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 dioxalate salt 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 8.7±0.2, 14.0±0.2, 19.4±0.2, and 22.9±0.2.
2. The crystalline dioxalate salt of claim 1 , wherein the powder x-ray diffraction pattern further comprises diffraction peaks at 2θ values selected from 7.7±0.2, 13.5±0.2, 14.8±0.2, 15.4±0.2, 15.8±0.2, 23.3±0.2, and 24.6±0.2.
3. The crystalline dioxalate salt of claim 1 , 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. 13 .
4. The crystalline dioxalate salt of claim 1 , characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 73.7° C.
5. The crystalline dioxalate salt of claim 1 , characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 15 .
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the crystalline dioxalate salt of claim 1 .
7. The composition of claim 6 , wherein the composition is formulated for administration by inhalation.
8. The composition of claim 6 , wherein the carrier is an aqueous isotonic saline solution having a pH in the range of from about 4 to about 6.
9. The composition of claim 8 , which comprises a citrate buffer.
10. A drug delivery device comprising a dry powder inhaler containing a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the crystalline dioxalate salt of claim 1 .
11. The crystalline dioxalate salt of claim 1 , in micronized form.
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the crystalline dioxalate salt of claim 1 , in micronized form.
13. The composition of claim 12 , wherein the carrier is lactose.
14. A process for preparing the crystalline dioxalate salt of claim 1 , comprising:
forming a seed crystal of a crystalline dioxalate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with oxalic acid;
forming a dioxalate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with oxalic acid, and dissolving the salt in an inert diluent to form a solution; and
adding the seed crystal to the solution.
15. A method for treating a pulmonary disorder, the method comprising administering to a patient a therapeutically effective amount of the crystalline dioxalate of claim 1 .
16. A method of producing bronchodilation comprising administering to a patient by inhalation, a bronchodilation-producing amount of the crystalline dioxalate salt of claim 1 .
17. A method of treating chronic obstructive pulmonary disease or asthma, comprising administering to a patient a therapeutically effective amount of the crystalline dioxalate salt of claim 1 .