Degradation of NSC-281612 (4-[bis[2-[(methylsulfonyl)oxy]ethyl]amino]-2-methyl-benzaldehyde), an experimental antineoplastic agent:: Effects of pH, solvent composition, (SBE)7m-β-CD, and HP-β-CD on stability
Degradation of NSC-281612 (4-[bis[2-[(methylsulfonyl)oxy]ethyl]amino]-2-methyl-benzaldehyde), an experimental antineoplastic agent:: Effects of pH, solvent composition, (SBE)7m-β-CD, and HP-β-CD on stability
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DOI：
10.1002/jps.10571
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发表时间：
2004-03-01
影响因子：
3.8
通讯作者：
Stella, VJ
中科院分区：
文献类型：
--
作者：
Jumaa, M;Chimilio, L;Stella, VJ
NSC-281612（4-F双[2-[（甲磺酰基）氧基]乙基]氨基]-2-甲基-苯甲醛，1）是一种化学性质不稳定、水溶性差的实验性防腐剂。在25 ℃下在水中的饱和溶解度被确定为类似于30 μ g/mL。在pH 2-11范围内，1显示pH非依赖性稳定性（t（50）约为24小时）。然而，在pH 12下观察到降解速率增加。在无缓冲剂和添加卤离子的情况下，甲烷磺酸盐基团水解为相应的羟基是水中的主要降解途径。在不含氯化钠的磷酸盐缓冲液中，除了单羟基和二羟基降解产物外，似乎还形成磷酸盐降解产物。当用氯化钠调节溶液的离子强度时，形成了其他降解产物，即单氯和二氯降解产物。当加入溴离子和碘离子时，形成相应的一卤化物和二卤化物。氯代化合物随后进一步降解为羟基产物。氘动力学溶剂同位素效应的研究表明，水是最低限度地参与速率决定步骤。添加（SBE）（7 m）-β-环糊精（CD）或HP-β-CD导致药物溶解度和稳定性的显著增强。HP-β-CD和（SBE）（7 m）-β-CD的表观结合常数分别为1，486和2，740 M-1。在0.1M HP-β-CD和（SBE）（7 m）-β-CD存在下，1的稳定性分别增强9倍和15倍。因此，（SBE）（7 m）-β-CD显示出比HP-β-CD更好的增溶和稳定功效。(C)2004Wiley-Liss，Inc.
NSC-281612 (4- Fbis[2-[(methylsulfonyl)oxy]ethyl]amino]-2-methyl-benz aldehyde, 1), is a chemically unstable, poorly water soluble, experimental antineoplastic agent. The saturated solubility in water at 25degreesC was determined as similar to30 mug/mL. In the pH range 2-11, 1 displayed pH-independent stability (t(50) was around 24 hr). However, an increase in the degradation rate was observed at pH 12. The hydrolysis of the methane sulfonate groups to the corresponding hydroxyl groups was the major degradation pathway in water in the absence of buffers and added halide ions. In phosphate buffer solutions without sodium chloride, phosphate degradants appear to be formed in addition to the mono- and dihydroxy degradants. Additional degradants, the mono- and dichloro degradation products, were formed when the ionic strength of the solution was adjusted with sodium chloride. When bromide and iodide ions were added, the corresponding mono-and dihalides were formed. The chloro compounds subsequently underwent further degradation to the hydroxy products. A deuterium kinetic solvent isotope effect study showed that water was minimally involved in the rate-determining step. The addition of either (SBE)(7m)-beta-cyclodextrin (CD) or HP-beta-CD resulted in a significant enhancement in drug solubility and stability. The apparent binding constants for HP-beta-CD and (SBE)(7m)-beta-CD were 1,486 and 2,740 M-1, respectively. The stability of 1 in the presence of 0.1M HP-beta-CD and (SBE)(7m)-beta-CD was enhanced 9- and 15-fold, respectively. Thus, (SBE)(7m)-beta-CD displayed better solubilization and stabilization efficacy than HP-beta-CD. (C) 2004Wiley-Liss, Inc.