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Methods of Ex Situ and In Situ Investigations of Structural Transformations: The Case of Crystallization of Metallic Glasses
Published on: June 7, 2018
Correlating thermodynamic and kinetic parameters with amorphous stability
Kirsten A Graeser1, James E Patterson, J Axel Zeitler
1School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, New Zealand.
Summary
Predicting amorphous drug stability is challenging. Thermodynamic properties correlate with stability above the glass transition temperature (T(g)), but kinetic factors like relaxation time are inadequate predictors below T(g).
Area of Science:
- Pharmaceutics
- Materials Science
- Physical Chemistry
Background:
- Poor physical stability of amorphous drugs hinders their pharmaceutical application.
- Current understanding often relies on individual case studies, limiting generalizability.
- Predictive models for amorphous solid-state stability are crucial for drug development.
Purpose of the Study:
- To investigate thermodynamic and kinetic parameters as predictors of amorphous drug physical stability.
- To analyze a larger sample set of 12 drugs, moving beyond case-study limitations.
- To correlate calculated parameters with experimentally observed stability.
Main Methods:
- Calculation of relaxation time and fragility index for 12 amorphous drugs.
- Determination of configurational thermodynamic properties (enthalpy, entropy, Gibbs free energy).
- Correlation analysis between these parameters and experimentally determined physical stability above and below the glass transition temperature (T(g)).
Main Results:
- All 12 drugs were classified as 'fragile', with fragility index values ranging from 8.9 to 21.3.
- Below T(g), relaxation time and fragility showed no correlation with physical stability.
- Above T(g), thermodynamic parameters, particularly configurational entropy (r²=0.685), demonstrated a reasonable correlation with stability.
Conclusions:
- Configurational entropy shows promise as a predictor of physical stability for amorphous drugs above T(g).
- Kinetic parameters like relaxation time are insufficient for predicting stability below T(g).
- A comprehensive approach considering both thermodynamic and kinetic factors may be necessary for accurate stability predictions.
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