# US 10,370,402 B2 · Process for the preparation of fluticasone propionate form 1 > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,370,402 B2 - Document ID: US10370402B2 - Status: Granted - Kind: B2 - Application number: 14/131,407 - Filed: 2012-07-06 - Published: 2014-05-22 - Granted: 2019-08-06 - Earliest claimed: 2011-07-08 - Assignees: Pfizer Inc. - Applicants: Martyn David Ticehurst; Ivan Marziano; Eleftherios Kougoulos - Inventors: Martyn David Ticehurst; Ivan Marziano; Eleftherios Kougoulos - Web page: https://patentgrep.com/patent/US10370402B2 ## CPC - A61P 11/00: Drugs for disorders of the respiratory system - C07J 31/00: Normal steroids containing one or more sulfur atoms not belonging to a hetero ring - A61P 11/02: Nasal agents, e.g. decongestants - A61P 17/00: Drugs for dermatological disorders - A61P 17/06: Antipsoriatics - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - C07J 31/006: {not covered by C07J31/003} - A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles} - C07B 2200/13: Crystalline forms, e.g. polymorphs - Y10T 428/2982: Particulate matter [e.g., sphere, flake, etc.] - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07J: STEROIDS (seco-steroids C07C) - 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) - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) - Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION ## Abstract The invention relates to a novel crystallization process for preparing fluticasone propionate as crystalline form 1 polymorph with controlled particle size and suitable for micronization. Said process comprises the step of dissolving fluticasone propionate in acetone or in a mixture of acetone and water and then adding this solution to water or to a mixture of water 10 and acetone, thereby causing fluticasone propionate to crystallize out of the solution as crystalline form. ## Claims ### Claim 1 A process for preparing fluticasone propionate as crystalline polymorphic Form 1 having a controlled particle size, comprising: dissolving fluticasone propionate in a first volume of a solvent to form a solution; then adding the entire solution to a vessel containing a second volume of a non-solvent, forming a solvent/non-solvent slurry, thereby causing fluticasone propionate to crystallise out of the solution as crystalline Form 1; and, after said adding the entire solution is completed, holding the slurry, with agitation, in said vessel; wherein the solvent comprises acetone and from 0% to 10% water, based on the volume of the solvent; wherein the non-solvent comprises water and from 0% to 25% acetone, based on the volume of the non-solvent; and wherein the process is a batch process, and the controlled particle size has a 10th percentile volume diameter D[v, 0.1] of between 1.3 microns and 3.4 microns; a 50th percentile volume diameter D[v, 0.5] of between 2.8 microns and 11.4 microns; and a 90th percentile volume diameter D [v, 0.9] of between 5.6 microns and 32.1 microns. ### Claim 2 (depends on 1) A process according to claim 1, wherein fluticasone propionate is dissolved in the solvent in an amount between 30 and 50 grams per liter of solvent. ### Claim 3 (depends on 1) A process according to claim 1, wherein said adding the entire solution takes place at a temperature between about 10° C. and about 40° C. ### Claim 4 (depends on 3) A process according to claim 3, wherein said holding the slurry comprises stirring the slurry for a period of time, said period being between about 1 and about 12 hours, and wherein said holding is followed by filtration of the slurry to recover fluticasone propionate as crystalline Form 1 and drying of the recovered fluticasone propionate. ### Claim 5 (depends on 1) A process according to claim 1, wherein said adding the entire solution takes place over a period of between about 10 minutes and about 6 hours. ### Claim 6 (depends on 1) A process according to claim 1, wherein said adding the entire solution occurs via a pump in the form of pulsed aliquots. ### Claim 7 (depends on 6) A process according to claim 6, wherein said holding the slurry comprises stirring the slurry for a period of time, said period being between about 1 and about 12 hours, and wherein said holding is followed by filtration of the slurry to recover fluticasone propionate as crystalline Form 1 and drying of the recovered fluticasone propionate. ### Claim 8 (depends on 1) A process according to claim 1, wherein said adding the entire solution occurs over a period of between about 10 minutes and about 6 hours via