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 pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester and phosphoric acid in a 1:2 molar ratio characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 15.0±0.2, 19.4±0.2, 21.6±0.2, and 23.7±0.2.
2. The composition of claim 1 , wherein the powder x-ray diffraction pattern comprises diffraction peaks at 2θ values of 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.
3. The composition of claim 1 , wherein the crystalline salt 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. 1 .
4. The composition of claim 1 , wherein the crystalline salt is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 2 .
5. The composition of claim 1 , wherein the crystalline salt contains about 6 weight percent of water.
6. The composition of claim 1 , wherein the crystalline salt is further characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 154.5° C.
7. The composition of claim 5 , wherein the crystalline salt contains about 6.23 weight percent of water.
8. The composition of claim 5 , wherein the crystalline salt contains about 6.54 weight percent of water.