Lyophilized cyclophosphamide composition and methods of preparation thereof
AssigneeAMPAC Fine Chemicals LLC
InventorsAndrew M. Smith, Timothy S. Dutill, Edward H. Trappler
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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.
Claims14
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;
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- (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.
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;
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- (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.
Dependencies are inferred from the claim text.