Matsunaga Y, Bando N, Yuasa H, Kanaya Y
Pharmaceutical Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Chem Pharm Bull (Tokyo). 1994 Dec;42(12):2582-7. doi: 10.1248/cpb.42.2582.
(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.
（E）-4-[1-[4-[2-（二甲氨基）乙氧基]苯基]-2-（4-异丙基）苯基]-1-丁烯基]苯基单磷酸酯（TAT-59）是一种用于治疗乳腺癌的新药。通过测定含水量、孔隙率以及形成的水解产物DP-TAT-59的量，评估了在0、300、600和1400 kg/cm²压力下压制的TAT-59与微晶纤维素混合物（1:9）的物理和化学稳定性。在25至60摄氏度、50%相对湿度（RH）条件下放置57天期间，这些片剂的含水量和孔隙率几乎没有变化。TAT-59的降解速率随压制压力和温度的升高而增加。根据降解速率的阿仑尼乌斯图确定了表观活化能和频率因子。这些片剂的活化能几乎相同，而频率因子倾向于随压制压力的增加而增大。含TAT-59片剂中的孔隙率和孔径随压力增加而减小。从这些观察结果推测，压制压力的增加减小了TAT-59与微晶纤维素之间的距离并增加了接触面积。压制使TAT-59与微晶纤维素表面存在的水分接近，这被认为会促进TAT-59的降解。
