Patent Description:
The compound N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)-propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (I) and manufacture thereof have been disclosed in <CIT>. Compound (I) is a potent androgen receptor (AR) modulator useful in the treatment of cancer, particularly AR dependent cancer such as prostate cancer, and other diseases where AR antagonism is desired. Compound (I) is represented by the structure:
<CHM>.

As the hydrogen atom of the pyrazole ring may exist in tautomeric equilibrium between the <NUM>- and <NUM>-position, it is recognized by the skilled person that the above structure and the chemical name "N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)-propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (I) ," as referred to herein, is inclusive of the tautomer of compound (I), namely N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)-propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide.

Compound (I) is poorly soluble in water. Poorly soluble compounds often suffer from low oral bioavailability. Enhancement of bioavailability of poorly soluble drugs is routinely attempted by micronization. Micronization, i.e. reduction of particle size to the range of only few micrometers, typically increases the dissolution rate of the poorly soluble drug through increased specific surface area (SSA). Micronized particles, however, often suffer from poor flow and dispersion properties causing drawbacks in subsequent pharmaceutical processing.

A stable crystalline form of compound (I) and a method for the preparation thereof by crystallization from a mixture of acetonitrile and water has been disclosed in <CIT>. The method produces small irregular particles with sharp edges. Such particles are not optimal for pharmaceutical processing purposes either, for example due to poor flowability of the powder or cumbersome isolation. Therefore, there is a need for crystalline particles of compound (I) which are better suited for pharmaceutical processing.

<CIT> discloses darolutamide as an intermediate compound recovered directly from the reaction mixture.

It has now been found that compound (I) can be obtained from the crystallization solvent as crystalline particles which have better properties for subsequent pharmaceutical processing. In one aspect, the obtained particles have consistent and relatively high specific surface area (SSA) in the range of <NUM> - <NUM><NUM>/g, preferably in the range of <NUM> - <NUM><NUM>/g (as measured by the three-point nitrogen adsorption technique based on the Brunauer, Emmett and Teller (BET) theory), large volume median diameter, in the range of <NUM> - <NUM> (as measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model), and narrow particle size distribution. Additionally, the particles have rounded particle shape, and are further characterized by mean aspect ratio higher than <NUM>, preferably higher than <NUM> and/or mean high sensitivity (HS) circularity higher than <NUM>, preferably higher than <NUM>, as determined by an optical microscopy method on a dry powder dispersion. The particles having rounded particle shape are also characterized by substantial lack of sharp edges. The particles of the present invention are easy to isolate, free flowing and exhibit reduced stickiness. Moreover, it was found that the specific surface area (SSA) of the particles in the range of from about <NUM> to about <NUM><NUM>/g, preferably from about <NUM> to about <NUM><NUM>/g (as measured by the three-point nitrogen adsorption technique based on the Brunauer, Emmett and Teller (BET) theory), does not significantly change even though the volume median diameter of the particles is reduced to the range of <NUM> - <NUM> (as measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model), e.g. by milling. This ascertains consistent bioavailability regardless of the variability in particle size.

Therefore the particles according to the present invention are particularly well suited for pharmaceutical processing.

Thus, according to one aspect, the present invention provides crystalline particles of N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)-propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (I) having.

wherein the crystalline particles are further characterized by mean aspect ratio higher than <NUM>, preferably higher than <NUM> and/or mean high sensitivity (HS) circularity higher than <NUM>, preferably higher than <NUM>, as determined by an optical microscopy method on a dry powder dispersion.

According to still another aspect, the present invention provides a pharmaceutical dosage form comprising N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)-propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (I) as an active ingredient, wherein the active ingredient is in the form of crystalline particles according to the invention.

According to still another aspect, the present invention provides a pharmaceutical dosage form, wherein the active ingredient is prepared from crystalline particles of the invention, for example by milling said particles to provide volume median diameter (Dv50) between <NUM> - <NUM> (as measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model).

According to still another aspect, the present invention provides a method for preparing crystalline particles of N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)-propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (I) according to the present invention, the method comprising the steps of.

