# US 11,078,190 B2 · Polymorphs of selinexor > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,078,190 B2 - Document ID: US11078190B2 - Status: Granted - Kind: B2 - Application number: 16/679,630 - Filed: 2019-11-11 - Published: 2020-09-10 - Granted: 2021-08-03 - Earliest claimed: 2014-08-15 - Assignees: Karyopharm Therapeutics Inc. - Applicants: Karyopharm Therapeutics inc. - Inventors: Brian C. Austad; David G. Roe - Web page: https://patentgrep.com/patent/US11078190B2 ## CPC - C07D 403/12: linked by a chain containing hetero atoms as chain links - A61K 31/497: containing further heterocyclic rings - A61P 35/00: Antineoplastic agents - C07B 2200/13: Crystalline forms, e.g. polymorphs - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) ## Abstract The present invention relates to crystalline forms of the compound represented by Structural Formula I, and compositions comprising crystalline forms of the compound represented by Structural Formula I described herein. The crystalline forms of the compound of Structural Formula I and compositions comprising the crystalline forms of the compound of Structural Formula I provided herein, in particular, single crystalline Form A, can be incorporated into pharmaceutical compositions, which can be used to treat various disorders associated with CRM1 activity, including cancer. Also described herein are methods for preparing the compound of Structural Formula I and its single crystalline forms. ## Claims ### Claim 1 A single crystalline form of a compound represented by Structural Formula I: wherein the single crystalline form is an acetonitrile solvate of Form D and is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 3.7°, 7.3°, 10.9°, 18.3° and 21.9°. ### Claim 2 (depends on 1) The single crystalline form of claim 1, characterized by X-ray powder diffraction peaks at 2θ angles of 3.7°, 7.3°, 10.9°, 18.3° and 21.9°. ### Claim 3 (depends on 2) The single crystalline form of claim 2, characterized by X-ray powder diffraction peaks at 2θ angles of 3.7°, 7.3°, 9.7°, 10.9°, 18.3°, 19.2° and 21.9°. ### Claim 4 (depends on 3) The single crystalline form of claim 3, characterized by X-ray powder diffraction peaks at 2θ angles of 3.7°, 7.3°, 9.7°, 10.9°, 11.1°, 18.3°, 19.2°, 19.5°, 20.6° and 21.9°. ### Claim 5 (depends on 1) The single crystalline form of claim 1, characterized by an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 2A. ### Claim 6 (depends on 1) The single crystalline form of claim 1, wherein the solvate comprises from about 0.5 to about 1.5 molar equivalents of solute per molar equivalent of the compound of Structural Formula I. ### Claim 7 (depends on 6) The single crystalline form of claim 6, wherein the solvate comprises about one molar equivalent of solute per molar equivalent of the compound of Structural Formula I. ### Claim 8 A method of preparing a single crystalline form of a compound represented by Structural Formula I: wherein the single crystalline form is Form A and is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.4°, 19.9°, 21.3° and 22.0°, the method comprising: (a) suspending single crystalline Form D of the compound of Structural Formula I in isopropanol or a mixture of isopropanol and water to form a slurry, wherein single crystalline Form D is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 3.7°, 7.3°, 10.9°, 18.3° and 21.9°; (b) heating the slurry to a temperature less than or equal to about 70° C. to form a second slurry or a solution; (c) cooling the second slurry or the solution and adding water to the second slurry or the solution, thereby forming solid particles of crystalline Form A of the compound of Structural Formula I; and (d) isolating the solid particles of crystalline Form A, thereby preparing a composition comprising particles of single crystalline Form A of the compound of Structural Formula I. ### Claim 9 A method of preparing a single crystalline form of a compound represented by Structural Formula I: wherein the single crystalline form is Form A and is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.4°, 19.9°, 21.3° and 22.0°, the method comprising: (a) suspending single crystalline Form D of the compound of Structural Formula I in isopropanol or a mixture of isopropanol and water to form a slurry, wherein single crystalline Form D is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 3.7°, 7.3°, 10.9°, 18.3° and 21.9°; (b) heating the slurry to a temperature less than or equal to about 70° C. to form a second slurry or a solution; (c) adding water to the second slurry or the solution and cooling the second slurry or the solution, thereby forming solid particles of crystalline Form A of the compound of Structural Formula I; and (d) isolating the solid particles of crystalline Form A, thereby preparing a composition comprising particles of single crystalline Form A of the compound of Structural Formula I. ### Claim 10 (depends on 8) The method of claim 8, wherein the solid particles have a unimodal particle size distribution characterized by a d(0.9) of 100 microns or less. ### Claim 11 (depends on 8) The method of claim 8, wherein the ratio of isopropanol to water by volume in the mixture of isopropanol and water is from about 0.1 to about 4. ### Claim 12 (depends on 8) The method of claim 8, wherein single crystalline Form D of the compound of Structural Formula I is suspended in an amount of isopropanol or mixture of isopropanol and water of from about 5 to about 10 parts by weight with respect to single crystalline Form D of the compound of Structural Formula I. ### Claim 13 (depends on 8) The method of claim 8, wherein the slurry is heated to a temperature of from