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Pharmaceutical Research, Vol. 25, No. 4, April 2008 ( # 2007) DOI: 10.1007/s11095-007-9444-8
Research Paper Molecular Mobility, Thermodynamics and Stability of Griseofulvin_s Ultraviscous and Glassy States from Dynamic Heat Capacity
E. Tombari,1 S. Presto,1 G. P. Johari,2,4 and Ravi M. Shanker3
Received May 28, 2007; accepted August 24, 2007; published online September 27, 2007
Purpose. 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, tcal, of its melt varies with the temperature T according to the relation, tcal s
10 13:3 exp 2; 292= TK
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 kineticsthermodynamics 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.
KEY WORDS: calorimetric relaxation time; complex heat capacity; glassy state; griseofulvin; stability.
INTRODUCTION
The Gibbs free energy of a non-crystalline solid pharmaceutical is greater than that of its crystalline form, and therefore its saturation solubility and hence the bioavailability is higher. This is the basis on which procedures for improving the bioavailability of poorly soluble pharmaceuticals are currently being developed. It is also known that non-crystalline states of different free energies of a pharmaceutical are produced by different techniques. Therefore, bioavailability of a given pharmaceutical varies with the method of its industrial production, such as lyophilization (freeze-drying), flocculation (precipitation with an external agent usually an ionic polymer), trituration (high-speed mechanical deformation) and vitrification by supercooling the melt. It also varies with time during storage...