Crystalline freebase forms of a biphenyl compound
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Publication Number
US-11691948-B2
Publication Date
2023-07-04
Expiration Date
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.
Core Innovation
The disclosure describes anhydrous crystalline freebase Forms III and IV of the specified biphenyl carbamate ester, distinguished by powder X-ray diffraction patterns and thermal properties. It describes pharmaceutical compositions and solutions containing the crystalline freebase, including aqueous isotonic citrate-buffered formulations at about pH 5, and identifies inhaled and nebulized formulations as suitable forms of use.
The background section is not included in the partial content, so the problem being solved is not explicitly described there. The provided description reports that the crystalline forms are non-deliquescent and acceptably hygroscopic, and identifies pulmonary-disorder uses including chronic obstructive pulmonary disease and asthma. It also reports properties of Form III relevant to water uptake and respirable particles.
Claims Coverage
The provided relevant claims identify ten independent claims: claims 1, 4, 6, and 15 through 21. They cover pharmaceutical compositions or solutions containing the specified crystalline freebase, with claim elements addressing its powder X-ray diffraction pattern or melting point and, in some claims, the carrier, solvent, pH, or intended treatment.
Copd-treatment composition at about pH 5
A pharmaceutical composition useful for treating chronic obstructive pulmonary disease in a human patient, comprising a solution of the specified crystalline freebase identified by a powder X-ray diffraction pattern and having a pH of about 5.
Carrier-containing composition at about pH 5
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the specified crystalline freebase, characterized by a powder X-ray diffraction pattern, dissolved in a solvent and then combined with the carrier, with the composition at a pH of about 5.
Aqueous composition of dissolved crystalline freebase
A pharmaceutical composition comprising the specified dissolved crystalline freebase and an aqueous pharmaceutical carrier, with the freebase identified by a powder X-ray diffraction pattern and the composition having a pH of about 5.
Composition containing crystalline freebase in solution
A pharmaceutical composition comprising the specified crystalline freebase in a solution, with the freebase identified by a powder X-ray diffraction pattern.
Carrier-containing composition with an extended diffraction pattern
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the specified crystalline freebase in solution with the carrier, identified by a powder X-ray diffraction pattern that includes the stated peaks and at least five additional peaks selected from the stated set.
Solution characterized by diffraction pattern or melting point
A pharmaceutical composition comprising a solution of the specified crystalline freebase, characterized by the stated powder X-ray diffraction peaks or by a melting point of about 125C.
Solution characterized by melting point
A pharmaceutical composition comprising a solution of the specified crystalline freebase characterized by a melting point of about 125C.
Solution characterized by diffraction pattern
A pharmaceutical composition comprising a solution of the specified crystalline freebase characterized by the stated powder X-ray diffraction peaks.
Solution of crystalline freebase characterized by melting point
A solution comprising the specified crystalline freebase, characterized by a melting point of about 125C.
Solution of crystalline freebase characterized by diffraction pattern
A solution comprising the specified crystalline freebase characterized by the stated powder X-ray diffraction peaks.
The independent claims cover compositions and solutions containing the specified crystalline freebase. Their claim elements include diffraction-pattern or melting-point characteristics, and, for selected compositions, a carrier, an aqueous carrier, a pH of about 5, or use in treating chronic obstructive pulmonary disease.
Stated Advantages
The crystalline forms are reported as non-deliquescent and acceptably hygroscopic.
Form III is reported to show reversible water uptake below 2%.
Form III is reported to produce micronized respirable particles.
The crystalline forms are described as suitable for pharmaceutical formulations, including inhaled and nebulized compositions.
Documented Applications
Pharmaceutical compositions and solutions containing the crystalline freebase, including inhaled and nebulized formulations.
Treatment of chronic obstructive pulmonary disease, including a composition described as useful for treating the disease in a human patient.
Treatment of asthma and other pulmonary disorders.
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