Claims for Patent: 11,168,058

Summary for Patent: 11,168,058

Title:	Manufacture of a crystalline pharmaceutical product
Abstract:	The present disclosure 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 specific surface area (SSA) in the range from about 8 to about 16 m.sup.2/g, preferably from about 10 to about 15 m.sup.2/g, and to the method for the preparation of such particles. Compound (I) is a potent androgen receptor (AR) modulator which is useful as a medicament for example in the treatment of prostate cancer.
Inventor(s):	Reunanen; Merja (Espoo, FI), Staffans; Anna (Espoo, FI)
Assignee:	ORION CORPORATION (Espoo, FI)
Application Number:	16/491,642
Patent Claims:	1. Crystalline particles of N--((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1- -hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a specific surface area (SSA) in a range from about 8 to about 16 m.sup.2/g. 2. The crystalline particles according to claim 1 having a volume median diameter (Dv50).gtoreq.10 .mu.m. 3. The crystalline particles according to claim 1 having a volume median diameter (Dv50) ranging from between 10 .mu.m and 1000 .mu.m. 4. The crystalline particles according to claim 1 having a volume median diameter (Dv50) ranging from between 100 .mu.m and 1000 .mu.m. 5. The crystalline particles according to claim 4, wherein the particles have a rounded particle shape. 6. The crystalline particles according to claim 5 characterized by a mean aspect ratio higher than 0.8, and/or a mean high sensitivity (HS) circularity higher than 0.89. 7. The crystalline particles according to claim 6 characterized by a mean aspect ratio higher than 0.8 and a mean high sensitivity (HS) circularity higher than 0.89. 8. The crystalline particles according to claim 7 characterized by a mean aspect ratio higher than 0.82 and a mean high sensitivity (HS) circularity higher than 0.9. 9. The crystalline particles according to claim 1 having a volume median diameter (Dv50) ranging from between 10 .mu.m and 100 .mu.m. 10. 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 rounded particle shape and a volume median diameter (Dv50) ranging from between 100 .mu.m and 1000 .mu.m. 11. 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 the crystalline particles according to claim 1. 12. 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 according to claim 10. 13. The pharmaceutical dosage form according to claim 12, wherein the crystalline particles are milled to provide a volume median diameter (Dv50) ranging from between 10 .mu.m and 100 .mu.m. 14. The crystalline particles according to claim 1, wherein the specific surface area (SSA) is analyzed using a three-point nitrogen adsorption technique based on the Brunauer, Emmett and Teller (BET) theory. 15. The crystalline particles according to claim 6, wherein the mean aspect ratio and/or mean high sensitivity (HS) circularity is determined by an optical microscopy method on a dry powder dispersion. 16. The crystalline particles according to claim 2, wherein the volume median diameter (Dv50) is measured by laser light diffraction using air as dispersion medium and applying Fraunhofer optical model. 17. A method for preparing crystalline particles of N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-- hydroxy-ethyl)-1H-pyrazole-3-carboxamide (I) according to claim 1: 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 which comprises ethanol and water, wherein the amount of water is 35-60%, per weight of the solvent; b) heating the mixture to about refluxing 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) has dissolved; c) cooling the mixture to about 20-35.degree. C. during at least 3 hours, optionally with seeding; d) adding, optionally simultaneously with step c), water during at least 1 hour, such that after step d) the amount of water in the solvent is 55-80% per weight of said solvent; and e) isolating the precipitate. 18. The method according to claim 17, wherein the particles have a volume median diameter (Dv50) ranging from between 100 .mu.m and 1000 .mu.m. 19. The method according to claim 17, wherein the particles have a rounded particle shape. 20. The method according to claim 17, wherein the particles have a specific surface area (SSA) in a range from about 8 to about 16 m.sup.2/g. 21. The method according to claim 17, wherein in step a) the solvent consists essentially of ethanol and water. 22. The method according to claim 21, wherein in step a) the solvent contains 35-60% of water and 40-65% of ethanol per weight of the solvent. 23. The method according to claim 17, wherein in step d) the temperature of the mixture is kept within about 20-35.degree. C. during the addition of water. 24. The method according to claim 17, wherein steps c) and d) are carried out simultaneously. 25. The method according to claim 17, wherein after step d) the mixture is cooled further to about 10-30.degree. C. for at least 1 hour. 26. The method according to claim 17, wherein during step c) the mixture is seeded at about 50-70.degree. C. 27. The method according to claim 17, wherein the amount of compound (I) in step a) is about 1-20% per weight of the solvent. 28. The method according to claim 17, wherein the isolated precipitate is dried under reduced pressure at a temperature of at least 30.degree. C. 29. The method according to claim 28, wherein the isolated precipitate is dried under reduced pressure at 40-60.degree. C.