Polymorphic forms of ST-246 and methods of preparation
View Patent ↗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 II 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 a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ 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-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide (ST-246) which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ 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-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide (ST-246) which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ 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-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide (ST-246) which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ 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.