a pump in the form of pulsed aliquots. ### Claim 9 (depends on 1) The process according to claim 1, wherein holding the slurry comprises stirring the slurry for a period of between about 1 and about 12 hours. ### Claim 10 (depends on 1) A process according to claim 1, wherein said holding the slurry comprises stirring the slurry for a period of time, said period being between about 1 and about 12 hours, and wherein said holding is followed by filtration of the slurry to recover fluticasone propionate as crystalline Form 1 and drying of the recovered fluticasone propionate. ### Claim 11 (depends on 1) The process according to claim 1, wherein a ratio of the first volume of the solvent to the second volume of the non-solvent is between 1:0.65 and 1:1.35. ### Claim 12 (depends on 1) The process according to claim 1, wherein: the non-solvent is water, and a ratio of the first volume of the solvent to the second volume of the non-solvent is 1:1. ### Claim 13 (depends on 1) The process according to claim 1, wherein: the non-solvent is a mixture of water and about 25% acetone, and a ratio of the first volume of the solvent to the second volume of the non-solvent is 1:1. ### Claim 14 A process for preparing fluticasone propionate as crystalline polymorphic Form 1 having a controlled particle size, comprising: dissolving fluticasone propionate in a first volume of a solvent to form a solution; and then adding the entire solution to a vessel containing a second volume of a non-solvent, forming a solvent/non-solvent slurry, thereby causing fluticasone propionate to crystallise out of the solution as crystalline Form 1; wherein the solvent comprises acetone and from 0% to 10% water, based on the volume of the solvent; wherein the non-solvent comprises water and from 0% to 25% acetone, based on the volume of the non-solvent; wherein after the step of adding the entire solution to the non-solvent is completed, the solvent/non-solvent slurry is stirred in said vessel over a period of between about 1 and about 12 hours followed by filtration of the slurry to recover fluticasone propionate as crystalline Form 1 and drying of the recovered fluticasone propionate; and wherein the process is a batch process, and the controlled particle size has a 10th percentile volume diameter D[v, 0.1] of between 1.3 microns and 3.4 microns; a 50th percentile volume diameter D[v, 0.5] of between 2.8 microns and 11.4 microns; and a 90th percentile volume diameter D [v, 0.9] of between 5.6 microns and 32.1 microns. ### Claim 15 (depends on 14) The process according to claim 14, wherein the period of time is between about 1 and about 8 hours. ### Claim 16 A process for preparing fluticasone propionate as crystalline polymorphic Form 1 having a defined median particle size, comprising: dissolving fluticasone propionate in a first volume of a solvent ‘to form a solution; then adding the entire solution to a container of a second volume of a water-containing nonsolvent, thereby causing fluticasone propionate to crystallize out of the solution as crystalline Form 1 in a solvent/non-solvent slurry and, after the adding the entire solution is completed; stirring the solvent/non-solvent slurry in the container for a period of between about 1 and about 12 hours in the absence of ultrasound; and removing the solvent/non-solvent slurry from the container after the stirring and recovering fluticasone propionate Form 1 by filtration of the solvent/non-solvent slurry, wherein the solvent comprises acetone and from 0% to 10% water, based on the volume of the solvent; and wherein the non-solvent comprises water and from 0% to 25% acetone, based on the volume of the non-solvent; and, wherein the process is a batch process, and the controlled particle size has a 10th percentile volume diameter D[v, 0.1] of between 1.3 microns and 3.4 microns; a 50th percentile volume diameter D[v, 0.5] of between 2.8 microns and 11.4 microns; and a 90th percentile volume diameter D [v, 0.9] of between 5.6 microns and 32.1 microns. ### Claim 17 (depends on 16) The process according to claim 16, wherein the non-solvent is pure water, and the defined median particle size is between about 2.8 microns and about 6.7 microns. ### Claim 18 (depends on 16) The process according to claim 16, wherein the non-solvent comprises water and 25% acetone, and the defined median particle size is between about 11.4 microns and about 20 microns. ### Claim 19 (depends on 16) The process according to claim 16, wherein the period of time is between about 1 and about 8 hours.