Crystalline salts of (4s,4as,5ar,12as)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide and methods of using the same

Abstract

A crystalline mono hydrochloride salt of (4S,4aS,5aR, 12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1, 11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide is disclosed having improved stability. In addition, a crystalline mono mesylate salt and crystalline mono sulfate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1, 4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide are also disclosed having improved stability. A pharmaceutical composition containing the crystalline salts and methods of treating inflammatory skin disorders and bacterial infections comprising administering the crystalline salts are also disclosed.

What is claimed is: 
     
         1 . A crystalline salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12,12a-tetrahydroxy-7- [(methoxy(methyl)amino)-methyl]-1,11-dioxo-1, 4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide, wherein the salt is selected from a group consisting of mono hydrochloride, mono mesylate and mono sulfate. 
     
     
         2 . The crystalline salt of  claim 1 , wherein the salt is substantially pure. 
     
     
         3 . The crystalline salt of  claim 1 , wherein the salt is mono hydrochloride. 
     
     
         4 . The crystalline salt of  claim 3 , having an XRPD pattern substantially as illustrated in  FIG. 1  after synthesis of the crystalline salt. 
     
     
         5 . The crystalline salt of  claim 3 , having characteristic peaks at diffraction angle 2-theta degrees appearing at least at about 13.4, about 20.5 and about 23.3, as measured by XRPD. 
     
     
         6 . The crystalline salt of  claim 3 , having a DSC curve substantially as illustrated in  FIG. 2  after synthesis of the crystalline salt. 
     
     
         7 . The crystalline salt of  claim 3 , having a TGA curve substantially as illustrated in  FIG. 3  after synthesis of the crystalline salt. 
     
     
         8 . The crystalline salt of  claim 3 , wherein the salt has a β-isomer content at 0 days of about 0.1% peak area to about 7.0% peak area, as measured by HPLC. 
     
     
         9 . The crystalline salt of  claim 1 , wherein the salt is mono mesylate. 
     
     
         10 . The crystalline salt of  claim 9 , having an XRPD pattern substantially as illustrated in  FIG. 4  after synthesis of the crystalline salt. 
     
     
         11 . The crystalline salt of  claim 9 , having characteristic peaks at diffraction angle 2-theta degrees appearing at least at about 9, about 15 and about 23.8, as measured by XRPD. 
     
     
         12 . The crystalline salt of  claim 9 , having a DSC curve substantially as illustrated in  FIG. 5  after synthesis of the crystalline salt. 
     
     
         13 . The crystalline salt of  claim 9 , having a TGA curve substantially as illustrated in  FIG. 6  after synthesis of the crystalline salt. 
     
     
         14 . The crystalline salt of  claim 9 , wherein the salt has a β-isomer content at 0 days of about 2.0% peak area to about 10.0% peak area, as measured by HPLC. 
     
     
         15 . The crystalline salt of  claim 1 , wherein the salt is mono sulfate. 
     
     
         16 . The crystalline salt of  claim 15 , having an XRPD pattern substantially as illustrated in  FIG. 7  after synthesis of the crystalline salt. 
     
     
         17 . The crystalline salt of  claim 15 , having characteristic peaks at diffraction angle 2-theta degrees appearing at least at about 15, about 17.8 and about 23.5, as measured by XRPD. 
     
     
         18 . The crystalline salt of  claim 15 , having a DSC curve substantially as illustrated in  FIG. 8  after synthesis of the crystalline salt. 
     
     
         19 . The crystalline salt of  claim 15 , having a TGA curve substantially as illustrated in  FIG. 9  after synthesis of the crystalline salt. 
     
     
         20 . The crystalline salt of  claim 15 , wherein the salt has a β-isomer content at 0 days of about 3.0% peak area to about 26.0% peak area, as measured by HPLC.