PROCESS FOR FREEZE DRYING CYCLOPHOSPHAMIDE - Patent Articles

(12) Patent: (11) CA 1215649
Application Number: (21) 457672
ABSTRACT:
PROCESS FOR FREEZE DRYING CYCLOPHOSPHAMIDE
ABSTRACT OF THE DISCLOSURE A two-stage process for freeze-drying an aqueous solution of a dosage amount of cyclophosphamide to yield a hydrate of cyclophosphamide
(referred to as "CPA" for brevity), comprises, in a first stage, freeze-drying asolution of CPA in combination with an excipient until the moisture content of the freeze-dried material is less than 2% by wt, based on the amount of anhydrous CPA present; and, in a second stage, rehydrating the freeze-dried material until the moisture content of the product is in the critical range of from about 2% to 7% by wt, based on the net wt of CPA product, it being essential for stability of the product that at least one sugar excipient be present. The process requires that a major amount by weight of the excipient(s) or all of it, be mannitol, optionally with an additional sugar and/or a carboxylic acid, and/or a buffer salt; and, the mannitol is present in an amount at least one-half (0.5 times) as much as the CPA (anhyd) present. To produce a dosage form of a 'plug' or 'cake' which is free of flakes and granules, or bubbles on its surface, and/or voids within the product (or "plug"), any of which are individually no greater than 2 mm in equivalent diameter
("equiv. dia."), requires a unique combination of carefully controlled process steps. The preferred CPA product obtained by the process provides a dosage amount of stable freeze-dried and rehydrated CPA as a hydrate which includes at least an equivalent amount by weight, and up to 5 times as much, of mannitol. The dosage amount may include sodium chloride to adjust tonicity, and a buffer salt to maintain pH.
(72) Inventors (Country): FRANCIS, DANIEL L. (United States)
(73) Owners (Country): CETUS-BEN VENUE THERAPEUTICS, A PARTNERSHIP (Not Available)
(71) Applicants (Country):
(74) Agent: GOWLING LAFLEUR HENDERSON LLP
(45) Issued: Dec. 23, 1986
(22) Filed: June 28, 1984
(41) Open to Public Inspection:
(52) Canadian Class (CPC): 167/264
(51) International Class (IPC): A61K 31/675
Patent Cooperation Treaty (PCT): No
(30) Application priority data: Application No. Country Date
612,626 United States May 21, 1984
524,899 United States Aug. 22, 1983
Availability of licence: N/A
Language of filing: English