Crystalline freebase forms of a biphenyl compound
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.
1. A pharmaceutical composition comprising a pharmaceutically acceptable dry powder excipient 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 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.
2. The composition of claim 1 , which further comprises an agent selected from β 2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors; or a pharmaceutically acceptable salt thereof and combinations thereof; wherein the crystalline form and the agent are formulated together or separately.
3. The composition of claim 2 , which comprises a β 2 adrenergic receptor agonist or a pharmaceutically acceptable salt thereof and a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt thereof.
4. The composition of claim 1 , wherein the crystalline compound is in micronized form.
5. The composition of claim 1 , wherein the excipient is selected from lactose, starch, mannitol, dextrose, polylactic acid, polylactide-co-glycolide, and combinations thereof.
6. The composition of claim 1 , wherein the excipient is lactose.
7. The composition of claim 2 , which comprises a β 2 adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof.
8. The composition of claim 2 , which comprises a steroidal anti-inflammatory agent, or a pharmaceutically acceptable salt thereof.
9. The composition of claim 2 , which comprises a phosphodiesterase-4 inhibitor, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising dry lactose having a particle size between about 1 μm and about 100 μm and micronized particles of 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 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.
11. 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.
12. The composition of claim 7 , wherein the β 2 adrenergic receptor agonist is formoterol or a pharmaceutically acceptable salt thereof.