# US 10,370,376 B2 · Amorphous substance of Idelalisib and preparation method therefor > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,370,376 B2 - Document ID: US10370376B2 - Status: Granted - Kind: B2 - Application number: 15/783,207 - Filed: 2017-10-13 - Published: 2018-02-08 - Granted: 2019-08-06 - Earliest claimed: 2015-04-15 - Assignees: Alnova Pharmaceuticals, Ltd. - Applicants: Alnova Pharmaceuticals, Ltd. - Inventors: Xini Zhang; Zhigang Xiong; Tao Hu - Web page: https://patentgrep.com/patent/US10370376B2 ## CPC - C07D 473/34: attached in position 6, e.g. adenine - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 35/00: Antineoplastic agents - A61P 37/00: Drugs for immunological or allergic disorders - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to an amorphous form of Idelalisib and its methods of preparation. Using a Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern does not contain sharp diffraction peaks at a diffraction angle expressed in degrees 2θ, and the X-ray powder diffraction pattern is shown in FIG. 1. The present invention also provides a preparation method for the amorphous form of Idelalisib. The amorphous form of Idelalisib of the present invention increases the solubility of Idelalisib and improves bioavailability of the drug product. As compared to the existing crystalline forms of Idelalisib, its solubility increases significantly, which improves body's absorption of the drug and makes it more efficacious in the clinical therapeutic treatment of diseases. Under the stress test conditions, the amorphous material can maintain good physical and chemical stabilities. The preparation method of amorphous Idelalisib according to the present invention is simple to operate and easy to implement. ## Claims ### Claim 1 A method for preparing an amorphous form of Idelalisib, comprising the steps of: 1) dissolving 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone in a solvent I selected from the group consisting of ether, halohydrocarbon, alcohol, amide, sulfoxide, and sulfone, each containing 8 or fewer carbons, to form a solution with a concentration of 0.01 to 1 g/ml; 2) adding the solution obtained from step 1) to a solvent II selected from hydrocarbons at temperature −80 to 100° C. to form a suspension, wherein the volume ratio of the solution obtained from step 1) and solvent II is 1:1 to 200; and 3) filtering the suspension formed in step 2) and drying the filter cake to obtain the amorphous form of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone. ### Claim 2 A method for preparing an amorphous Idelalisib, comprising: 1) dissolving 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone in an aqueous acid solution to form an acidic solution with a concentration of 0.01 to 1 g/ml; wherein molar ratio of the acid and 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone in the aqueous acid solution is 1 to 20:1; 2) adding the acidic solution obtained in step 1) to an aqueous base solution, and adjusting pH value to not less than 10, at the temperature of −50 to 100° C., to form a suspension, the volume ratio of the acidic solution and the aqueous base solution is 1:1 to 100; wherein, the molar ratio of the base in the aqueous base solution and the acid in the aqueous acid solution is 0.3 to 10:1; and 3) filtering the suspension formed in step 2), and drying the filter cake, to obtain amorphous 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone. ### Claim 3 (depends on 2) The method of claim 2, wherein the aqueous acid solution or the aqueous base solution comprises an organic solvent, and the organic solvent is selected from at least one of water-miscible alcohol, ether, ketone, and nitrile, each containing 8 or fewer carbons. ### Claim 4 (depends on 2) The method of claim 2, wherein the acid in the aqueous acid solution is selected from at least one of hydrochloric acid, sulfuric acid, alkyl sulfonic acid, aryl sulfonic acid, nitric acid, phosphoric acid, and trifluoroacetic acid. ### Claim 5 (depends on 2) The method of claim 2, wherein the base in the aqueous base solution is selected from at least one of alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen phosphate, and alkali metal phosphate. ### Claim 6 (depends on 3) The method of claim 3, wherein the acid in the aqueous acid solution is selected from at least one of hydrochloric acid, sulfuric acid, alkyl sulfonic acid, aryl sulfonic acid, nitric acid, phosphoric acid, and trifluoroacetic acid. ### Claim 7 (depends on 3) The method of claim 3, wherein the base in the aqueous base solution is selected from at least one of alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen phosphate, and alkali metal phosphate. ### Claim 8 A method for preparing an amorphous form of Idelalisib, comprising the steps of: 1) dissolving 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone in a solvent I selected from the group consisting of ether, halohydrocarbon, alcohol, amide, sulfoxide, and sulfone, each containing 8 or fewer carbons, to form a solution with a concentration of 0.01 to 1 g/ml; 2) adding the solution obtained from step 1) to a solvent II selected from hydrocarbons at temperature −80 to 100° C. to form a suspension, wherein the volume ratio of the solution obtained from step 1) and solvent II is 1:1 to 200; 3) filtering the suspension formed in step 2) and drying the filter cake to obtain the amorphous form of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone. ### Claim 9 (depends on 8) The method of claim 8, wherein the solvent I is selected from the group consisting of dichloromethane, tetrahydrofuran, N,N,-dimethylformamide, and methanol. ### Claim 10 (depends on 8) The method of claim 8, wherein the solvent II is selected from the group consisting of hexanes, heptanes, octanes, and water. ### Claim 11 (depends on 1) The method of claim 1, wherein the solvent I is selected from the group consisting of dichloromethane, tetrahydrofuran, N,N,-dimethylformamide, and methanol. ### Claim 12 (depends on 1) The method of claim 1, wherein the solvent II is selected from the group consisting of hexanes, heptanes, octanes, and water.