The term "particles having rounded particle shape", as used herein, refers to particles according to the present invention having substantially spherical, elliptical or potato-like geometries with curved surfaces substantially lacking sharp or rough edges, such geometries and surfaces being consistent and apparent when the particles are examined under a scanning electron microscope, particularly with <NUM> - <NUM> fold magnification. The rounded particles according to the invention are further characterized by having mean aspect ratio higher than <NUM>, preferably higher than <NUM> and/or mean HS (high sensitivity) circularity higher than <NUM>, preferably higher than <NUM> (as determined by an optical microscopy method on a dry powder dispersion).

The term "aspect ratio", as used herein, refers to the ratio of the shortest dimension to the longest dimension of a particle and is in the range of <NUM> to <NUM>.

The term "high sensitivity (HS) circularity", as used herein, refers to a parameter which is equal to the square of the circularity where the circularity is equal to the ratio of the circumference of a circle equal to the particle's projected area to the actual circumference (perimeter) of a particle. Thus, high sensitivity (HS) circularity is calculated as (4π x Area)/(Perimeter<NUM>).

The mean aspect ratio and mean high sensitivity (HS) circularity of the particles are determined by an optical microscopy based method on a dry dispersion, such as Morphologi G3™ particle size and particle shape analyser (Malvern Instruments). The sample can be prepared by using the Morphologi G3™ integrated dry powder disperser (Malvern Instruments), for example using sample amount of <NUM><NUM> and dispersion pressure of <NUM> bar. The automated image analysis is suitably performed without filters. The applied magnification depends on the particle size of the analysed powder being typically 10x.

The term "crystalline particles of N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)-propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (I)", as used herein, refers to particles of compound (I) wherein compound (I) is at least partly in crystalline, including microcrystalline, form. For example, the term includes particles of compound (I) wherein compound (I) is at least partly in the crystalline form I, disclosed in <CIT>. The X-ray powder diffraction (XRPD) pattern of crystalline form I has characteristic peaks at about <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> degrees <NUM>-theta. Accordingly, the term includes particles which show XRPD characteristic peaks at about <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> degrees <NUM>-theta.

The particle size distribution of crystalline particles of compound (I) are analyzed by laser light diffraction, for example using Beckman Coulter LS13320 laser diffraction particle size analyzer equipped with Tornado Dry Powder System using air as dispersion medium with measurement pressure <NUM>"H<NUM>O ± <NUM>"H<NUM>O, sample amount <NUM>, system controlled target <NUM> % for obscuration and applying Fraunhofer optical model.

The parameters considered are the volumetric diameters in µm of the <NUM>th, <NUM>th and <NUM>th percentiles of the particles, expressed as Dv10, Dv50 and Dv90 respectively, which are determined by assuming that the particles have a geometric shape equivalent to a sphere.

The specific surface area (SSA) of crystalline particles of compound (I) are analyzed using the three-point nitrogen adsorption technique based on the Brunauer, Emmett and Teller (BET) theory, for example using TriStar <NUM> automated gas adsorption analyzer, (Micromeritics, Inc. The samples are suitably vacuum dried for <NUM> hours at <NUM>. The volumetric method can be used at the relative pressure range of <NUM> - <NUM> P/P<NUM>.

The present invention provides a method for preparing crystalline particles of N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)-propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (I) according to the present invention, the method comprising the steps of.

The solvent to be used in step a) generally comprises ethanol and water. The amount of water in the solvent of step a) is about <NUM> - <NUM> %, preferably <NUM> - <NUM> %, more preferably <NUM> - <NUM> %, per weight of the solvent. Preferably, the solvent consists essentially of ethanol and water. For example, the solvent of step a) contains <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, preferably <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, more preferably <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent. According to one embodiment, the solvent of step a) contains <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent. According to another embodiment, the solvent of step a) contains <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent.

