Polymorphic forms of ST-246 and methods of preparation
Polymorph forms of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide are disclosed as well as their methods of synthesis and pharmaceutical compositions.
1. A polymorph Form VI of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide (ST-246) which shows an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of 6.43, 7.10, 8.23, 10.46, 12.62, 13.72, 15.71, 17.84, 19.34, 21.52, 23.73, 24.17, 24.71, 26.71, 27.26, 30.11 and 31.00 degrees.
2. A polymorph according to claim 1 that is at least about 70% free of other forms.
3. A polymorph according to claim 1 that is at least about 80% free of other forms.
4. A polymorph according to claim 1 that is at least about 90% free of other forms.
5. A polymorph according to claim 1 that is at least about 95% free of other forms.
6. A polymorph according to claim 1 that is at least about 99% free of other forms.
7. A pharmaceutical composition comprising the polymorph of claim 1 and further comprising one or more pharmaceutically acceptable ingredients selected from the group consisting of carriers, excipients, diluents, additives, fillers, lubricants and binders.
8. The pharmaceutical composition of claim 7 , wherein the composition is formulated for oral administration.
9. A method of producing crystal polymorphic Form VI of ST-246, comprising the steps of:
a) dissolving ST-246 in at least one solvent to make a solution;
b) cooling said solution to a temperature that causes the preferential crystallization of said ST-246 polymorphic Form VI; and
c) optionally drying the formed crystals of ST-246,
wherein said solvent is selected from the group consisting of nitromethane, methanol and chloroform.
10. The method of claim 9 further comprising adding seed crystals of polymorphic Form VI ST-246 during step (b).
11. The method of claim 9 , wherein said solvent does not contain water.
12. The method of claim 9 , wherein said solvent is nitromethane.
13. A dosage unit form for oral administration comprising the pharmaceutical composition of claim 8 , wherein ST-246 has a D90% particle size diameter of up to about 300 microns.
14. A dosage unit form according to claim 13 , wherein said ST-246 has a D90% particle size diameter of about 5 microns.
15. A dosage unit form according to claim 13 , wherein said ST-246 has a D90% particle size diameter of about 16.6 microns.
16. A dosage unit form according to claim 13 , wherein said ST-246 has a D90% particle size diameter of about 26.6 microns.
17. A dosage unit form according to claim 13 , wherein said ST-246 has a D90% particle size diameter of about 75 microns.
18. A unit dosage form for oral administration comprising:
(a) about 200 mg of ST-246, wherein ST-246 is ST-246 polymorph Form VI;
(b) about 33.15 mg of lactose monohydrate;
(c) about 42.90 mg of croscarmellose sodium;
(d) about 1.95 mg of colloidal silicon dioxide;
(e) about 13.65 mg of hydroxypropoyl methylcellulose;
(f) about 7.8 mg of sodium lauryl sulfate;
(g) about 1.95 mg of magnesium stearate; and
(h) a quantity of microcrystalline cellulose up to about 88.60 mg such that the total weight of the dosage form is about 390 mg.