Molecular Mobility, Thermodynamics and Stability of Griseofulvin’s Ultraviscous and Glassy States from Dynamic Heat Capacity

Abstract

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.

Fast Surface Crystallization of Amorphous Griseofulvin Below T g

“…dynamics are negligible (8,9). Therefore, the molecular mobility, mainly a bulk property, cannot be responsible for the observed fast surface crystallization kinetics below T g .…”

“…One approach to predict the stability of amorphous phase against crystallization is to measure its molecular mobility that is believed to correlate with crystal growth in supercooled liquids (5). Although the quantitative correlation between molecular mobility and crystallization kinetics has not been well established, in practice, this correlation has been used to predict physical stability in lieu of complete understanding of crystallization mechanism and direct monitoring of crystallization kinetics below T g (6)(7)(8)(9). It has been suggested that amorphous pharmaceutical solids are expected to be stable at temperatures about fifty degrees below their glass transition, where the molecular mobility is usually negligible according to the spectroscopic and calorimetric measurements.…”

“…1) that has been used to study the crystallization kinetics of amorphous pharmaceutical solids (8,9,12). Yamamura et al reported that the crystallization of amorphous GSF was biphasic with an initial fast crystallization stage followed by a slow crystallization stage.…”

Solubility Advantage of Amorphous Pharmaceuticals: II. Application of Quantitative Thermodynamic Relationships for Prediction of Solubility Enhancement in Structurally Diverse Insoluble Pharmaceuticals

“…The melting points spanned a range of 116.2 K (423.2 to 539.4 K), and the glass transition temperatures varied over a range of 72 K (315.4 to 387.3 K). These large differences in T m and T g values for organic molecules (glasses) likely reflect differences in H-bond interactions in the solids (23,24). The heat of fusion values ranged from 30.0 to 55.4 KJ/mole, and the heat capacity difference between crystal and liquid (ΔCp x,l ) values ranged from 92 to 448 J/molK.…”

Specific heat of hydrated lysozyme, water's contribution to its dynamics, and criteria for glass formation of biomaterials

“…To examine this further, we do a direct calculation of the C p and C p values. The calculations were done as previously, 26 where the β KWW value was fitted to the C p and C p isochrones and τ was determined as a function of T.…”