Effects of compression pressure on physical and chemical stability of tablets containing an anticancer drug TAT-59.

(E)-4-[1-[4-[2-(Dimethylamino)ethoxy]phenyl]-2-(4-isopropyl) phenyl]-1-butenyl]phenyl monophosphate (TAT-59) is a new drug for the treatment of breast cancer. Physical and chemical stability of mixtures of TAT-59 and microcrystalline cellulose (1:9) compressed at 0, 300, 600 and 1400 kg/cm2 was evaluated by determination of water content, porosity and the amount of hydrolysis product, DP-TAT-59, formed. The water contents and porosity of these tablets scarcely changed during 57 d at 25-60 degrees C under 50% relative humidity (RH). The degradation rate of TAT-59 increased with increasing compression pressure as well as temperature. The apparent activation energy and frequency factor were determined from an Arrhenius plot of the degradation rate. Activation energy of these tablets was almost the same, while the frequency factor tended to increase with increasing compression pressure. The porosity and pore sizes in TAT-59-containing tablets decreased with increasing compressive force. We speculated from these observations that the increase in compression pressure decreased the distance and increased the contact area between TAT-59 and microcrystalline cellulose. The proximity between TAT-59 and moisture presented at the surface of microcrystalline cellulose by compression was considered to enhance the degradation of TAT-59.