analyzed using a three-point nitrogen adsorption technique based on the Brunauer, Emmett, and Teller (BET) theory, for example, using a TriStar 3000 automated gas adsorption analyzer (Micromeritics, Inc.). The sample is preferably dried under vacuum at 40°C for 20 hours. The volumetric method can be used within a relative pressure range of 0.1-0.3 P / P0.

[0046] The present invention provides a method for preparing crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I), the method comprising the following steps:

[0047] a) providing N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) in a solvent comprising ethanol and water, wherein the amount of water is 35-60%, preferably 40-58%, more preferably 42-55% by weight of the solvent;

[0048] b) heating the mixture to approximately reflux temperature until N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) dissolves;

[0049] c) cooling the mixture to about 20-35° C. over a period of at least 3 hours, preferably about 4 to about 8 hours, optionally with the addition of seed crystals;

[0050] d) adding water over a period of at least 1 hour, preferably from about 2 to about 10 hours, such that after step d), the amount of water in the solvent is 55-80%, preferably 58-78%, more preferably 60-75% by weight of the solvent, optionally simultaneously with step c); and

[0051] e) separating the precipitate.

[0052] The solvent used in step a) typically comprises ethanol and water. The amount of water in the solvent of step a) is approximately 35–60%, preferably 40–58%, and more preferably 42–55%, by weight of the solvent. Preferably, the solvent consists essentially of ethanol and water. For example, the solvent of step a) comprises 35–60% water and 40–65% ethanol, preferably 40–58% water and 42–60% ethanol, more preferably 42–55% water and 45–58% ethanol, by weight of the solvent. According to one embodiment, the solvent of step a) comprises 45–52% water and 48–55% ethanol, by weight of the solvent. According to another embodiment, the solvent of step a) comprises 48–55% water and 45–52% ethanol, by weight of the solvent.

[0053] The amount of compound (I) used in step a) is suitably about 1-20%, preferably about 5-15%, for example 6-12% by weight of the solvent. For example, in a suitable reactor, 150-250 kg of compound (I) is provided in 1500-3800 kg of ethanol-water solvent. The mixture is then heated under stirring, suitably to about reflux temperature, for example to about 65-85°C, until compound (I) dissolves. In step c), the mixture is then slowly cooled to 20-35°C while stirring gently, typically at a stirring speed of less than 80 rpm. Cooling is carried out for at least 3 hours, preferably for about 4 to about 8 hours, and crystals of compound (I) are optionally added as seeds. The addition of seeds is suitably carried out at a temperature starting from about 75°C, and optionally at a lower temperature. For example, when the temperature of the mixture is about 50-70°C, seeds may be added one or more times. The amount of crystals added for seeding is typically less than 0.5% of the weight of compound (I) initially provided to the reactor. Crystals of Compound (I) used as seed crystals can be prepared, for example, using the method described in WO 2016 / 120530.

[0054] In step d), more water is slowly added to the mixture such that, after the addition of the water, the amount of water in the solvent is 55–80%, preferably 58–78%, and more preferably 60–75%, by weight of the solvent. Preferably, the solvent consists essentially of ethanol and water. For example, after step d), the solvent comprises 55–80% water and 20–45% ethanol, preferably 58–78% water and 22–42% ethanol, and more preferably 60–75% water and 25–40% ethanol, by weight of the solvent.

[0055] According to one embodiment, the solvent after step d) comprises 60-65% water and 35-40% ethanol by weight of the solvent. According to another embodiment, the solvent after step d) comprises 65-70% water and 30-35% ethanol by weight of the solvent. According to yet another embodiment, the solvent after step d) comprises 70-75% water and 25-30% ethanol by weight of the solvent.

[0056] According to another embodiment, the solvent of step a) comprises 48-55% water and 45-52% ethanol by weight of the solvent, and the solvent after step d) comprises 60-65% water and 35-40% ethanol by weight of the solvent. According to another embodiment, the solvent of step a) comprises 45-52% water and 48-55% ethanol by weight of the solvent, and the solvent after step d) comprises 70-75% water and 25-30% ethanol by weight of the solvent.

