Salts and polymorphs of a tetracycline compound
View Patent ↗Crystalline forms, including salts and polymorphs, of a compound useful in the treatment of tetracycline compound-responsive states are provided herein. The crystalline compounds are useful for the treatment or prevention of conditions and disorders such as bacterial infections and neoplasms, as well as other known applications for tetracycline compounds in general.
1. A method of preparing a stable crystalline tosylate salt of Compound 1:
wherein the method comprises:
dissolving a freebase of Compound 1 in a first solvent or combination of solvents to form a first solution;
dissolving p-toluenesulfonic acid in a second solvent or combination of solvents to form a second solution;
combining the first and second solution to form a third solution;
adding a polymorph of a tosylate salt of Compound 1 to the third solution to form a fourth solution; and
crystallizing from the fourth solution a stable crystalline tosylate salt of Compound 1.
2. The method of claim 1 , wherein the first solvent or combination of solvents and the second solvent or combination of solvents are the same.
3. The method of claim 1 , wherein the first solvent or combination of solvents and the second solvent or combination of solvents are different.
4. The method of claim 1 , wherein the first combination of solvents and the second combination of solvents are each independently a combination of alcoholic solvents.
5. The method of claim 4 , wherein the first combination of solvents and the second combination of solvents are each independently a combination of two alcoholic solvents.
6. The method of claim 5 , wherein the two alcoholic solvents are ethanol and isopropanol.
7. The method of claim 6 , wherein the ethanol and isopropanol are at a volume-to volume ratio of 2 to 1.
8. The method of claim 1 , wherein the first combination of solvents and the second combination of solvents each comprises an alcoholic solvent and an anti-solvent.
9. The method of claim 8 , wherein the alcoholic solvent is methanol.
10. The method of claim 8 , wherein the anti-solvent is selected from a ketone, an ester and an ether.
11. The method of claim 10 , wherein the ether is methyl-t-butyl ether.
12. The method of claim 1 , wherein the first combination of solvents and the second combination of solvents each consists of methanol and methyl-t-butyl ether.
13. The method of claim 12 , wherein the methanol and methyl-t-butyl ether are at a volume-to-volume ratio of 1 to 1.2.
14. The method of claim 1 , wherein the p-toluenesulfonic acid is provided in an amount of from 25 to 75 wt % relative to the amount of Compound 1.
15. The method of claim 1 , wherein the p-toluenesulfonic acid is provided in a form of a p-toluenesulfonic acid monohydrate.
16. The method of claim 1 , wherein the fourth solution forms a slurry upon stirring.
17. The method of claim 16 , wherein the method further comprises drying the slurry.
18. The method of claim 1 , wherein the polymorph is characterized by an X-ray powder diffraction pattern including peaks at approximately 8.06, 13.02, and 18.83 °2θ using Cu Kα radiation.
19. The method of claim 1 , wherein the polymorph is characterized by an X-ray powder diffraction pattern including peaks at approximately 5.11 and 15.60 °2θ using Cu Kα radiation.
20. The method of claim 1 , wherein the polymorph is characterized by an X-ray powder diffraction pattern including peaks at approximately 11.88 and 16.12 °2θ using Cu Kα radiation.