# US 10,307,431 B2 · Lyophilized cyclophosphamide composition and methods of preparation thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,307,431 B2 - Document ID: US10307431B2 - Status: Granted - Kind: B2 - Application number: 15/813,736 - Filed: 2017-11-15 - Published: 2018-09-13 - Granted: 2019-06-04 - Earliest claimed: 2017-03-09 - Assignees: AMPAC Fine Chemicals LLC - Applicants: AMPAC Fine Chemicals LLC - Inventors: Andrew M. Smith; Timothy S. Dutill; Edward H. Trappler - Web page: https://patentgrep.com/patent/US10307431B2 ## CPC - A61K 31/661: Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos} - A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} - A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin - 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) ## Abstract An improved lyophilized cyclophosphamide solid composition is described. The lyophilized cyclophosphamide solid composition is thermally stable, contains anhydrous cyclophosphamide and mannitol, and is substantially free of cyclophosphamide monohydrate. A method for preparing the lyophilized cyclophosphamide solid composition is also provided. ## Claims ### Claim 1 A process for producing a lyophilized cyclophosphamide solid composition having a moisture content of less than 2% by weight, the process comprising: (1) preparing a solution containing cyclophosphamide, mannitol, and water; (2) filling a receptacle with the solution; (3) inserting the receptacle filled with the solution into a lyophilizer having a first shelf temperature of 0° C. to 25° C., and maintaining the first shelf temperature to allow all the solution to equilibrate at the first shelf temperature; (4) cooling the lyophilizer to a second shelf temperature of −75° C. to −30° C. at a first controlled rate, and maintaining the second shelf temperature to allow the solution to form ice and to allow the temperature of the ice to reach a steady state; (5) chilling a condenser of the lyophilizer to a temperature below −40° C.; (6) evacuating a chamber of the lyophilizer to a pressure of less than 4500 μm Hg; (7) warming the lyophilizer to a third shelf temperature of −30° C. to 40° C. at a second controlled rate, and maintaining the third shelf temperature and the chamber pressure at the pressure of less than 4500 μm Hg to allow sublimation of the ice and thereby produce a sublimed composition; and (8) setting the lyophilizer to a fourth shelf temperature of 0° C. to 40° C., and maintaining the fourth shelf temperature and the chamber pressure at the pressure of less than 4500 μm Hg to desorb remaining moisture and thereby produce the lyophilized cyclophosphamide solid composition having a moisture content of less than 2% by weight. ### Claim 2 (depends on 1) The process according to claim 1, wherein in step (1), the solution is prepared by a method comprising: (a) adding mannitol to water to obtain a mannitol solution; (b) chilling the mannitol solution to 0° C. to 20° C.; and (c) admixing cyclophosphamide monohydrate to the mannitol solution at 0° C. to 20° C. to obtain the solution containing cyclophosphamide, mannitol, and water. ### Claim 3 (depends on 2) The process according to claim 2, wherein the solution is sterilized. ### Claim 4 (depends on 2) The process according to claim 2, wherein the cyclophosphamide monohydrate has a particle size of d(0.5) particle size distribution of 100-400 μm. ### Claim 5 (depends on 1) The process according to claim 1, wherein the solution contains 5 to 25 mg/mL cyclophosphamide monohydrate and 5 to 25 mg/mL mannitol. ### Claim 6 (depends on 1) The process according to claim 1, wherein in step (3), the first shelf temperature is maintained for 1 to 15 hours, in step (4), the lyophilizer is cooled to the second shelf temperature at an average rate of 6 to 120 ° C. per hour and the second shelf temperature is maintained for 1 to 20 hours, and in step (7), the lyophilizer is warmed to the third shelf temperature at an average rate of 6 to 120 ° C. per hour and the third shelf temperature and the chamber pressure at the pressure of less than 4500 μm Hg are maintained for 10 to 360 hours. ### Claim 7 (depends on 1) The process according to claim 1, wherein after cooling the lyophilizer to the second shelf temperature of −75° C. to −30° C. and prior to chilling of the condenser, the process further comprises warming the lyophilizer to a shelf temperature of −20° C. to -10° C. at a controlled rate, then cooling the lyophilizer back to the second shelf temperature of −75° C. to −30° C. at a controlled rate, and maintaining the second shelf temperature to allow the solution to form ice and to allow the temperature of the ice to reach a steady state. ### Claim 8 (depends on 1) The process according to claim 1, further comprising raising the pressure of the chamber of the lyophilizer to about 1 to 14.7 psia and stoppering the container. ### Claim 9 A process for producing a lyophilized cyclophosphamide solid composition having a moisture content of less than 2% by weight, the process comprising: (1) preparing a solution consisting of cyclophosphamide, mannitol, and water; (2) filling a receptacle with the solution; (3) inserting the receptacle filled with the solution into a lyophilizer having a first shelf temperature of 0° C. to 10° C., and maintaining the first shelf temperature to allow all the solution to equilibrate at the first shelf temperature; (4) cooling the lyophilizer to a second shelf temperature of −55° C. to −40° C. at a first controlled rate, and maintaining the second shelf temperature to allow the solution to form ice and to allow the temperature of the ice to reach a steady state; (5) chilling a condenser of the lyophilizer to a temperature of −50° C. or below; (6) evacuating a chamber of the lyophilizer to a pressure of 150-250 μm Hg; (7) warming the lyophilizer to a third shelf temperature of 5° C. to 15° C. at a second controlled rate, and maintaining the third shelf temperature and the chamber pressure at the pressure of 150-250 μm Hg to allow sublimation of the ice and thereby produce a sublimed composition; and (8) setting the lyophilizer to a fourth shelf temperature of 0° C. to 30° C., and maintaining the fourth shelf temperature and the chamber pressure at the pressure of 150-250 μm Hg to desorb remaining moisture and thereby produce the lyophilized cyclophosphamide solid composition having a moisture content of less than 2% by weight. ### Claim 10 (depends on 9) The process according to claim 9, wherein in step (1), the solution is prepared by a method comprising: (a) adding mannitol to water to obtain a mannitol solution; (b) chilling the mannitol solution to 0° C. to 20° C.; and (c) admixing cyclophosphamide monohydrate to the mannitol solution at 0° C. to 20° C. to obtain the solution consisting of cyclophosphamide, mannitol, and water. ### Claim 11 (depends on 10) The process according to claim 10, wherein the cyclophosphamide monohydrate has a particle size of d(0.5) particle size distribution of 100-400 μm. ### Claim 12 (depends on 9) The process according to claim 9, wherein the solution contains 5 to 25 mg/mL cyclophosphamide monohydrate and 5 to 25 mg/mL mannitol. ### Claim 13 (depends on 1) The process according to claim 1, wherein, in step (4), the lyophilizer is cooled to the second shelf temperature at an average rate of 6° C. to 30° C. per hour. ### Claim 14 (depends on 9) The process according to claim 9, wherein, in step (4), the lyophilizer is cooled to the second shelf temperature at an average rate of 6° C. to 30° C. per hour.