Crystalline forms of a biphenyl compound
The invention provides crystalline forms of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester, and pharmaceutically acceptable solvates thereof. The crystalline form can be a freebase, or a salt such as a diphosphate, monosulfate or dioxalate salt. The invention also provides pharmaceutical compositions comprising these crystalline compounds or prepared using these compounds; processes and intermediates for preparing the crystalline compounds; and methods of using these compounds to treat a pulmonary disorder.
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 pattern having:
(a) two or more diffraction peaks at 2θ values selected from 4.7±0.2, 9.6±0.2, 12.7±0.2, 13.7±0.2, 16.7±0.2, 17.4±0.2, 18.5±0.2, 19.4±0.2, 20.8±0.2, 21.4±0.2, 24.2±0.2, and 25.6±0.2; or
(b) two or more diffraction peaks at 2θ values selected from 4.6±0.2, 9.3±0.2, 12.9±0.2, 13.6±0.2, 14.0±0.2, 14.6±0.2, 16.5±0.2, 18.6±0.2, 19.1±0.2, 20.9±0.2, 22.1±0.2, 22.7±0.2, and 25.7±0.2.
2. The crystalline freebase of claim 1 , wherein the powder x-ray diffraction pattern in (a) comprises diffraction peaks at 2θ values of 4.7±0.2, 18.5±0.2, 20.8±0.2, and 25.6±0.2.
3. The crystalline freebase of claim 1 , wherein the powder x-ray diffraction pattern in (a) is 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. 18 .
4. The crystalline freebase of claim 1 , wherein the compound of (a) is characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 102.7° C.
5. The crystalline freebase of claim 1 , wherein the compound of (a) is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 19 .
6. The crystalline freebase of claim 1 , wherein the powder x-ray diffraction pattern in (b) comprises diffraction peaks at 2θ values of 4.6±0.2, 18.6±0.2, 22.1±0.2, and 22.7±0.2.
7. The crystalline freebase of claim 1 , wherein the powder x-ray diffraction pattern in (b) is 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. 23 .
8. The crystalline freebase of claim 1 , wherein the compound of (b) is characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 98.6° C.
9. The crystalline freebase of claim 1 , wherein the compound of (b) is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 25 .
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the crystalline freebase of claim 1 .
11. The composition of claim 10 , wherein the composition is formulated for administration by inhalation.
12. The composition of claim 10 ; wherein the carrier is an aqueous isotonic saline solution having a pH in the range of from about 4 to about 6.
13. The composition of claim 12 ; which comprises a citrate buffer.
14. The crystalline freebase of claim 1 in micronized form.
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the crystalline freebase of claim 1 in micronized form.
16. The composition of claim 15 , wherein the carrier is lactose.
17. A method of producing bronchodilation comprising administering to a patient by inhalation, a bronchodilation-producing amount of the crystalline freebase of claim 1 .
18. A method of treating chronic obstructive pulmonary disease or asthma, comprising administering to a patient a therapeutically effective amount of the crystalline freebase of claim 1 .
19. A process for preparing the crystalline freebase of claim 1 comprising:
forming a seed crystal of a crystalline freebase by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with an inert diluent;
forming a crystalline freebase by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with an inert diluent, and dissolving the resulting crystalline ester to form a solution; and
adding the seed crystal to the solution.