Method for hydrating lyophilized cyclophosphamide composition and product thereof
Provided are a hydration method for a lyophilized cyclophosphamide composition and a composition and preparation prepared thereby. The hydration method comprises: (a) providing an aqueous solution comprising cyclophosphamide and an optional pharmaceutically acceptable excipient; (b) freeze-drying the solution to obtain a lyophilized composition; and (c) hydrating the lyophilized composition by using liquid water to obtain the product.
1. An injectable composition, comprising cyclophosphamide and mannitol,
wherein the porosity of the composition is greater than 96%, and
the composition has a moisture content of 7.8% to about 9.0%, based on cyclophosphamide monohydrate.
2. A method for making the injectable composition of claim 1 , comprising:
(a) providing an aqueous solution comprising cyclophosphamide and mannitol;
(b) freeze-drying the aqueous solution to give a solid composition; and
(c) hydrating the solid composition with vapor phase moisture from liquid water to give the injectable composition.
3. The method according to claim 2 , wherein the liquid water is a water solution.
4. The method according to claim 3 , wherein the water solution comprises a strong acid, a strong alkali, an inorganic salt, a glycerol, a pharmaceutically acceptable excipient or inorganic salt.
5. The method according to claim 4 , wherein the water solution provides a relative humidity during (c) of about 60% to about 98%.
6. The method according to claim 2 , wherein the hydrating is performed under a micro negative pressure of about 10-90 kPa.
7. The method of claim 4 , wherein the relative humidity during (c) is about 70% to about 95%.
8. The injectable composition of claim 1 ,
wherein the particle size distribution of the composition is characterized by a D50 value of less than 11.0 μm,
the bulk density of the composition is less than about 0.0600 g/mL, and
at least about 99% of the cyclophosphamide is retained after 3 weeks at 45° C.
9. The injectable composition of claim 8 , wherein a redissolving time of 500 mg of the composition in 25 ml of a 0.9% NaCl aqueous solution with cyclotron mixing in a glass vial oscillate at 250 rpm at room temperature is less than 2 minutes.
10. The injectable composition of claim 8 , wherein the tapped density of the composition is less than about 0.3000 g/mL.
11. The injectable composition of claim 8 , wherein the skeletal density of the composition is greater than 1.4700 g/mL.
12. The injectable composition of claim 8 , wherein the particle size distribution of the composition is characterized by a D90 value of less than 36.0 μm.
13. The injectable composition of claim 12 , wherein the particle size distribution of the composition is characterized by a D90 value of less than 29.0 μm.
14. The injectable composition of claim 8 , wherein the mannitol comprises δ-mannitol.
15. The injectable composition of claim 14 , wherein the mannitol consists of δ-mannitol.
16. The injectable composition of claim 8 , wherein the composition comprises less than 0.1% cyclophosphamide impurity B, as measured by HPLC, after the composition is maintained at a temperature of about 45° C. for up to 7 days.
17. The injectable composition of claim 8 , wherein the composition comprises less than 0.1% cyclophosphamide impurity A, as measured by HPLC, after the composition was maintained at a temperature of about 45° C. for up to 7 days.
18. The injectable composition of claim 1 , wherein the composition has a moisture content of 8.0% to about 9.0%, based on cyclophosphamide monohydrate.