Crystalline freebase forms of a biphenyl compound

1. 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 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 further characterized by 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; and having a melting point of about 125° C.

2. The crystalline compound of claim 1 , 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 crystalline compound of claim 1 , further characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 1 .

4. The compound of claim 1 , further characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 4 .

5. 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 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 further characterized by having five or more additional diffraction peaks at 2θ values selected from 10.6±0.1, 15.0±0.1, 16.0±0.1, 17.3±0.1, 17.7±0.1, 20.9±0.1, 21.4±0.1, 22.6±0.1, 24.6±0.1, and 27.8±0.1; designated as Form IV; and having a melting point of about 119° C.

6. The crystalline compound of claim 5 , further characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 2 .

7. The compound of claim 5 , further characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 5 .

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .

9. The composition of claim 8 , 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.

10. The composition of claim 9 , which comprises a β 2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

11. The compound of claim 1 in micronized form.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 5 .

13. The composition of claim 12 , 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.

14. The composition of claim 13 , which comprises a β 2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

15. The compound of claim 5 in micronized form.

16. A process for preparing the crystalline freebase Form III of claim 1 , comprising contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with a solvent consisting of acetonitrile, wherein the ratio of milligrams of the ester to total milliliters of acetonitrile is about 100:1, and the acetonitrile is added in two steps.

17. A process for preparing the crystalline freebase Form IV of claim 5 , comprising a) forming a seed crystal of the crystalline freebase Form III by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with a solvent consisting of acetonitrile, wherein the ratio of milligrams of the ester to total milliliters of acetonitrile is about 100:1, and the acetonitrile is added in two steps; b) dissolving the crystalline freebase Form III in acetonitrile to form a solution; c) and adding the seed crystal to the solution.