Patent EA-003205-B1 (EA)
Title: Crystalline forms of (r)-(+)-n-[[3-[1-benzoyl-3-(3,4-duchrolophenyl)piperidin-3-yl]prop-1-yl]-4-phenyl piperidin-4-yl]-n-methylacetamide
Inventor: ALCADE ALAIN
IPC: C07D211/58
Filed: 1999-08-03
Abstract: 1. Process for preparation of crystalline (R)-(+)-N-[[3-[1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl]prop-1-yl]-4-phenyl piperidin-4-yl]-N-methylacetamide (Osanetant) by crystallization of amorphous osanetant comprising less than 20% of impurities in an ethanol/water mixture or from iso-propanol to give the crystalline form I or in an ethanol/isopropyl ether/water mixture to give the crystalline form II. 2. Process according to Claim I, characterized in that the osanetant to be crystallized comprises less than 10% of impurities. 3. Process for the preparation of osanetant in crystalline form I according to Claim 1 or Claim 2, characterized in that osanetant is crystallized from an ethanol/water mixture or from iso-propanol. 4. Process for the preparation of osanetant in crystalline form II according to Claim 1 or Claim 2, characterized in that osanetant is crystallized from an ethanol/isopropyl ether mixture. 5. Process according to Claim 1 or Claim 2, characterized in that - either water is added to a solution of osanetant in ethanol and heating is carried out to a temperature of less than or equal to the reflux temperature of the solvent and then cooling is carried out in order to obtain osanetant - crystalline form I; - or a solution of osanetant in iso-propanol is heated to a temperature of less than or equal to the reflux temperature of the solvent and cooling is carried out in order to obtain osanetant - crystalline form I; - or isopropyl ether and water are added to a solution of osanetant in ethanol, heating is carried out to a temperature of less than or equal to the reflux temperature of the solvent and cooling is carried out in order to obtain osanetant - crystalline form II. 6. Process according to Claim 5 for the preparation of osanetant - crystalline form I, characterized in that: - either water is added to a solution of osanetant in ethanol and heating is carried out to a temperature of 60 degree C to 75 degree C and then cooling is carried out; - or a solution of osanetant in iso-propanol is heated to 60 degree C-80 degree C and cooling is carried out. 7. Process according to Claim 6, characterized in that water is added to a solution of osanetant in ethanol, heating is carried out to a temperature of 60 to 75 degree C and then cooling is carried out. 8. Process according to Claim 7, characterized in that cooling is carried out to 20-25 degree C, then either the crystallization is initiated or there is a wait for the first crystals to appear, and, subsequently, the temperature is increased to 45-50 degree C, cooling is then carried out to 0 degree C and this temperature is maintained. 9. Process according to Claim 7, characterized in that cooling is carried out to a temperature in the region of 40 degree C, the crystallization is initiated, cooling is continued to 20-25 degree C, the osanetant suspension formed is reheated to 45-50 degree C and then cooling is carried out to 20-25 degree C. 10. Process according to Claim 6, characterized in that a solution of osanetant in isopropanol is heated to a temperature of 60-80 degree C and then cooling is carried out. 11. Process according to Claim 10, characterized in that cooling is carried out to a temperature of between 0 and 50 degree C, the crystallization is then initiated, cooling is subsequently carried out to 0 degree C and the mixture is maintained at 0 degree C. 12. Process according to Claim 5 for the preparation of osanetant - crystalline form II, characterized in that isopropyl ether and water are added to a solution of osanetant in ethanol, heating is carried out to reflux, then cooling is carried out in an ethanol/isopropyl ether mixture, isopropyl ether and water are added, heating is carried out to reflux and then cooling is carried out. 13. Process according to Claim 12, characterized in that a solution of osanetant in an ethanol/isopropyl ether mixture is heated to reflux, isopropyl ether and water are added, cooling to 40-50 degree C is allowed to take place, then either the crystallization is initiated or there is a wait for the first crystals to appear, and cooling is subsequently carried out to 20-25 degree C. 14. Process according to any one of Claims 1 to 13, characterized in that the osanetant to be crystallized is prepared by neutralization of its benzenesulfonate. 15. Osanetant - crystalline form I, capable of being obtained by a process according to any one of Claims 1, 2 and 5 to 11 and characterized in that it exhibits: - a melting temperature with a peak with a maximum at 143.6 +- 0.5 degree C - an enthalpy of fusion of 68.5 +- 0.5 J/g. 16. Osanetant - crystalline form II, capable of being obtained by a process according to any one of Claims 1, 2, 4, 5, 12 or 13 and characterized in that it exhibits: - a melting temperature with a peak with a maximum at 143.6 +- 0.5 degree C - an enthalpy of fusion of 68.5 +- 0.5 J/g. 17. Osanetant - crystalline form I according to Claim 15, characterized in that its powder X-ray diffractogram exhibits characteristic Bragg 2.theta lines at approximately 17.81 degree , 11.04 degree and 16.84 degree . 18. Osanetant - crystalline form II according to Claim 16, characterized in that its powder X-ray diffractogram exhibits characteristic Bragg 2.theta lines at approximately 18.35 degree , 18.58 degree and 18.97 degree . 19. Pharmaceutical composition comprising, as active principle, a compound according to either one of Claims 15 and 17. 20. Pharmaceutical composition comprising, as active principle, a compound according to either one of Claims 16 and 18. 21. Composition according to Claims 19 or 20, characterized in that it is in the form of a dosage unit comprising 0.5 to 500 mg of active principle. 22. Composition according to Claim 21, characterized in that said dosage unit comprises from 1 to 250 mg of active principle.