PREFORMULATION STUDIES TO AID IN THE DEVELOPMENT OF A READY-TO-USE INJECTABLE SOLUTION OF THE ANTITUMOR AGENT, TOPOTECAN

Topotecan ((S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochlor ide; SKF-S-104864-A) is a promising anticancer agent that is currently available as a lyophilized formulation. To evaluate the feasibility o f formulating topotecan as a ready-to-use injectable solution, the pH- solubility profile was generated over a pH range of 2.5 to 4.5 at 25 d egrees C, and the pH-stability profile was generated over a pH range o f 2 to 4, a temperature range of 60-80 degrees C; and at an ionic stre ngth of similar to 0.15 M. The former experiments revealed that desira ble solubilities (i.e. 2.5 mg/ml in free base equivalents) are achieva ble at pH < 4, whereas extrapolation of the degradation kinetics to 25 degrees C indicated that desirable stabilities (i.e. less than or equ al to 2% degradation of topotecan over 2 years) are achievable at pH < 3. The stability results are consistent with a degradation mechanism involving deamination of topotecan proceeding through a reactive quino ne methide intermediate. Subsequent attack of water on this intermedia te gives the dihydroxylated product, 9-hydroxymethyl-10-hydroxycamptot hecin, which may then lose formaldehyde to form the monohydroxylated p roduct, 10-hydroxycamptothecin. The overall study results suggest that a solution pH of less than or equal to 2.5 is most appropriate for th e formulation of a ready-to-use solution. Prototype formulations meeti ng these criteria have been placed on long-term stability.