The amount of compound (I) used in step a) is suitably about <NUM> - <NUM> %, preferably about <NUM> - <NUM> %, for example <NUM> - <NUM> %, per weight of the solvent. For example, <NUM> - <NUM> of compound (I) is provided in <NUM> - <NUM> of ethanol-water solvent in a suitable reactor. The mixture is then heated with stirring, suitably to about refluxing temperature, for example to about <NUM> - <NUM>, until compound (I) has been dissolved. In step c) the mixture is then cooled slowly to <NUM> - <NUM> while stirring mildly, typically with stirring speed less than <NUM> rpm. The cooling is carried out during at least <NUM> hours, preferably during about <NUM> to about <NUM> hours, optionally with seeding using crystals of compound (I). The seeding is suitably carried out at a temperature starting from about <NUM> and optionally again at lower temperatures. For example, the seeding can be carried out once or several times when the temperature of the mixture is about <NUM> - <NUM>. The amount of seeding crystals is typically less than <NUM> % per weight of the compound (I) initially provided to the reactor. The seeding crystals of compound (I) can be prepared, for example, using the method described in <CIT>.

In step d) more water is added slowly to the mixture such that after the water addition the amount of water in the solvent is <NUM> - <NUM> %, preferably <NUM> - <NUM> %, more preferably <NUM> - <NUM> %, per weight of the solvent. Preferably, the solvent consists essentially of ethanol and water. For example, the solvent after step d) contains <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, preferably <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, more preferably <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent.

According to one embodiment, the solvent after step d) contains <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent. According to another embodiment, the solvent after step d) contains <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent. According to still another embodiment, the solvent after step d) contains <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent.

According to another embodiment, the solvent of step a) contains <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent, and after step d) <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent. According to another embodiment, the solvent of step a) contains <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent, and in step d) <NUM> - <NUM> % of water and <NUM> - <NUM> % of ethanol, per weight of the solvent.

The addition of water is carried out during at least <NUM> hour, preferably during about <NUM> to about <NUM> hours, for example during about <NUM> to about <NUM> hours. The mixture is stirred mildly during water addition, typically with stirring speed less than <NUM> rpm. The temperature of the mixture is suitably kept within about <NUM> - <NUM> during the addition of water.

Alternatively, steps c) and d) can be carried out simultaneously. In this embodiment water is added during the cooling step. The procedure of water addition can be carried out as explained above while cooling the mixture to about <NUM> - <NUM> including the optional seeding. The simultaneous cooling and water addition is suitably carried out during at least <NUM> hours, preferably during <NUM> - <NUM> hours.

After step d) the mixture can be cooled further, preferably to about <NUM> - <NUM>, for example to <NUM> - <NUM>, during at least <NUM> hour, for example during <NUM> - <NUM>. After the cooling the mixture is suitably stirred until the precipitation is complete. The precipitated crystalline particles are easy to isolate, for example by centrifuging followed by washing with water and/or ethanol. The isolated precipitate can be dried under reduced pressure, for example at vacuum, at a temperature which is at least <NUM>, for example <NUM> - <NUM>, for a period needed to complete the drying.

The particles obtained by the above method are crystalline, have rounded particle shape and exhibit specific surface area (SSA) in the range from about <NUM> to about <NUM><NUM>/g, more typically from about <NUM> to about <NUM><NUM>/g (as measured by the three-point nitrogen adsorption technique based on the Brunauer, Emmett and Teller (BET) theory). The particles obtained have volume median diameter (Dv50) between <NUM> - <NUM>, preferably between <NUM> - <NUM>, more preferably between <NUM> - <NUM>, in particular between <NUM> - <NUM>, for example between <NUM> - <NUM> (as measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model). Dv10 is generally greater than about <NUM>, preferably greater than about <NUM>, more preferably greater than about <NUM>, in particular between <NUM> - <NUM>, for example between <NUM> - <NUM> (as measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model). Dv90 is generally lower than <NUM>, preferably lower than <NUM>, more preferably lower than <NUM>, in particular between <NUM> - <NUM>, for example between <NUM> - <NUM> (as measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model).

Moreover, <NUM> vol-% of the particles is generally between <NUM> - <NUM>, preferably between <NUM> - <NUM>, more preferably between <NUM> - <NUM>, in particular between <NUM> - <NUM>, for example between <NUM> - <NUM>.

