Tombari E, Presto S, Johari G P, Shanker Ravi M
Istituto per i Processi Chimico-Fisici del CNR, 56124, Pisa, Italy.
Pharm Res. 2008 Apr;25(4):902-12. doi: 10.1007/s11095-007-9444-8. Epub 2007 Sep 27.
To determine the calorimetric relaxation time needed for modeling griseofulvin's stability against crystallization during storage.
Both temperature-modulated and unmodulated scanning calorimetry have been used to determine the heat capacity of griseofulvin in the glassy and melt state.
The calorimetric relaxation time, tau cal, of its melt varies with the temperature T according to the relation, tau cal [s] = 10(-13.3) exp [2, 292 /(T[K] - 289.5)] , and the distribution of relaxation times parameter is 0.67. The unrelaxed heat capacity of the griseofulvin melt is equal to its vibrational heat capacity.
Griseofulvin neither crystallizes on heating to 373 K at 1 K/h rate, nor on cooling. Molecular mobility and vibrational heat capacity measured here are more reliable for modeling a pharmaceutical's stability against crystallization than the currently used kinetics-thermodynamics relations, and molecular mobility in the (fixed structure) glassy state is much greater than the usual extrapolation from the melt state yields. Molecular relaxation time of the glassy state of griseofulvin is about 2 months at 298 K, and longer at lower temperatures. It would spontaneously increase with time. If the long-range motions alone were needed for crystallization, griseofulvin would become more stable against crystallization during storage.
确定在储存过程中模拟灰黄霉素抗结晶稳定性所需的量热弛豫时间。
采用温度调制和非调制扫描量热法测定灰黄霉素在玻璃态和熔融态的热容量。
其熔融态的量热弛豫时间τcal随温度T的变化关系为τcal [s] = 10(-13.3) exp [2, 292 /(T[K] - 289.5)]，弛豫时间参数分布为0.67。灰黄霉素熔融态的未弛豫热容量等于其振动热容量。
灰黄霉素在以1 K/h的速率加热至373 K时或冷却时均不会结晶。此处测得的分子迁移率和振动热容量对于模拟药物的抗结晶稳定性比目前使用的动力学 - 热力学关系更可靠，并且（固定结构）玻璃态下的分子迁移率远大于从熔融态外推得到的值。灰黄霉素玻璃态在298 K时的分子弛豫时间约为2个月，在较低温度下更长。它会随时间自发增加。如果结晶仅需要长程运动，那么灰黄霉素在储存过程中抗结晶性会变得更强。
