Crystalline form of a biphenyl compound

1. A crystalline naphthalene-1,5-disulfonic acid salt of biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester or a solvate thereof.

2. The crystalline salt of claim 1 , wherein the salt is characterized by an x-ray powder diffraction pattern having two or more diffraction peaks at 2θ values selected from 11.95±0.25, 12.88±0.25, 13.88±0.25, 18.43±0.25, 20.45±0.25, 22.98±0.25, 23.83±0.25, and 25.94±0.25.

3. The crystalline salt of claim 2 , wherein the x-ray powder diffraction pattern comprises diffraction peaks at 2θ values of 18.43±0.25, 20.45±0.25, and 23.83±0.25.

4. The crystalline salt of claim 1 , wherein the salt is characterized by an x-ray powder diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 1 .

5. The crystalline salt of claim 1 , wherein the salt is characterized by a differential scanning calorimetry trace which shows an onset of endothermic heat flow at about 200° C.

6. The crystalline salt of claim 1 , wherein the salt is characterized by an differential scanning calorimetry trace substantially in accordance with that shown in FIG. 2 .

7. The crystalline salt of claim 1 , wherein the salt has infrared absorption spectrum with significant absorption bands at 689±1, 706±1, 749±1, 768±1, 806±1, 841±1, 994±1, 1065±1, 1098±1, 1165±1, 1221±1, 1252±1, 1283±1, 1437±1, 1474±1, 1533±1, 1613±1, and 1668±1 cm −1 .

8. The crystalline salt of claim 1 , wherein the salt is characterized by an infrared absorption spectrum substantially in accordance with that shown in FIG. 4 .

9. A pharmaceutical composition prepared from the crystalline salt of claim 1 , the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a naphthalene-1,5-disulfonic acid salt of biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester or a solvate thereof.

10. The pharmaceutical composition of claim 9 , wherein the composition further comprises a steroidal anti-inflammatory agent.

11. The pharmaceutical composition of claim 9 , wherein the composition further comprises a phosphodiesterase-4 inhibitor.

12. The pharmaceutical composition of claim 9 , wherein the composition is formulated for administration by inhalation.

13. A method for treating a pulmonary disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of the pharmaceutical composition of claim 9 .

14. A method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of the pharmaceutical composition of claim 9 .

15. A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of the pharmaceutical composition of claim 9 .

16. The crystalline salt of claim 1 , wherein the salt is in micronized form.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the salt of claim 16 .

18. The pharmaceutical composition of claim 17 , wherein the carrier is lactose.

19. A process for preparing the crystalline salt of claim 1 ; the process comprising contacting biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester with 1,5-naphthalenedisulfonic acid.

20. A process for purifying biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester; the process comprising forming a crystalline naphthalene-1,5-disulfonic acid salt of biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester.

21. A process for preparing crystalline naphthalene-1,5-disulfonic acid salt of biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester or a solvate thereof, the process comprising:

(a) contacting a compound of formula II:

wherein R a , R b and R c are independently selected from C 1-4 alkyl, phenyl, —C 1-4 alkyl-(phenyl), or one of R a , R b and R c is —O—(C 1-4 alkyl); with fluoride ion; and

(b) contacting the product from step (b) with naphthalene-1,5-disulfonic acid to form a crystalline naphthalene-1,5-disulfonic acid salt of biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]nonyl}-piperidin-4-yl ester or a solvate thereof, wherein step (a) and (b) are conducted in the same reaction vessel without isolation of the product of step (a).