[0057] The addition of water is carried out over a period of at least 1 hour, preferably about 2 to about 10 hours, for example about 6 to about 10 hours. The mixture is gently stirred during the addition of water, typically at a stirring speed of less than 80 rpm. During the addition of water, the temperature of the mixture is suitably maintained at about 20-35°C.

[0058] Alternatively, steps c) and d) can be performed simultaneously. In this embodiment, water is added during the cooling step. The water addition procedure described above, including the optional addition of seed crystals, can be performed while the mixture is cooled to approximately 20-35°C. The simultaneous cooling and water addition are suitably performed over a period of at least 3 hours, preferably over a period of 4-10 hours.

[0059] After step d), the mixture can be further cooled, preferably to at least 10-30°C, for example, 10-20°C, for a period of at least 1 hour, for example, 1-3 hours. After cooling, the mixture is stirred appropriately until precipitation is complete. The precipitated crystalline particles are easily separated, for example, by centrifugation, and then washed with water and / or ethanol. The separated precipitate can be dried under reduced pressure, for example, under vacuum, at a temperature of at least 30°C, for example, 40-60°C, for a period of time to complete drying.

[0060] The particles obtained by the above process are crystalline, generally have a rounded particle shape, and exhibit a specific surface area (SSA) generally in the range of about 8 to about 16 m 2 / g, more typically from about 10 to about 15 m 2 / g. The particles obtained typically have a volume median diameter (Dv50) of 100–1000 μm, preferably 120–800 μm, more preferably 150–750 μm, in particular 180–700 μm, for example 200–650 μm. Dv10 is typically greater than about 50 μm, preferably greater than about 60 μm, more preferably greater than about 70 μm, in particular 80–500 μm, for example 100–400 μm. Dv90 is typically less than 2000 μm, preferably less than 1500 μm, more preferably less than 1400 μm, in particular 300–1300 μm, for example 400–1200 μm.

[0061] Furthermore, 80 volume-% of the particles are typically 50-2000 μm, preferably 60-1500 μm, more preferably 70-1400 μm, in particular 80-1300 μm, for example 100-1200 μm.

[0062] The round particles obtained by the above method are typically characterized by an average aspect ratio greater than 0.8 and / or an average high sensitivity (HS) circularity greater than 0.89. More typically, the round particles are characterized by an average aspect ratio greater than 0.8 and an average high sensitivity (HS) circularity greater than 0.89. Even more typically, the round particles are characterized by an average aspect ratio greater than 0.82 and an average high sensitivity (HS) circularity greater than 0.9.

[0063] Since the particles obtained by the above method have a large volume median diameter, a narrow particle size distribution and a round particle shape characterized by being substantially free of sharp edges, they are easy to separate, free-flowing and exhibit reduced stickiness. The specific surface area (SSA) of the round particles obtained by the above method is from about 8 to about 16 m 2 / g, preferably about 10 to about 15m 2 / g, and even when the volume median diameter (Dv50) of the particles is reduced, for example, by milling or other suitable means to a range of 10-100 μm, the specific surface area does not change significantly. This ensures consistent bioavailability regardless of how the particle size changes. Therefore, if the tableting material is more uniform (as required), the round particles can be ground to a particle size with a Dv50 in the range of, for example, 10-100 μm, preferably 15-95 μm, and typically 20-90 μm, which is very suitable for preparing pharmaceutical dosage forms such as tablets for oral administration.

[0064] Therefore, the crystalline round particles of compound (I) obtained by the process of the present invention can be used as such or in a ground form together with excipients known in the art for the preparation of pharmaceutical dosage forms such as tablets, capsules or powders.

[0065] The present invention is further illustrated by the following examples.

