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 diphosphate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester comprising about 1.8 to about 2.2 molar equivalents of phosphate per molar equivalent of ester and about 6 weight percent of water, and characterized by a powder x-ray diffraction pattern having two or more diffraction peaks at 2θ values selected from 6.4±0.2, 7.6±0.2, 8.6±0.2, 13.7±0.2, 15.0±0.2, 19.4±0.2, 21.6±0.2, 22.1±0.2, 22.9±0.2, and 23.7±0.2.
2. The compound of claim 1 , comprising about 1.9 to about 2.1 molar equivalents of phosphate per molar equivalent of ester.
3. The compound of claim 1 , wherein the powder x-ray diffraction pattern comprises diffraction peaks at 2θ values of 15.0±0.2, 19.4±0.2, 21.6±0.2, and 23.7±0.2.
4. The compound 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. 1 .
5. The compound of claim 1 , characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 154.5° C.
6. The compound of claim 1 , characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 2 .
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .
8. The compound of claim 1 , in micronized form.
9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 , in micronized form.
10. The composition of claim 9 , wherein the carrier is lactose.
11. A method for treating a pulmonary disorder, the method comprising administering to a patient a therapeutically effective amount of the compound of claim 1 .
12. A method of producing bronchodilation comprising administering to a patient by inhalation, a bronchodilation-producing amount of the compound of claim 1 .
13. A method of treating chronic obstructive pulmonary disease or asthma, comprising administering to a patient a therapeutically effective amount of the compound of claim 1 .
14. A process for preparing the compound of claim 1 , comprising contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with phosphoric acid.