NOVEL SALTS AND CRYSTALS
The disclosure provides a new, stable, pharmaceutically acceptable bis-tosylate salt form of 1-(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9, 10, 10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, together with methods of making and using them, and pharmaceutical compositions comprising them.
1 . A stable bis-tosylate salt of 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4, 5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, e.g., in a homogenous crystal form, free or substantially free of other forms of 1-(4-fluorophenyl)-4-((6bR, 10aS)-3 -methyl-2,3 ,6b,9, 10, 10a-hexahy dro-1H,7H-pyrido[3′,4′:4,5]pyrrol 0[1,2,3 -de]quinoxalin-8-yl)-butan-1-one.
2 . The salt according to claim 1 , which is a salt formed by combining free ITI-007 free base and toluenesulfonic acid in a molar ratio from 1:1 to 1:3.
3 . The salt according to claim 1 , wherein the salt is formed from a slurry of ITI-007 free base and toluenesulfonic acid in 2-butanone solvent.
4 . The salt according to claim 1 , which is a salt crystal having an X-ray diffraction pattern as shown, or substantially as shown, in the upper curve of FIG. 1 .
5 . The salt according to claim 1 , which is a salt crystal having a DSC/TGA thermogram as shown, or substantially as shown, in FIG. 2 .
6 . The salt according to claim 1 , which is a salt crystal having a proton NMR spectrum as shown, or substantially as shown, in FIG. 3 .
7 . The salt according to claim 1 , which is a salt crystal having a proton NMR spectrum indicating the presence of about two toluenesulfonic acid moieties per ITI-007 base moiety.
8 . The salt according to claim 1 , wherein the salt contains less than 10 wt % of any other ITI-007 tosylate salt form.
9 . The salt according to claim 1 , wherein the salt contains less than 10 wt % of ITI-007 free base form.
10 . A method making a salt according to claim 1 , comprising
(a) reacting 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) free base with toluenesulfonic acid.
and
(b) recovering the salt thus formed.
11 . The method according to claim 10 , wherein the reaction is carried out in an organic solvent.
12 . A pharmaceutical composition comprising the salt according to claim 1 , in combination or association with a pharmaceutically acceptable diluent or carrier.
13 . A method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT 2A receptor, serotonin transporter (SERT), and/or dopamine D 1 /D 2 receptor signaling pathways comprising administering to said human an effective amount of a salt according to claim 1 .