The rounded particles obtained by the above method are characterized by mean aspect ratio higher than <NUM> and/or mean high sensitivity (HS) circularity higher than <NUM> (as determined by an optical microscopy method on a dry powder dispersion). More typically, the rounded particles are characterized by mean aspect ratio higher than <NUM> and mean high sensitivity (HS) circularity higher than <NUM> (as determined by an optical microscopy method on a dry powder dispersion). Still more typically, the rounded particles are characterized by mean aspect ratio higher than <NUM> and mean high sensitivity (HS) circularity higher than <NUM> (as determined by an optical microscopy method on a dry powder dispersion).

As the particles obtained by the above method have large volume median diameter, narrow particle size distribution and rounded particle shape characterized by substantial lack of sharp edges, they are easy to isolate, free flowing and exhibit reduced stickiness. The specific surface area (SSA) of the rounded particles obtained by the above method is in the range from about <NUM> to about <NUM><NUM>/g, preferably from about <NUM> to about <NUM><NUM>/g (as measured by the three-point nitrogen adsorption technique based on the Brunauer, Emmett and Teller (BET) theory), and does not significantly change even though the volume median diameter (Dv50) of the particles is reduced, for example, to the range of <NUM> - <NUM> (as measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model) by milling or other suitable means. This ascertains consistent bioavailability regardless of the variability in particle size. Therefore, if higher homogenity of the tableting mass if desired, the rounded particles can be milled to the particle size having Dv50, for example, in the range of <NUM> - <NUM>, preferably between <NUM> - <NUM>, typically between <NUM> - <NUM> (as measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model), such particles being well suited in the preparation pharmaceutical dosage forms for oral administration such as tablets.

The crystalline rounded particles of compound (I) obtained by the method of the invention can therefore be used as such or in milled form in the preparation of pharmaceutical dosage forms, such as tablets, capsules or powders together with excipients which are known in the art.

The invention is further illustrated by the following examples.

Granular sodium borohydride (<NUM>) and EtOH (<NUM>) were placed into the <NUM><NUM> enamel reaction vessel. The mixture was solubilized by stirring for <NUM> at <NUM>. (S)-<NUM>-acetyl-N-(<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyano-phenyl)-<NUM>-pyrazol-<NUM>-yl)propan-<NUM>-yl)-<NUM>-pyrazole-<NUM>-carboxamide (<NUM>) was added to the reaction vessel. The mixture was then stirred at <NUM> for <NUM> hours to complete the reaction. Then pH of the mixture was adjusted to acidic with HCl in water. Water (<NUM>) was then added and the pH of the mixture was set to <NUM> ± <NUM> by addition of NaOH in water. The mixture was warmed to <NUM> and then transferred to <NUM><NUM> jacketed steel reaction vessel. The mixture was warmed to <NUM> to dissolve the mixture. The solution was cooled to <NUM> under nitrogen atmosphere. The solution was seeded at <NUM> under mild stirring. The solution was then cooled during <NUM> to <NUM> under mild stirring. Thereafter water (<NUM>) was added during <NUM> - <NUM> at <NUM> under mild stirring. The mixture was cooled during <NUM> to <NUM> under mild stirring and then stirred further for <NUM>. The precipitated product was isolated by centrifuge, washed with water and dried under vacuum at <NUM> - <NUM> to obtain <NUM> of crystalline particles with rounded particle shape.

Water (<NUM>), EtOH (<NUM>) and (N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (<NUM>) were placed into the <NUM><NUM> steel reaction vessel with <NUM> of rinse EtOH. The mixture was dissolved by warming to <NUM>. Activated carbon SX Ultra (<NUM>) and Celite (<NUM>) were added followed by stirring at <NUM> for <NUM>. The mixture was cooled to <NUM> under nitrogen atmosphere and filtered. The filtrate was transferred into <NUM><NUM> jacketed steel reaction vessel. The carbon/celite cake was washed with a warmed (<NUM>) mixture of water (<NUM>) and EtOH (<NUM>). The washing liquid was also added to the reaction vessel. The solution was stirred at <NUM> for <NUM> and then cooled to <NUM>. Mild stirring was maintained during the rest of the process. The solution was seeded at <NUM> and then cooled during <NUM> to <NUM> ± <NUM>. Thereafter water (<NUM>) was added during <NUM> at <NUM> ± <NUM>. The mixture was cooled during <NUM> to <NUM> and then stirred further for <NUM>. The precipitated product was isolated by centrifuge, washed with EtOH and dried under vacuum at <NUM> - <NUM> to obtain <NUM> of crystalline particles with rounded particle shape.

