Polymorphic Forms of ST-246 and Methods of Preparation
AssigneeSiga Technologies, Inc.
InventorsShanthakumar R. Tyavanagimatt, Melialani A.C.L. Stone, William C. Weimers, Dylan Nelson, Tove' C. Bolken, Dennis E. Hruby, Michael H. O'Neill, Gary Sweetapple, Kelley A. McCloughan
Life of this patent
Estimating the term…
Abstract
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.
Claims116
A polymorph Form I of ST-246 which shows an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 7.63, 10.04, 11.47, 14.73, 15.21, 15.47, 16.06, 16.67, 16.98, 18.93, 19.96, 20.52, 20.79, 22.80, 25.16, 26.53, 27.20, 27.60, 29.60, 30.23, 30.49, 30.68, 31.14, 33.65, 34.33, 35.29, 35.56, 36.30, 37.36, 38.42, 38.66 degrees.
A polymorph Form II of ST-246 which shows a X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ according to FIG. 2.
A method of treating eczema vaccinatum comprising administering to a patient in need thereof a therapeutically effective amount of the polymorph of claim 21.
A polymorph Form III of ST-246 which shows an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 6.71, 9.05, 12.49, 13.03, 13.79, 14.87, 15.72, 16.26, 16.74, 18.10, 18.43, 19.94, 21.04, 21.51, 23.15, 23.51, 25.32, 26.24, 26.87, 27.32, 27.72, 28.55, 29.08, 29.50, 29.84, 31.27, 33.48, 35.36, 39.56 degrees.
A polymorph Form IV of ST-246 which shows an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ as shown in FIG. 4.
A polymorph Form VI of ST-246 which shows an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ as shown in FIG. 6.
A method of producing a crystal polymorphic Form I of ST-246, comprising the steps of:
- a) dissolving ST-246 in at least one organic solvent and an amount of water to make a solution;
- b) cooling said solution to a temperature that causes the preferential crystallization of said ST-246 polymorphic Form I;
- and
- c) optionally drying the formed crystals of ST-246,
- wherein said organic solvent is selected from a group consisting of isopropyl alcohol (IPA), ethyl acetate, ethanol, methanol, acetone, isopropyl acetate and tetrahydrofuran (THF).
A method of producing crystal polymorphic Form II 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 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).
A method of producing crystal polymorphic Form II of ST-246, 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.
A method of producing crystal polymorphic Form III of ST-246, comprising the steps of:
- a) dissolving ST-246 in at least one organic solvent and water to make a solution;
- b) cooling said solution to a temperature that causes the preferential crystallization of said ST-246 polymorphic Form III;
- and
- c) optionally drying the formed crystals of ST-246,
- wherein the organic solvent is selected from the group consisting of isopropyl alcohol (IPA), ethyl acetate and ethanol.
A method of producing crystal polymorphic Form III of ST-246, comprising the steps of:
- a) dissolving ST-246 in at least one organic solvent to make a solution;
- b) cooling said solution to a temperature that causes the preferential crystallization of said ST-246 polymorphic Form III;
- and
- c) optionally drying the formed crystals of ST-246,
- wherein the organic solvent is selected from the group consisting of acetone, isopropyl alcohol (IPA), dimethylformamide (DMF), dimethylamine (DMA), pyridine, trifluoroethanol (TFE), methanol, ethanol, chloroform, acetonitrile (ACN), and tetrahydrofuran (THF).
A method for producing crystal polymorphic Form III of ST-246, comprising the steps of:
- a) suspending an anhydrous form of ST-246 or polymorphic Form V in water;
- and
- b) optionally drying the formed crystals of ST-246.
A method of producing crystal polymorphic Form IV of ST-246, comprising the steps of:
- a) dissolving ST-246 in at least one organic solvent optionally containing water to make a solution;
- b) cooling said solution to a temperature that causes the preferential crystallization of said ST-246 polymorphic Form IV:
- and
- c) optionally drying the formed crystals of ST-246,
- wherein said solvent is selected from the group consisting of:
- a mixture of acetonitrile and ethyl acetate, a mixture of ethanol and toluene, a mixture of water and ethyl acetate, and a mixture of trifluoroethanol and THF.
A method of producing crystal polymorphic Form IV 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 IV;
- and
- c) optionally drying the formed crystals of ST-246,
- wherein said solvent is selected from the group consisting of 1-butanol, trifluoroethanol (TFE), chloroform, dichloromethane and toluene.
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.
A unit dosage form for oral administration comprising:
- (a) about 200 mg of ST-246, wherein ST-246 is selected from the group consisting of ST-246 polymorph Form I, ST-246 polymorph Form II, ST-246 polymorph Form III, ST-246 polymorph Form IV and 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.
Dependencies are inferred from the claim text.