FREEZE-DRIED, POWDERY CYCLOPHOSPHAMIDE COMPOSITION, AS WELL AS PROCESS FOR ITS PREPARATION

Abstract: The invention relates to a freeze-dried, powdery cyclophosphamide compo­ sition which contains the cyclophosphamide-monohydrate without any addi­ tion. Also the invention provides a process for preparing such a compo­ sition by freeze-drying the cyclophosphamide without any addition and controlling the freeze-drying conditions in such a way that the monohy­ drate is obtained.

Description: The invention relates to a freeze-dried, powdery pharmaceutically acceptable cyclophosphamide and to a process for preparing same. Freeze-dried powdery cyclophosphamide compositions are known in several forms, as appears e.g. from Journal of Parenteral Science and Technology, Vol. 42, no. 1, pages 29-37 and no 5, pages 165-173. According to the abovementioned articles, cyclosphosphamide, mixed with a carrier was freeze-dried to a completely anhydrous product and then wetted, in most cases yielding the monohydrate. From the abovementioned articles it further appears that the stability of-in particular a mixture of cyclophosphamide with mannitol is substantially improved if the cyclophosmamide is converted to the monohydrate. According to the first mentioned article it was already known that cyclosphosphamide-monohydrate is crystaline and stable at room temperature, but quickly decomposes at elevated temperatures and in aqueous solution. Very little was known of the stability of freeze-dried cyclophosphamide. In the abovementioned articles no experiments with freeze-dried cyclophosphamide-monohydrate have been reported, but the monohydrate was prepared from the freeze-dried anhydrate and only tested for stability in solution. In the past a pharmaceutical composition has been marketed which contains the cyclophosphamide-monohydrate in the form of a coarse powder, mixed with common salt for the purpose of making it isotonic, but in the meantime this composition has been replaced by the freeze-dried mixture of cyclophosphamide-monohydrate and mannitol. Further references illustrating the above state of the art are US-A-4,537,883 and EP-A-271622. The latter reference discloses on page 3, lines 14 a.f. that "CPA-hydrate, whether by itself, or with an excipient, is known to defy freeze-drying so as to give a pharmaceutically elegant product" by "pharmaceutically elegant product" a visually pleasing product is meant. Furthermore , it is stated in this reference on page 4, lines 35/36 that effords to freeze-dry CPA-monohydrate without any addition were not successful. "Rote Liste 1989" number 85006 relates to a composition of cyclosphosphamide-monohydrate in the form of dragees and powders with can be reconstituted for injection. There is no indication that this product would not have been prepared in accordance with the above principles, and it is mentioned that storage prescriptions should be given. The compositions according to the above discussed state of the art also have the drawback that the cyclophosphamide is always delivered in a mixture with another substance. It has now been found that freeze-dried, powdery pharmaceutically acceptable cyclophosphamide can be obtained in the form of "pure" cyclophosphamide-monohydrate without any further addition. ("Pure" referring to to a monohydrate without any hydrates being present). In addition to the above product, the invention provides a process for preparing a freeze-dried, powdery pharmaceutically acceptable cyclophosphamide, which is characterized by the fact that the cyclophosphamide is freeze-dried without any addition and the freeze-drying conditions are controlled in such a way that pure monohydrate is obtained. The freeze-dried cyclophosphamide-monohydrate according to the invention is not only stable, but has the further advantage that it has a satisfactory appearance and dissolves quickly, while it does not contain any further addition. Freeze-drying cyclophosphamide in such a way that pure monohydrate is obtained, per se does not offer particular difficulties. Of course, the correct conditions are dependent on the used freeze-drying apparatus. The following examples describe experiments with freeze-drying apparatus which are now used the applicant. However, it should be stressed here that when using other apparatus the optimum conditions thereof may be different. Example 1 Freeze-drying of 100 vials of cyclophosphamide, 500 mg A perfect monohydrate was obtained. Example 2 Freeze-drying of 100 vials of cyclophosphamide, 100 mg A perfect monohydrate was obtained. Example 3 Freeze-drying of 1200 vials of cyclophosphamide, 100 mg A perfect monohydrate was obtained. Stability tests The products of the above examples which were glass vials, containing the amounts of cyclophosphamide-monohydrate mentioned in the examples were stored at a temperature of 22-25°C. The results are indicated in the following tables. In these tables n.c. means (not changed).

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Freeze-dried, powdery, pharmaceutically acceptable cyclosphosphamide, characterised by the fact that it is pure cyclosphosphamide-monohydrate without any further addition. Process for preparing freeze-dried, powdery, pharmaceutically acceptable cyclophosphamide, characterized by the fact that cyclophosphamide is freeze-dried without any further addition and the freeze-drying conditions are controlled in such a way that pure monohydrate is obtained. Claims for the following Contracting States : ES, GR Process for preparing freeze-dried, powdery pharmaceutically acceptable cyclophosphamide, characterized by the fact that cyclophosphamide is freeze-dried without any further addition and the freeze-drying conditions are controlled in such a way that pure monohydrate is obtained.

Inventors: NIJKERK, ALFRED JAMES, VERMEER, JOHANNA MARIA PIETERNELLA
Applicants: PHARMACHEMIE B.V.
Application year: 1990
Main classification: A61K31
IPC codes: A61K9, A61K31