Water (<NUM>), EtOH (<NUM>) and (N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (<NUM>) were placed into the <NUM><NUM> steel reaction vessel. The mixture was dissolved by warming to <NUM>. Activated carbon SX Ultra (<NUM>) and Celite (<NUM>) were added followed by stirring for <NUM>. The mixture was then filtered as hot. The filtrate was transferred into <NUM><NUM> jacketed steel reaction vessel. The carbon/celite cake was washed with EtOH (<NUM>). The washing liquid was also added to the reaction vessel. Temperature was adjusted to <NUM>. The solution was seeded at <NUM> and then cooled to <NUM>. Then the mixture was cooled to <NUM> in <NUM> hours and water (<NUM>) was added simultaneously. The mixture was stirred further for <NUM> minutes. The precipitated product was isolated by centrifuge, washed with water and dried under vacuum at <NUM> to obtain <NUM> of crystalline particles with rounded particle shape.

The particle size distribution of the crystalline rounded particles of compound (I) prepared according to the present invention was determined by laser light diffraction. The determination was carried out by using Beckman Coulter LS13320 laser diffraction particle size analyzer equipped with Tornado Dry Powder System using air as dispersion medium with measurement pressure <NUM>"H<NUM>O ± <NUM>"H<NUM>O, sample amount <NUM>, system controlled target <NUM> % for obscuration and applying Fraunhofer optical model. The results of the particle size analysis are shown in <FIG>. According to the analysis, Dv10 value of the particles is <NUM>, Dv50 is <NUM> and Dv90 is <NUM>.

Crystalline rounded particles of compound (I) prepared according to the present invention were characterized by scanning electron microscope imaging. The SEM figure is shown in <FIG> (<NUM> fold magnification, bar <NUM>). As a comparison, a SEM image of the particles prepared according to Example <NUM> of <CIT> is shown in <FIG> (<NUM> fold magnification, bar <NUM>). The particles prepared according to the present invention exhibit rounded particle shape with narrow particle size distribution while the particles prepared according to <CIT> are small and irregular with sharp edges.

The specific surface area (SSA) and particle size distribution (PSD) were determined for two batches (A and B) of crystalline rounded particles of compound (I) prepared according to the present invention. The particles of the two batches were then milled followed by the determination of SSA and PSD. The results are shown in Tables <NUM> and <NUM>. The results show that the specific surface area (SSA) of the particles did not significantly change even if the particles were milled to reduced particle size.

Claim 1:
Crystalline particles of N-((S)-<NUM>-(<NUM>-(<NUM>-chloro-<NUM>-cyanophenyl)-<NUM>-pyrazol-<NUM>-yl)-propan-<NUM>-yl)-<NUM>-(<NUM>-hydroxyethyl)-<NUM>-pyrazole-<NUM>-carboxamide (I) having:
- specific surface area (SSA) in the range from <NUM> to <NUM><NUM>/g, preferably from <NUM> to <NUM><NUM>/g, as measured by the three-point nitrogen adsorption technique based on the Brunauer, Emmett and Teller (BET) theory;
- volume median diameter (Dv50) between <NUM> - <NUM>, preferably between <NUM> - <NUM>, more preferably between <NUM> - <NUM>, as measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model; and
- rounded particle shape,
wherein the crystalline particles are further characterized by mean aspect ratio higher than <NUM>, preferably higher than <NUM> and/or mean high sensitivity (HS) circularity higher than <NUM>, preferably higher than <NUM>, as determined by an optical microscopy method on a dry powder dispersion.