Claims for Patent: 11,691,948

Summary for Patent: 11,691,948

Title:	Crystalline freebase forms of a biphenyl compound
Abstract:	The invention provides two crystalline freebase forms of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. The invention also provides pharmaceutical compositions comprising the crystalline freebase or prepared using the crystalline freebases; processes and intermediates for preparing the crystalline freebases; and methods of using the crystalline freebases to treat a pulmonary disorder.
Inventor(s):	Grahame Woollam
Assignee:	Theravance Biopharma R&D IP LLC
Application Number:	US17/301,820
Patent Claims:	1. A pharmaceutical composition useful for treating chronic obstructive pulmonary disease in a human patient, produced by the following step: dissolving a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{1[4-(4-carbamoylpiperidin-1-ylmethyl) benzoyl]methylamino}-ethyl)piperidin-4-yl ester in a solvent to form a solution; wherein the crystalline freebase is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 20 values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1; and wherein the pharmaceutical composition has a pH of about 5. 2. The pharmaceutical composition of claim 1, wherein the solution is combined with an aqueous pharmaceutical carrier. 3. The pharmaceutical composition of claim 1, wherein the solvent is an aqueous pharmaceutical carrier. 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and 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 comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1, and further characterized by having five or more additional diffraction peaks at 2θ values selected from 8.8±0.1, 10.1±0.1, 11.4±0.1, 11.6±0.1, 14.8±0.1, 15.2±0.1, 16.1±0.1, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1; and wherein crystalline freebase is dissolved in a solvent and then combined with the pharmaceutically acceptable carrier; and wherein the pharmaceutical composition has a pH of about 5. 5. The pharmaceutical composition of claim 4, wherein the crystalline freebase is further characterized by a melting point of about 125° C. 6. A pharmaceutical composition comprising: a dissolved crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl) benzoyl]methylamino}-ethyl)piperidin-4-yl ester and an aqueous pharmaceutical carrier; wherein the crystalline freebase is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1; and wherein the pharmaceutical composition has a pH of about 5. 7. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is isotonic. 8. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is buffered with citrate buffer to a pH of about 5. 9. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition contains about 0.05m/mL to about 10 mg/mL of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino }ethyl)piperidin-4-yl ester. 10. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is administered by inhalation using a nebulizer inhaler. 11. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is isotonic. 12. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is buffered with citrate buffer to a pH of about 5. 13. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition contains about 0.05 μm/mL to about 10 mg/mL of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. 14. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is administered by inhalation using a nebulizer inhaler. 15. A pharmaceutical composition comprising: a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester in a solution; wherein the crystalline freebase is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1. 16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and 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 comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1, and further characterized by having five or more additional diffraction peaks at 20 values selected from 8.8±0.1, 10.1±0.1, 11.4±0.1, 11.6±0.1, 14.8±0.1, 15.2±0.1, 16.1±0.1, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1, wherein the crystalline freebase is in solution with the pharmaceutically acceptable carrier. 17. A pharmaceutical composition comprising a solution of a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester characterized by (i) a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1 or (ii) a melting point of about 125° C. 18. A pharmaceutical composition comprising a solution comprising a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester; wherein the crystalline freebase is characterized by a melting point of about 125° C. 19. A pharmaceutical composition comprising a solution comprising a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester; wherein the crystalline freebase is characterized by a powder x-ray diffraction comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1. 20. A solution comprising a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester; wherein the crystalline freebase is characterized by a melting point of about 125° C. 21. A solution comprising a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester; wherein the crystalline freebase is characterized by a powder x-ray diffraction comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1.