Yoshioka S, Aso Y, Kojima S
National Institute of Health Sciences, Tokyo, Japan.
Pharm Res. 2000 Aug;17(8):925-9. doi: 10.1023/a:1007566919000.
We studied the temperature dependence of acetyl transfer between aspirin and sulfadiazine, a bimolecular reaction, in lyophilized formulations at temperatures near the glass transition temperature (Tg) and NMR relaxation-based critical mobility temperature (Tmc), to further understand the effect of molecular mobility on chemical degradation rates in solid pharmaceutical formulations. The temperature dependence of the hydrolysis rates of aspirin and cephalothin in lyophilized formulations was also studied as a model of bimolecular reactions in which water is a reactant.
Degradation of lyophilized aspirin-sulfadiazine formulations containing dextran and various amounts of water at temperatures ranging from 1 degrees C to 80 degrees C was analyzed by HPLC. The degradation of cephalothin in lyophilized formulations containing dextran and methylcellulose was also analyzed at temperatures ranging from 10 degrees C to 70 degrees C.
Acetyl transfer in lyophilized aspirin--sulfadiazine formulations containing dextran exhibited a temperature dependence with a distinct break around Tmc, which may be ascribed to a change in the translational mobility of aspirin and sulfadiazine molecules. The hydrolysis of aspirin and cephalothin in lyophilized formulations, which is also a bimolecular reaction, did not show a distinct break, suggesting that water diffusion is not rate-limiting.
The diffusion barrier of water molecules in lyophilized formulations appears to be smaller than the activational barrier of the hydrolysis of aspirin and cephalothin based on the results of this study that the temperature dependence of the hydrolysis rate is almost linear regardless of Tmc and Tg. On the other hand, the diffusion barrier of aspirin and sulfadiazine molecules appears to be comparable to the activational barrier of the acetyl transfer reaction between these compounds, resulting in nonlinear temperature dependence.
我们研究了阿司匹林与磺胺嘧啶之间乙酰基转移（一种双分子反应）在冻干制剂中，于接近玻璃化转变温度（Tg）和基于核磁共振弛豫的临界迁移温度（Tmc）的温度下对温度的依赖性，以进一步了解分子迁移率对固体药物制剂中化学降解速率的影响。还研究了冻干制剂中阿司匹林和头孢噻吩水解速率对温度的依赖性，以此作为水作为反应物的双分子反应模型。
通过高效液相色谱法分析含右旋糖酐和不同水量的冻干阿司匹林 - 磺胺嘧啶制剂在1℃至80℃温度范围内的降解情况。还分析了含右旋糖酐和甲基纤维素的冻干制剂中头孢噻吩在10℃至70℃温度范围内的降解情况。
含右旋糖酐的冻干阿司匹林 - 磺胺嘧啶制剂中的乙酰基转移表现出对温度的依赖性，在Tmc附近有明显的转折点，这可能归因于阿司匹林和磺胺嘧啶分子平移迁移率的变化。冻干制剂中阿司匹林和头孢噻吩的水解（也是一种双分子反应）未显示出明显的转折点，这表明水的扩散不是限速步骤。
基于本研究结果，即无论Tmc和Tg如何，水解速率的温度依赖性几乎呈线性，冻干制剂中水分子的扩散屏障似乎小于阿司匹林和头孢噻吩水解的活化屏障。另一方面，阿司匹林和磺胺嘧啶分子的扩散屏障似乎与这些化合物之间乙酰基转移反应的活化屏障相当，导致温度依赖性呈非线性。