about 35° C. to about 70° C. ### Claim 14 (depends on 8) The method of claim 8, wherein the second slurry or the solution is cooled to from about 0° C. to about 55° C. ### Claim 15 (depends on 8) The method of claim 8, wherein water is added to the second slurry or the solution in an amount of from about 5 parts by weight to about 15 parts by weight with respect to single crystalline Form D of the compound of Structural Formula I. ### Claim 16 A method of preparing a single crystalline form of a compound represented by Structural Formula I: wherein the single crystalline form is Form A and is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.4°, 19.9°, 21.3° and 22.0°, the method comprising: heating single crystalline Form D of the compound of Structural Formula I and inducing formation of solid particles of crystalline Form A; or maturing single crystalline Form D of the compound of Structural Formula I in a solvent system and inducing formation of solid particles of crystalline Form A; or drying single crystalline Form D of the compound of Structural Formula I, thereby forming solid particles of crystalline Form A; or any combination of the foregoing; and isolating the solid particles of crystalline Form A, thereby preparing single crystalline Form A of the compound of Structural Formula I. ### Claim 17 A method of preparing a single crystalline form of a compound represented by Structural Formula I: wherein the single crystalline form is an acetonitrile solvate of Form D and is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 3.7°, 7.3°, 10.9°, 18.3° and 21.9°, the method comprising: dissolving the compound of Structural Formula I in a solvent system comprising greater than 20% by volume acetonitrile; inducing formation of solid particles of crystalline Form D of the compound of Structural Formula I, wherein the temperature of the solvent system is below 50°; and isolating the solid particles of crystalline Form D, thereby preparing the acetonitrile solvate of single crystalline Form D of the compound of Structural Formula I. ### Claim 18 (depends on 17) The method of claim 17, wherein inducing formation of solid particles of the acetonitrile solvate of crystalline Form D comprises cooling the solution formed by dissolving the compound of Structural Formula I in a solvent system comprising acetonitrile. ### Claim 19 A method of preparing a single crystalline form of a compound represented by Structural Formula I: wherein the single crystalline form is Form A and is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.4°, 19.9°, 21.3° and 22.0°, the method comprising: (a) combining a trialkylamine, 2-methyltetrahydrofuran, a compound of Structural Formula II: and a compound of Structural Formula III: to form a reaction mixture; (b) cooling the reaction mixture to from about −80° C. to about 0° C.; (c) treating the reaction mixture with propylphosphonic anhydride to provide a mixture comprising the compound of Structural Formula I; (d) isolating the compound of Structural Formula I from the mixture; (e) dissolving the isolated compound of Structural Formula I in a solvent system comprising acetonitrile; (f) inducing formation of solid particles of crystalline Form D of the compound of Structural Formula I and isolating the solid particles of crystalline Form D to obtain single crystalline Form D of the compound of Structural Formula I, wherein single crystalline Form D is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 3.7°, 7.3°, 10.9°, 18.3° and 21.9°; (g) heating single crystalline Form D, and inducing formation of solid particles of crystalline Form A; or maturing single crystalline Form D, in a solvent system and inducing formation of solid particles of crystalline Form A; or drying single crystalline Form D, thereby forming solid particles of crystalline Form A; or any combination of the foregoing; and (h) isolating the particles of crystalline Form A, thereby preparing single crystalline Form A of the compound of Structural Formula I. ### Claim 20 A method of preparing a single crystalline form of a compound represented by Structural Formula I: wherein the single crystalline form is Form A and is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.4°, 19.9°, 21.3° and 22.0°, the method comprising: (a) combining a trialkylamine, 2-methyltetrahydrofuran, a compound of Structural Formula II: and a compound of Structural Formula III: to form a reaction mixture; (b) cooling the reaction mixture to from about −80° C. to about 0° C.; (c) treating the reaction mixture with propylphosphonic anhydride to provide a mixture comprising the compound of Structural Formula I; (d) isolating the compound of Structural Formula I from the mixture; (e) dissolving the isolated compound of Structural Formula I in a solvent system comprising acetonitrile; (f) inducing formation of solid particles of crystalline Form D of the compound of Structural Formula I and isolating the solid particles of crystalline Form D, wherein single crystalline Form D is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 3.7°, 7.3°, 10.9°, 18.3° and 21.9°; (g) suspending single crystalline Form D in isopropanol or a mixture of isopropanol and water to form a slurry; (h) heating the slurry to a temperature less than or equal to about 70° C. to form a second slurry or a solution; (i) cooling the second slurry or the solution and adding water to the second slurry or the solution, thereby forming solid particles of crystalline Form A of the compound of Structural Formula I; and (j) isolating the solid particles of crystalline Form A, thereby preparing single crystalline Form A of the compound of Structural Formula I.