Crystalline freebase forms of a biphenyl compound

Patent metadata

Field	Value
Publication number	US-9226896-B2
Application number	US-201414547455-A
Country	US
Kind code	B2
Filing date	Nov 19, 2014
Priority date	Jul 15, 2009
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

The invention provides two crystalline freebase forms of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. The invention also provides pharmaceutical compositions comprising the crystalline freebase or prepared using the crystalline freebases; processes and intermediates for preparing the crystalline freebases; and methods of using the crystalline freebases to treat a pulmonary disorder.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a pharmaceutically acceptable propellant and a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1; and having five or more additional diffraction peaks at 2θ values selected from 8.8±0.1, 10.1±0.1, 11.4±0.1, 11.6±0.1, 14.8±0.1, 15.2±0.1, 16.1±0.1, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1; designated as Form III.

2. The composition of claim 1 , wherein the crystalline compound is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values selected from 6.6±0.1, 11.4±0.1, 13.1±0.1, 16.1±0.1, 17.5±0.1, 18.2±0.1, 18.6±0.1, 19.3±0.1, 19.7±0.1, 19.9±0.1, 20.2±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1.

3. The composition of claim 1 , which further comprises an agent selected from β 2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof; wherein the crystalline form and the agent are formulated together or separately.

4. The composition of claim 3 , which comprises a β 2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

5. The composition of claim 1 , wherein the crystalline compound is in a suspension.

6. The composition of claim 1 , wherein the propellant is a hydrofluoroalkane.

7. The composition of claim 6 , wherein the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane.

8. The composition of claim 6 , wherein the hydrofluoroalkane is 1,1,1,2,3,3,3-heptafluoro-n-propane.

9. The composition of claim 1 , wherein the composition further comprises a co-solvent selected from ethanol and pentane.

10. The composition of claim 1 , wherein the composition further comprises a surfactant selected from the sorbitan trioleate, oleic acid, lecithin, and glycerin.

11. The composition of claim 1 , comprising from about 0.01 to 5% by weight of the crystalline compound; from about 0 to 20% by weight ethanol; and from about 0 to 5% by weight surfactant; with the remainder being a hydrofluoroalkane propellant.

12. The composition of claim 1 , wherein the crystalline compound is micronized.

13. A pharmaceutical composition comprising 1,1,1,2-tetrafluoroethane and a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-( 4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1; and having five or more additional diffraction peaks at 2θ values selected from 8.8±0.1, 10.1±0.1, 11.4±0.1, 11.6±0.1, 14.8±0.1, 15.2±0.1, 16.1±0.1, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1; designated as Form III.

14. A pharmaceutical composition comprising 1,1,1,2,3,3,3- heptafluoro-n-propane and a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl) piperidin-4-yl ester characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1; and having five or more additional diffraction peaks at 2θ values selected from 8.8±0.1, 10.1±0.1, 11.4±0.1, 11.6±0.1, 14.8±0.1, 15.2±0.1, 16.1±0.1, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1; designated as Form III.

15. The composition of claim 3 , which comprises a β 2 adrenergic receptor agonist.

16. The composition of claim 3 , which comprises a steroidal anti-inflammatory agent.

17. The composition of claim 3 , which comprises a phosphodiesterase-4inhibitor.

Assignees

• Woollam Grahame
• Theravance Biopharma R&D Ip Llc

Inventors

• Woollam Grahame

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P11/08

  Bronchodilators · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title