Crystalline forms of fosnetupitant

Patent metadata

Field	Value
Publication number	US-10005803-B2
Application number	US-201615282016-A
Country	US
Kind code	B2
Filing date	Sep 30, 2016
Priority date	Oct 6, 2015
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

The present invention provides crystalline forms of the chloride monohydrochloride salt of fosnetupitant, methods of making the crystalline forms, and pharmaceutical dosage forms that make use of the crystalline forms.

First claim

The invention claimed is:

1. A method of making a crystalline form of the chloride hydrochloride salt of (4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methylpiperazin-1-ium-1-yl)methyl hydrogen phosphate (fosnetupitant) which is Form I (“Form I fosnetupitant”), comprising less than 0.5 wt. % of impurities other than water and organic volatile impurities, comprising:
a. contacting the chloride hydrochloride salt of fosnetupitant with methylacetate and methanol to form a first liquid;
b. separating the methylacetate and methanol from the chloride hydrochloride salt of fosnetupitant of step (a);
c. contacting the chloride hydrochloride salt of fosnetupitant from step (b) with heptane to form a second liquid; and
d. separating the heptane from the chloride hydrochloride salt of fosnetupitant of step (c).

2. The method of claim 1 wherein:
a. step (a) further comprises contacting said chloride hydrochloride salt of fosnetupitant with hydrochloric acid;
b. step (b) comprises evaporating said methanol from said first liquid product of step (a);
c. step (d) comprises evaporating said heptane from said second liquid at a pressure less than atmospheric and a temperature of from 20 to 50° C.

3. The method of claim 1 wherein, prior to step (a), said chloride hydrochloride salt of fosnetupitant is dissolved in methanol to form a solution, methanol is partially distilled from said solution, and methylacetate is added to said solution to form said first liquid.

4. A crystalline form of the chloride hydrochloride salt of (4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methylpiperazin-1-ium-1-yl)methyl hydrogen phosphate which is Form II (“Form II fosnetupitant”).

5. The crystalline form of claim 4 having an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of 6.0, 6.7, 7.0, 7.6, 8.6, 9.7, 11.3, 11.8, 12.0, 12.5, 12.9, 13.2, 14.1, 15.3, 16.0, 16.5, 17.9, 18.4, 18.9, 19.4, 20.0, 20.6, 21.4, 21.7, 22.7, 23.2, 23.8, 24.4, 25.1, 26.0, 27.4, 28.3, 29.2, 30.6, 31.8, 33.4, 36.3, 37.2, 38.3°±0.2°.

6. The crystalline form of claim 4 having an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of 6.0, 6.7, 7.6, 9.7, 11.3, 14.1, 15.3, 17.9, 18.4, 19.4, 20.0, 20.6, 21.4, 22.7, 23.2, 25.1, 26.0, 28.3, 29.2, 33.4°±0.2°.

7. The crystalline form of claim 4 having an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of 6.0, 7.6, 14.1, 17.9, 19.4, 20.6, and 21.4°±0.2°.

8. The crystalline form of claim 4 characterized by the X-ray powder diffraction patterns shown in FIGS. 6 and 16 .

9. The Form II fosnetupitant of claim 4 having a differential scanning calorimetry (DSC) thermogram characterized by an endotherm at 142.9±4° C.

10. The Form II fosnetupitant of claim 4 having a differential scanning calorimetry thermogram (DSC) substantially as shown in FIG. 9 .

11. The crystalline form of claim 4 , having a thermogravimetric analysis (TGA) substantially as shown in FIG. 8 .

12. A composition comprising the Form II fosnetupitant of claim 4 and amorphous fosnetupitant.

13. A pharmaceutical composition comprising the Form II fosnetupitant of claim 5 and one or more pharmaceutically acceptable excipients.

14. A method of making a pharmaceutical composition comprising admixing the Form II fosnetupitant of claim 5 and one or more pharmaceutically acceptable excipients.

15. A process for preparing the Form II fosnetupitant of claim 5 comprising:
a. combining the chloride hydrochloride salt of fosnetupitant with a solution comprising acetone and water to provide a mixture;
b. slurrying the mixture;
c. filtering the slurried mixture; and
d. isolating a crystalline solid of Form II fosnetupitant.

16. A crystalline form of the chloride hydrochloride salt of (4-(5-2-3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methylpiperazin-1-ium-1-yl)methyl hydrogen phosphate which is Form III (“Form III fosnetupitant”).

17. The Form III fosnetupitant of claim 16 characterized by the X-ray powder diffraction patterns shown in FIG. 11 .

18. The Form III fosnetupitant of claim 16 having a differential scanning calorimetry (DSC) thermogram characterized by an endotherm at 153.0±4° C.

19. The Form III fosnetupitant of claim 16 having a thermogravimetric analysis (TGA) substantially as shown in FIG. 13 .

20. A composition comprising the Form III fosnetupitant of claim 16 and amorphous fosnetupitant.

21. A pharmaceutical composition comprising the Form III fosnetupitant of claim 16 and one or more pharmaceutically acceptable excipients.

22. A method of making a pharmaceutical composition comprising admixing the Form III fosnetupitant of claim 16 and one or more pharmaceutically acceptable excipients.

23. A process for preparing the Form III fosnetupitant of claim 16 comprising combining the chloride hydrochloride salt of fosnetupitant with a solution comprising cyclohexane to afford a mixture;
a. slurrying the mixture;
b. filtering the slurried mixture; and
c. isolating the crystalline solid.

Assignees

• Helsinn Healthcare Sa

Inventors

• Fadini Luca
• Venturini Alessio

Classifications

• A61P1/08

  for nausea, cinetosis or vertigo; Antiemetics · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• C07F9/650952 Primary

  having the nitrogen atoms in the positions 1 and 4 · CPC title

• C07F9/65583 Primary

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title