Aqueous fludarabine phosphate composition

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the discovery that an aqueous fludarabine phosphate composition having enhanced stability at elevated temperatures may be prepared by controlling the pH of the composition.
The present invention is directed to an injectable aqueous fludarabine phosphate composition which comprises fludarabine phosphate, a base, and water, and has a pH from about 5.
5 to 7.
1.
As used herein, the term "elevated temperatures" refers to temperatures at or above ambient temperatures.
The term "ambient temperature" refers to temperatures ranging from about 22.
degree.
C.
to about 28.
degree.
C.
The term "enhanced stability" refers to an aqueous fludarabine phosphate composition which, when compared to another aqueous fludarabine phosphate composition, contains at least 0.
8% less of fludarabine phosphate 2-hydroxy analog and at least 1.
0% less total fludarabine degradation products when both compositions are subjected to a temperature of 40.
degree.
C.
for a period of 1 month.
For example, the term "enhanced stability" may be used to distinguish between two otherwise comparable aqueous fludarabine phosphate compositions as follows: Two aqueous fludarabine phosphate compositions, A and B, differ only in the pH of the respective compositions.
Compositions A and B have pH values of 6.
5 and 7.
7, respectively.
After storing both compositions at 40.
degree.
C.
for 1 month, composition A is found to contain a level of fludarabine phosphate 2-hydroxy analog that is less that the level of quantitation (i.
e, less than 0.
1%) and a total fludarabine phosphate impurity level of 0.
2%, whereas composition B is found to contain a level of fludarabine phosphate 2-hydroxy analog of 0.
8% and a total fludarabine phosphate impurity level of 1.
3%.
Composition A has "enhanced stability" with respect to composition B because composition B showed a level of fludarabine phosphate 2-hydroxy analog at least 0.
8% greater than that of composition A and a total fludarabine phosphate impurity level at least 1