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 method for treating chronic obstructive pulmonary disease in a human patient, the method comprising:
administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester;
wherein the crystalline freebase is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1 and 20.2±0.1.
2. The method of claim 1 , wherein the crystalline freebase is further characterized by a melting point of about 125° C.
3. The method of claim 1 , wherein the crystalline freebase is further characterized by a differential scanning calorimetry thermograph which shows an onset of endothermic heat flow at about 123° C.
4. The method of claim 1 , wherein the pharmaceutical composition is isotonic.
5. The method of claim 1 , wherein the pharmaceutical composition has a pH of about 4-6.
6. The method of claim 1 , wherein the pharmaceutical composition is buffered with citrate buffer to a pH of about 5.
7. The method of claim 1 , wherein the pharmaceutical composition contains about 0.05 μg/mL to about 10 mg/mL of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester.
8. The method of claim 1 , wherein the pharmaceutical composition is administered to the human patient using a nebulizer.
9. A crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester, wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 20 values of 11.4±0.1 and 11.6±0.1.
10. The crystalline form of claim 9 , wherein the crystalline form is characterized by a DSC thermograph which shows an onset of endothermic heat flow at about 123° C.
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form of claim 9 .
12. A crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester, wherein the crystalline form is characterized by a differential scanning calorimetry thermograph which shows an onset of endothermic heat flow at about 123° C.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form of claim 12 .
14. A method for treating chronic obstructive pulmonary disease in a human patient, the method comprising:
administering the pharmaceutical composition of claim 11 .
15. The method of claim 14 , wherein the pharmaceutical composition is isotonic.
16. The method of claim 14 , wherein the pharmaceutical composition has a pH of about 4-6.
17. The method of claim 14 , wherein the pharmaceutical composition is buffered with citrate buffer to a pH of about 5.
18. The method of claim 14 , wherein the pharmaceutical composition contains about 0.05 μg/mL to about 10 mg/mL of biphenyl-2-ylcarbamic acid -(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester.
19. The method of claim 14 , wherein the pharmaceutical composition is administered to the human patient using a nebulizer.
20. A method for treating chronic obstructive pulmonary disease in a human patient, the method comprising:
administering the pharmaceutical composition of claim 13 .
21. The method of claim 20 , wherein the pharmaceutical composition is isotonic.
22. The method of claim 20 , wherein the pharmaceutical composition has a pH of about 4-6.
23. The method of claim 20 , wherein the pharmaceutical composition is buffered with citrate buffer to a pH of about 5.
24. The method of claim 20 , wherein the pharmaceutical composition contains about 0.05 μg/mL to about 10 mg/mL of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester.
25. The method of claim 20 , wherein the pharmaceutical composition is administered to the human patient using a nebulizer.
26. A pharmaceutical composition prepared from a crystalline form of claim 9 by adding a pharmaceutically acceptable carrier.
27. A pharmaceutical composition prepared from a crystalline form of claim 12 by adding a pharmaceutically acceptable carrier.