Polymorphs of Ivacaftor, process for its preparation and pharmaceutical composition thereof

Patent metadata

Field	Value
Publication number	US-9957234-B2
Application number	US-201515533595-A
Country	US
Kind code	B2
Filing date	Dec 9, 2015
Priority date	Dec 9, 2014
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

The present invention relates to novel polymorphic forms of ivacaftor, process for its preparation and pharmaceutical compositions comprising the same.

First claim

We claim:

1. An ivacaftor Form-L2 polymorph characterized by a powder X-Ray diffraction pattern having one or more peaks at about 5.6, 7.0, 13.1, 13.4, 14.1, 15.2, 16.8, 20, 20.4, 24.4 and 28.5±0.2° 2θ.

2. The ivacaftor Form-L2 of claim 1 , further characterized by a powder X-Ray diffraction pattern substantially in accordance with FIG. 4 , a differential scanning calorimetry curve substantially in accordance with FIG. 5 or a thermo gravimetric analysis (TGA) result substantially in accordance with FIG. 6 .

3. A process for the preparation of the ivacaftor Form-L2 of claim 1 , comprising:
a) suspending or mixing ivacaftor in n-heptane;
b) heating the suspension;
c) isolating the solid; and
d) drying the solid at about 85° C. to about 95° C.

4. The process of claim 3 , wherein the ivacaftor of step a) is ivacaftor ethanol solvate,
wherein the heating step b) is carried out at a temperature of about 60° C. to reflux temperature,
wherein the step c) further comprises the steps of i) cooling the suspension of step b) to less than 35° C. and ii) filtering the suspension, and
wherein the drying of step d) is carried out for a time period of about 16 to 30 hours.

5. An ivacaftor Form-L1 polymorph characterized by a powder X-Ray diffraction pattern having one or more peaks at about 5.48, 5.74, 6.46, 8.12, 8.56, 9.82, 10.28, 1 1.00, 1 1.70, 13.40, 13.90, 14.38, 15.22, 15.64, 16.38, 16.64, 17.30, 17.80, 18.24, 18.96, 19.22, 20.62, 20.86, 21.12, 21.74, 21.98, 23.06, 23.96, 24.82, 25.30, 25.94, 26.82, 28.08, 28.48 and 30.34±0.2° 2θ.

6. The ivacaftor Form-L1 of claim 5 , further characterized by a powder X-Ray diffraction pattern substantially in accordance with FIG. 1 , a differential scanning calorimetry curve substantially in accordance with FIG. 2 , or a thermo gravimetric analysis (TGA) result substantially in accordance with FIG. 3 .

7. A process for the preparation of the ivacaftor Form-L1 of claim 5 , comprising:
a) suspending or mixing ivacaftor in n-heptane;
b) heating the suspension;
c) isolating the solid; and
d) drying the solid at about 45° C. to about 65° C.

8. An ivacaftor Form-L3 polymorph characterized by a powder X-Ray diffraction pattern having one or more peaks at about 5.70, 7.96, 10.36, 1 1.22, 12.88, 14.10, 15.60, 17.34, 18.14, 18.80, 19.84, 20.90, 22.48, 23.68, 24.64, 25.62 and 28.00±0.2° 2θ.

9. The ivacaftor Form-L3 of claim 8 , further characterized by a powder X-Ray diffraction pattern substantially in accordance with FIG. 7 , a differential scanning calorimetry curve substantially in accordance with FIG. 8 , or a thermo gravimetric analysis (TGA) result substantially in accordance with FIG. 9 .

10. A process for preparation of the ivacaftor Form-L3 of claim 8 , comprising:
a) dissolving ivacaftor in a mixture of acetonitrile and an acid;
b) adding water to the step a) solution at about 25° C. to about 35° C.;
c) isolating the solid; and
d) drying the solid obtained in step c) at about 25° C. to about 35° C. for about 16 hours.

11. The process of claim 10 , wherein the acid is selected from acetic acid, methanesulfonic acid, and mixtures thereof, and wherein dissolving the ivacaftor in the acid is done at a temperature of about 25° C. to about 45° C.

12. An ivacaftor Form-L4 polymorph characterized by a powder X-Ray diffraction pattern having one or more peaks at about 5.74, 8.26, 10.68, 11.56, 13.30, 14.60, 15.76, 17.88, 21.02, 22.90, 23.78, 25.14, 25.94, 28.20 and 29.98±0.2° 2θ.