[0066] Example 1 Preparation of Crystalline Particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I)

[0067] Granular sodium borohydride (15 kg) and EtOH (1370 kg) were placed in a 6.3 m 3The mixture was dissolved by stirring at 22°C for 30 minutes. (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propane-2-yl)-1H-pyrazole-5-carboxamide (225 kg) was added to the reaction vessel. The mixture was then stirred at 22°C for 4 hours to complete the reaction. The pH of the mixture was then adjusted to acidic with aqueous HCl solution. Water (800 kg) was then added, and the pH of the mixture was set to 7.0 ± 1.0 by adding NaOH in water. The mixture was warmed to 65°C and then transferred to a 6.3 m 3 The mixture was heated to 78°C in a jacketed steel reaction vessel to dissolve the mixture. The solution was cooled to 64°C under a nitrogen atmosphere. Seed crystals were added to the solution at 64°C with gentle stirring. The solution was then cooled to 30°C over 8 hours with gentle stirring. Water (2600 kg) was then added at 30°C with gentle stirring over 7-10 hours. The mixture was cooled to 20°C over 2 hours with gentle stirring and then stirred for an additional hour. The precipitated product was separated by centrifugation, washed with water, and vacuum dried at 40-60°C to obtain 214 kg of crystalline particles in the form of round particles.

[0068] Example 2 Preparation of Crystalline Particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I)

[0069] Water (450 kg), EtOH (920 kg) and (N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide (215 kg) were placed in a 6.3 m flask with 100 kg rinse EtOH. 3 The mixture was dissolved by heating to 75°C. Activated carbon SX Ultra (11 kg) and diatomaceous earth (21 kg) were added, followed by stirring at 78°C for 1 hour. The mixture was cooled to 75°C under a nitrogen atmosphere and filtered. The filtrate was transferred to a 6.3 m 3Jacketed steel reaction vessel. The carbon / diatomaceous earth cake was washed with a warm (75°C) mixture of water (970 kg) and EtOH (345 kg). The washing liquid was also added to the reaction vessel. The solution was stirred at 78°C for 30 minutes and then cooled to 70°C. Gentle stirring was maintained for the remainder of the operation. The solution was seeded at 70°C and then cooled to 30±5°C over a period of 4 hours. Water (840 kg) was then added at 30±5°C over a period of 6 hours. The mixture was cooled to 20°C over a period of 2 hours and then stirred for an additional 1 hour. The precipitated product was separated by centrifugation, washed with EtOH, and dried in vacuo at 40-60°C to obtain 190 kg of crystalline particles in the shape of round particles.

[0070] Example 3 Preparation of Crystalline Particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I)

[0071] Water (1400 kg), EtOH (1215 kg) and (N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide (210 kg) were placed in a 6.3 m 3 The mixture was dissolved by heating to 75°C. Activated carbon SX Ultra (11 kg) and diatomaceous earth (21 kg) were added and stirred for 1 hour. The mixture was then filtered hot. The filtrate was transferred to a 6.3 m 3 A jacketed steel reaction vessel was prepared. The carbon / diatomaceous earth cake was washed with EtOH (170 kg). The washings were also added to the reaction vessel. The temperature was adjusted to 70°C. The solution was seeded at 70°C and then cooled to 60°C. The mixture was then cooled to 30°C over 4 hours, and water (1050 kg) was added simultaneously. The mixture was stirred for an additional 30 minutes. The precipitated product was centrifuged, washed with water, and dried under vacuum at 70°C to obtain 190 kg of crystalline particles in the form of round particles.

[0072] Example 4 .Determination of particle size distribution

[0073] The particle size distribution of the crystalline round particles of compound (I) prepared according to the present invention was determined by laser diffraction. The measurement was performed using a Beckman Coulter LS13320 laser diffraction particle size analyzer equipped with a Tornado dry powder system, using air as the dispersion medium, a measurement pressure of 24" H2O ± 2" H2O, a sample volume of 10 ml, a system control target of 5% for turbidity, and the Fraunhofer optical model. The results of the particle size analysis are shown in FIG. Figure 1According to the analysis, the Dv10 value of the particles was 359 μm, the Dv50 was 632 μm, and the Dv90 was 925 μm.

