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

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Abstract

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, τ cal , of its melt varies with the temperature T according to the relation, \( \tau _{{{{cal}}}} {\left[ s \right]} = 10^{{ - 13.3}} \exp {\left[ {{2,292} \mathord{\left/ {\vphantom {{2,292} {{\left( {T{\left[ K \right]} - 289.5} \right)}}}} \right. \kern-\nulldelimiterspace} {{\left( {T{\left[ K \right]} - 289.5} \right)}}} \right]} \), 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.

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Acknowledgements

This research was financially supported by Pfizer as part of collaborative program. The experimental part of this study was performed at CNR, IPCF Pisa.

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Authors and Affiliations

  1. Istituto per i Processi Chimico-Fisici del CNR, 56124, Pisa, Italy

    E. Tombari & S. Presto

  2. Department of Materials Science and Engineering, McMaster University, Hamilton, Ontario, L8S 4L7, Canada

    G. P. Johari

  3. Groton Laboratories, Pfizer Inc., Groton, Connecticut, 06340, USA

    Ravi M. Shanker

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  1. E. Tombari
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Correspondence to G. P. Johari.

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Tombari, E., Presto, S., Johari, G.P. et al. Molecular Mobility, Thermodynamics and Stability of Griseofulvin’s Ultraviscous and Glassy States from Dynamic Heat Capacity. Pharm Res 25, 902–912 (2008). https://doi.org/10.1007/s11095-007-9444-8

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