Polymorphic forms of ST-246 and methods of preparation
Inventors
Tyavanagimatt, Shanthakumar R. • Anderson, Melialani A. C. L. S. • Weimers, William C. • Nelson, Dylan • Bolken, Tove′ C. • Hruby, Dennis E. • O'Neill, Michael H. • Sweetapple, Gary • McCloughan, Kelley A.
Assignees
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Publication Number
US-10933050-B2
Publication Date
2021-03-02
Expiration Date
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.
Core Innovation
The invention relates to a polymorph Form VI of ST-246 that is characterized by an X-ray powder diffraction pattern with specified characteristic peaks at defined reflection angles 2θ. The Form VI polymorph is identified as 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). Characterization is supported by XRPD and FTIR described in the disclosure, including relationships among polymorphic forms I–VI.
The disclosure presents crystal polymorphic Form VI as a product of solvent selection and crystallization conditions that cause preferential crystallization of Form VI. A method is described in which ST-246 is dissolved in a selected solvent and the solution is cooled to promote preferential crystallization of polymorphic Form VI. Solvents are selected from nitromethane, methanol and chloroform, and formed crystals can optionally be dried.
The invention also encompasses pharmaceutical composition and oral unit dosage forms that include ST-246 polymorph Form VI and defined pharmaceutically acceptable ingredients. The disclosure ties polymorph identity to oral administration concepts and includes dosage-unit particle-size limitations characterized by D90 particle-size diameter in relation to dissolution-related behavior reported for Form I in the disclosure. A specific oral unit dosage formulation containing about 200 mg ST-246 in Form VI with named excipients and a defined total unit weight is described.
Claims Coverage
The document includes three independent claims that cover a defined crystalline polymorph, a method for producing Form VI crystals, and an oral unit dosage form formulation containing ST-246 Form VI with defined excipients and quantities.
Form VI polymorph defined by XRPD characteristic peaks
A polymorph Form VI of ST-246 showing an X-ray powder diffraction pattern having characteristic peaks at 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.
Production of Form VI crystals by preferential crystallization on cooling
A method of producing crystal polymorphic Form VI of ST-246 comprising dissolving ST-246 in at least one solvent to make a solution, cooling the solution to a temperature that causes preferential crystallization of Form VI, and optionally drying the formed crystals, wherein the solvent is selected from nitromethane, methanol and chloroform.
Oral unit dosage form containing ST-246 polymorph Form VI with defined excipients
A unit dosage form for oral administration comprising about 200 mg of ST-246 wherein ST-246 is ST-246 polymorph Form VI, and specified quantities of lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, hydroxypropoyl methylcellulose, sodium lauryl sulfate, magnesium stearate, and microcrystalline cellulose up to about 88.60 mg such that the total weight of the dosage form is about 390 mg.
Overall, claim coverage focuses on a defined XRPD peak pattern for Form VI of ST-246, preferential crystallization during cooling from specific solvents, and an oral unit dosage containing ST-246 Form VI with defined excipients and quantities.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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