[0074] Example 5 . Characterization of particles by scanning electron microscopy (SEM) images

[0075] The crystalline round particles of compound (I) prepared according to the present invention were characterized by scanning electron microscopy imaging. The SEM image shows Figure 2 In the figure (50 times magnification, bar length 500 μm). For comparison, the SEM image of the particles prepared according to Example 1 of WO 2016 / 120530 is shown in Figure 3 (500x magnification, bar length 30 μm). The particles produced according to the present invention exhibit round particle shape with a narrow particle size distribution, while the particles produced according to WO 2016 / 120530 are small and irregular with sharp edges.

[0076] Example 6 .Determination of particle specific surface area (SSA)

[0077] The specific surface area (SSA) and particle size distribution (PSD) of two batches (A and B) of crystalline round particles of Compound (I) prepared according to the present invention were determined. The two batches of particles were then ground, and the SSA and PSD were determined. The results are shown in Tables 1 and 2. The results show that even after the particles were ground to a reduced particle size, the specific surface area (SSA) of the particles did not change significantly.

[0078] Table 1

[0079]

[0080]

[0081] Table 2

[0082]

[0083] The specific surface area was determined using a three-point nitrogen adsorption technique based on the Brunauer, Emmett, and Teller (BET) theory using a TriStar 3000 automated gas adsorption analyzer (Micromeritics, Inc.). The samples were vacuum dried at 40°C for 20 hours. This volumetric method was applied over a relative pressure range of 0.1–0.3 P / P0.

Claims

1. Crystalline particles of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a molecular weight of 8 to 16 m 2 The particles have a specific surface area SSA in the range of 100 μm / g, a volume median diameter Dv50 of 100-1000 μm, and a round particle shape, wherein the average aspect ratio of the particles is higher than 0.8 and the average high sensitivity HS circularity is higher than 0.

89.

2. The crystalline particles according to claim 1, which have a particle size of 10 to 15 μm. 2 The specific surface area SSA is in the range of 1.5 ~ 2.5 g / cm2.

3. The crystalline particles according to claim 1, characterized in that The average aspect ratio is higher than 0.82 and the average high sensitivity HS circularity is higher than 0.

9.

4. The crystalline particles according to claim 1, having a volume median diameter Dv50 of 120 to 800 μm.

5. A pharmaceutical dosage form comprising as active ingredient N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I), wherein the active ingredient is in the form of crystalline particles according to any one of claims 1 to 4.

6. A pharmaceutical dosage form comprising N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) as an active ingredient, wherein the active ingredient is prepared from the crystalline particles of any one of claims 1 to 4 by milling the particles to provide a volume median diameter Dv50 of 10-100 μm.

7. A method for preparing the crystalline particles according to any one of claims 1 to 4, comprising the steps of: a) providing N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) in a solvent comprising ethanol and water, wherein the amount of water is 35-60% by weight of the solvent; b) heating the mixture to approximately reflux temperature until N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) dissolves; c) cooling the mixture to 20-35° C. over a period of at least 3 hours, optionally adding seed crystals; d) adding water over a period of at least 1 hour so that after step d) the amount of water in the solvent is 55-80% by weight of the solvent, said addition of water optionally being carried out simultaneously with step c); and e) separating the precipitate.

8. The process according to claim 7, wherein in step a), the solvent consists of ethanol and water.

9. The method according to claim 7, wherein in step a), the solvent comprises 35-60% water and 40-65% ethanol by weight of the solvent.

10. The process according to claim 7, wherein in step d), the temperature of the mixture is maintained within the range of 20-35°C during the addition of water.

11. The method according to claim 7, wherein steps c) and d) are performed simultaneously.

12. The process according to claim 7, wherein after step d), the mixture is further cooled during a period of at least 1 hour.

13. The process according to claim 7, wherein during step c), the mixture is seeded at 50-70°C.

14. The process according to claim 7, wherein the amount of compound (I) in step a) is 1-20% by weight of the solvent.

15. The process according to claim 7, wherein the separated precipitate is dried under reduced pressure at a temperature of at least 30°C.

16. The process according to claim 15, wherein the separated precipitate is dried at 40-60°C under reduced pressure.

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