13. The ivacaftor Form-L4 of claim 12 , further characterized by a powder X-Ray diffraction pattern substantially in accordance with FIG. 10 , a differential scanning calorimetry curve substantially in accordance with FIG. 11 , or a thermo gravimetric analysis result substantially in accordance with FIG. 12 .

14. A process for preparation of the ivacaftor Form-L4 of claim 12 , comprising:
a) dissolving ivacaftor in a mixture of acetonitrile and an acid;
b) adding water to the step a) solution at about 25° C. to about 35° C.;
c) isolating the solid; and
d) drying the solid obtained in step c) at about 25° C. to about 35° C. for about 24 hours.

15. The process of claim 14 , wherein the suitable acid is selected from acetic acid, methanesulfonic acid, and mixtures thereof.

16. An ivacaftor Form-L5 polymorph characterized by a powder X-Ray diffraction pattern having one or more peaks at about 5.78, 6.42, 8.08, 10.18, 11.24, 12.90, 14.02, 14.34, 15.52, 17.40, 18.38, 19.28, 20.90, 22.60, 23.84, 24.76, 25.82, 27.16, 28.00 and 29.86±0.2° 2θ.

17. Ivacaftor Form-L5 of claim 16 , further characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with FIG. 13 , a differential scanning calorimetry (DSC) substantially in accordance with FIG. 14 , or a thermo gravimetric analysis (TGA) substantially in accordance with FIG. 15 .

18. A process for preparation of the ivacaftor Form-L5 of claim 16 , comprising:
a) dissolving ivacaftor in a mixture of acetonitrile and an acid;
b) adding water to the step a) solution at about 25° C. to about 35° C.;
c) isolating the solid; and
d) drying the solid obtained in step c) at about 55° C. to about 65° C. for about 16 hours.

19. The process of claim 18 , wherein the acid is selected from acetic acid, methanesulfonic acid, and mixtures thereof.

20. An ivacaftor Form-L6 polymorph characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.38, 7.32, 8.10, 9.94, 11.12, 12.84, 14.64, 15.56, 17.44, 19.28, 20.66, 21.46, 25.46 and 29.62±0.2° 2θ.

21. The ivacaftor Form-L6 of claim 20 , further characterized by a powder X-Ray diffraction pattern substantially in accordance with FIG. 16 , a differential scanning calorimetry curve substantially in accordance with FIG. 17 , or a thermo gravimetric analysis result substantially in accordance with FIG. 18 .

22. A process for preparation of the ivacaftor Form-L6 of claim 20 , comprising:
a) dissolving ivacaftor in a mixture of acetonitrile and an acid;
b) adding water to the step a) solution at 25° C. to about 35° C.;
c) isolating the solid; and
d) drying the solid obtained in step c) at about 55° C. to about 65° C. for 24 hours.

23. The process of claim 22 , wherein the acid is selected from acetic acid, methanesulfonic acid, and mixtures thereof.

24. An ivacaftor Form-L7 polymorph characterized by a powder X-Ray diffraction pattern having one or more peaks at about 5.0, 7.32, 8.46, 10.08, 12.38, 13.66, 15.62, 16.54, 18.58, 20.18, 21.88, 22.36, 23.00, 24.30, 24.80, 25.12, 25.64, 26.30, 26.54, 27.60, 28.06 and 29.30±0.2° 2θ.

25. The ivacaftor Form-L7 of claim 24 , further characterized by a powder X-Ray diffraction pattern substantially in accordance with FIG. 19 , a differential scanning calorimetry curve substantially in accordance with FIG. 20 , or a thermo gravimetric analysis result substantially in accordance with FIG. 21 .

26. A process for preparation of the ivacaftor Form-L7 of claim 24 , comprising:
a) dissolving ivacaftor in a mixture of acetonitrile and an acid;
b) adding water to the step a) solution at 25° C. to about 35° C.;
c) isolating the solid; and
d) drying the solid obtained in step c) at about 75° C. to about 100° C. to obtain the ivacaftor Form-L7.

27. The process of claim 26 , wherein the acid is selected from acetic acid, methanesulfonic acid, and mixtures thereof.

28.

Assignees

• Laurus Labs Ltd

Inventors

• Thaimattam Ram
• Dama Venkata Srinivasa Rao
• Indukuri Venkata Sunil Kumar
• Gorantla Seeta Rama Anjaneyulu
• Chava Satyanarayana

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D215/56 Primary

  with oxygen atoms in position 4 · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title