Molecular mobility, thermodynamics and stability of griseofulvin's ultraviscous and glassy states from dynamic heat capacity.
OBJECTIVE
To determine the calorimetric relaxation time needed for modeling griseofulvin's stability against crystallization during storage.


METHODS
Both temperature-modulated and unmodulated scanning calorimetry have been used to determine the heat capacity of griseofulvin in the glassy and melt state.


RESULTS
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.


CONCLUSIONS
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.
Tombari
E
E
Istituto per i Processi Chimico-Fisici del CNR, 56124, Pisa, Italy.
Presto
S
S
Johari
G P
GP
Shanker
Ravi M
RM
D000935:Antifungal Agents / Q000737:chemistry*; D002151:Calorimetry / Q000379:methods; D003460:Crystallization; D004355:Drug Stability; D004356:Drug Storage; D006118:Griseofulvin / Q000737:chemistry*; D006358:Hot Temperature; D008956:Models, Chemical; D009038:Motion; D013816:Thermodynamics; D013997:Time Factors; D014732:Vibration; D014783:Viscosity
D000935:Antifungal Agents; D006118:Griseofulvin