Crystalline forms of osanetant
View Patent ↗The invention relates to crystalline forms of (R)-(+)-N-[[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide and to processes for preparing them.
1. A process for the crystallization of osanetant wherein:
osanetant is crystallized from an ethanol/water mixture by heating a solution of osanetant in ethanol/water mixture to a temperature of less than or equal to the reflux temperature of the solvent and then cooling to obtain crystalline form I of osanetant; or heating a solution of osanetant in isopropanol to a temperature of less than or equal to the reflux temperature of the solvent and then cooling to give the crystalline form I.
2. A process for the preparation of osanetant wherein:
osanetant is crystallized from an ethanol/isopropyl ether/water mixture by adding isopropyl ether and water to a solution of osanetant in ethanol and heating to a temperature of less than or equal to the reflux temperature of the solvent and then cooling to give the crystalline form II of osanetant.
3. A process according to claim 1 wherein:
either water is added to a solution of osanetant in ethanol and heating is carried out to a temperature of less than 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 isopropanol is heated to a temperature of less than the reflux temperature of the solvent and cooling is carried out in order to obtain osanetant-crystalline form I.
4. A process according to claim 3 for the preparation of osanetant-crystalline form I wherein:
either water is added to a solution of osanetant in ethanol and heating is carried out to a temperature of 60° C. to 75° C. and then cooling is carried out;
or a solution of osanetant in isopropanol is heated to 60° C.–80° C. and cooling is carried out.
5. A process according to claim 4 wherein water is added to a solution of osanetant in ethanol, heating is carried out to a temperature of 60 to 75° C. and then cooling is carried out.
6. A process according to claim 5 wherein cooling is carried out to 20–25° 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° C., cooling is then carried out to 0° C. and this temperature is maintained.
7. A process according to claim 5 wherein cooling is carried out to a temperature in the region of 40° C., the crystallization is initiated, cooling is continued to 20–25° C., the osanetant suspension formed is reheated to 45–50° C. and then cooling is carried out to 20–25° C.
8. A process according to claim 4 wherein a solution of osanetant in isopropanol is heated to a temperature of 60–80° C. and then cooling is carried out.
9. A process according to claim 8 wherein cooling is carried out to a temperature of between 0 and 50° C., the crystallization is then initiated, cooling is subsequently carried out to 0° C. and the mixture is maintained at 0° C.
10. A process according to claim 2 for the preparation of osanetant-crystalline form II wherein isopropyl ether and water are added to a solution of osanetant in ethanol, heating is carried out to reflux and then cooling is carried out.
11. A process according to claim 10 wherein a solution of osanetant in an ethanol/isopropyl ether mixture is heated to reflux, isopropyl ether and water are added, cooling to 40–50° 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° C.
12. A process according to claim 1 wherein the osanetant to be crystallized is prepared by neutralization of its benzenesulfonate.
13. Osanetant-crystalline form I, wherein it exhibits:
a melting temperature with a peak with a maximum at 143.6±0.5° C.
an enthalpy of fusion of 68.5±0.5 J/g; and
wherein its powder X-ray diffractogram exhibits characteristic Bragg 2θ lines at approximately 17.81°, 11.04° and 16.84°.
14. Osanetant-crystalline form II, wherein it exhibits:
a melting temperature with a peak with a maximum at 141.8±0.5° C.
an enthalpy of fusion of 65.0±0.5 J/g; and
wherein its powder X-ray diffractogram exhibits characteristic Bragg 2θ lines at approximately 18.35°, 18.58° and 18.97°.
15. Osanetant-crystalline form I according to claim 13 , wherein it exhibits:
a melting temperature with a peak with a maximum at 143.6±0.5° C.
an enthalpy of fusion of 68.5±0.5 J/g.
16. Osanetant-crystalline form I according to claim 13 , wherein its powder X-ray diffractogram exhibits characteristic Bragg 2θ lines at approximately 17.81°, 11.04° and 16.84°.
17. Osanetant-crystalline form II according to claim 14 , wherein it exhibits:
a melting temperature with a peak with a maximum at 143.8±0.5° C.
an enthalpy of fusion of 65.0±0.5 J/g.
18. Osanetant-crystalline form II according to claim 14 wherein its powder X-ray diffractogram exhibits characteristic Bragg 2θ lines at approximately 18.35°, 18.58° and 18.97°.