US 12,076,315 B2
Stable polymorphic compositions of brequinar sodium and methods of use and manufacture thereof
Abdolsamad Tadayon, Shanghai (CN); Ping Huang, Shanghai (CN); Chaoyi Deng, Shanghai (CN); Jinsuo Yang, Shanghai (CN); Qingqing Lu, Shanghai (CN); Lin Cui, Shanghai (CN); Mo Jia, Shanghai (CN); Xianjun You, Shanghai (CN); David P. Hesson, Malvern, PA (US); and Siyi Jiang, Shanghai (CN)
Assigned to Clear Creek Bio, Inc., Cambridge, MA (US)
Filed by Clear Creek Bio, Inc., Cambridge, MA (US)
Filed on Mar. 19, 2021, as Appl. No. 17/207,518.
Claims priority of provisional application 63/043,382, filed on Jun. 24, 2020.
Claims priority of provisional application 63/043,388, filed on Jun. 24, 2020.
Claims priority of provisional application 63/043,384, filed on Jun. 24, 2020.
Claims priority of provisional application 63/043,386, filed on Jun. 24, 2020.
Claims priority of provisional application 63/043,380, filed on Jun. 24, 2020.
Claims priority of provisional application 63/030,677, filed on May 27, 2020.
Claims priority of provisional application 63/020,460, filed on May 5, 2020.
Claims priority of provisional application 62/992,720, filed on Mar. 20, 2020.
Prior Publication US 2021/0292280 A1, Sep. 23, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 215/52 (2006.01); A61K 9/00 (2006.01); A61K 31/47 (2006.01); A61K 31/4704 (2006.01); A61K 31/706 (2006.01); A61K 45/06 (2006.01); A61P 31/14 (2006.01)
CPC A61K 31/4704 (2013.01) [A61K 9/0014 (2013.01); A61K 9/0019 (2013.01); A61K 9/0053 (2013.01); A61K 31/47 (2013.01); A61K 31/706 (2013.01); A61K 45/06 (2013.01); A61P 31/14 (2018.01); C07D 215/52 (2013.01); C07B 2200/13 (2013.01)] 14 Claims
OG exemplary drawing
 
1. A method of making a crystal comprising at least 80% polymorphic form C of brequinar sodium salt, the method comprising the steps of:
combining a solid form of brequinar acid, sodium hydroxide (NaOH), and a solvent comprising isopropanol and water to produce a solution and removing insoluble material from the combined brequinar acid, NaOH, and solvent;
crystallizing brequinar sodium salt from the solution to produce a crystal comprising polymorphic form C of brequinar sodium salt, wherein the crystallizing step comprises sequentially performing the steps of:
adding a seed crystal of polymorphic form C of brequinar sodium salt to the solution to produce a seeded mixture;
adding n-heptane to the seeded mixture to produce an alkane-containing mixture and incubating the alkane-containing mixture at from about 15° C. to about 35° C.; and
removing the solvent from the seeded mixture at a temperature below ambient temperatures, wherein the removing step results in a crystal comprising at least 80% polymorphic form C of brequinar sodium salt as measured by X-ray Diffraction (XRD).