Details for Patent: 9,744,154

Title:	Polymorphic forms of ST-246 and methods of preparation
Abstract:	Polymorph forms of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocy- cloprop[f]isoindol-2(1H)-yl)-benzamide are disclosed as well as their methods of synthesis and pharmaceutical compositions.
Inventor(s):	Tyavanagimatt; Shanthakumar R. (Corvallis, OR), Anderson; Melialani A.C.L.S. (Corvallis, OR), Weimers; William C. (Corvallis, OR), Nelson; Dylan (Portland, OR), Bolken; Tove' C. (Keizer, OR), Hruby; Dennis E. (Albany, OR), O'Neill; Michael H. (Painesville, OH), Sweetapple; Gary (Madison, OH), McCloughan; Kelley A. (South Haven, MI)
Assignee:	SIGA TECHNOLOGIES, INC. (Corvallis, OR)
Filing Date:	Dec 04, 2015
Application Number:	14/959,180
Claims:	1. A polymorph Form II of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocy- cloprop[f]isoindol-2(1H)-yl)-benzamide (ST-246) which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2.theta. of 12.74, 16.03, 16.99, 19.64, 21.96, 23.80 and 25.39 degrees. 2. An isolated polymorph according to claim 1 that is at least about 70% free of other forms. 3. An isolated polymorph according to claim 1 that is at least about 80% % free of other forms. 4. An isolated polymorph according to claim 1 that is at least about 90% % free of other forms. 5. An isolated polymorph according claim 1 that is at least about 95% % free of other forms. 6. An isolated polymorph according 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 treating Orthopoxvirus infections comprising administering to a patient in need thereof a therapeutically effective amount of the polymorph of claim 1. 10. A method of treating eczema vaccinatum comprising administering to a patient in need thereof a therapeutically effective amount of the polymorph of claim 1. 11. A method of producing crystal polymorphic Form II of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocy- cloprop[f]isoindol-2(1H)-yl)-benzamide (ST-246) which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2.theta. of 12.74, 16.03, 16.99, 19.64, 21.96, 23.80 and 25.39 degrees: 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 II; and c) optionally drying the formed crystals of ST-246, wherein said solvent is selected from the group consisting of ethyl acetate, chloroform and 1-propanol, isopropyl alcohol (IPA), ethanol, acetone, acetonitrile (ACN), toluene, isopropyl acetate and dimethylformamide (DMF). 12. The method of claim 11 further comprising adding seed crystals of polymorphic Form II ST-246 during step (b). 13. The method of claim 11, wherein said solvent does not contain water. 14. The method of claim 11, wherein said solvent is selected from the group consisting of ethyl acetate and chloroform. 15. A method of producing crystal polymorphic Form II of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocy- cloprop[f]isoindol-2(1H)-yl)-benzamide (ST-246) which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2.theta. of 12.74, 16.03, 16.99, 19.64, 21.96, 23.80 and 25.39 degrees; comprising the steps of: a) dissolving ST-246 in ethanol and water to make a solution; b) cooling said solution to a temperature that causes the preferential crystallization of said ST-246 polymorphic Form II; and c) optionally drying the formed crystals of ST-246. 16. The method of claim 15 further comprising adding seed crystals of polymorphic Form II ST-246 during step (b). 17. The method of claim 15, wherein the volume ratio of ethanol: water is about 1:1. 18. A dosage unit form comprising the pharmaceutical composition of claim 8, wherein ST-246 has a D90% particle size diameter of up to about 300 microns. 19. A dosage unit form according to claim 18, wherein said ST-246 has a D90% particle size diameter of about 5 microns. 20. A dosage unit form according to claim 18, wherein said ST-246 has a D90% particle size diameter of about 16.6 microns. 21. A dosage unit form according to claim 18, wherein said ST-246 has a D90% particle size diameter of about 26.6 microns. 22. A dosage unit form according to claim 18, wherein said ST-246 has a D90% particle size diameter of about 75 microns. 23. A unit dosage form for oral administration comprising: (a) about 200 mg of ST-246, wherein ST-246 is polymorphic Form II of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocy- cloprop[f]isoindol-2(1H)-yl)-benzamide (ST-246) which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2.theta. of 12.74, 16.03, 16.99, 19.64, 21.96, 23.80 and 25.39 degrees; (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.