Correlation between Glass-Forming Ability and Fragility of Pharmaceutical Compounds

Abstract

Fragility is a measure of the departure from non-Arrhenius behavior for supercooled liquids and glasses, and various simple methods are available for its quantification. However, the obtained values usually do not agree with each other. One of the purposes of this study was to compare the fragility values obtained by different methodologies. Thermodynamic fragility (FT) is a simple concept that is evaluated from the heat capacity change at the glass transition temperature (Tg). Dynamic fragility is evaluated using three methodologies in this study: extrapolation of the configurational entropy (Sc) to the Kauzmann temperature (Tk) (FDC), ramp-rate dependence of Tg (FDTg), and that of the fictive temperature (Tf) (FDTf). FT and FDC of 19 pharmaceutical compounds were correlated, whereas FDTg and FDTf did not correlate with either of them. This result seems reasonable because both FT and FDC are calculated from thermodynamic parameters in the quasi-equilibrium state, but FDTg and FDTf are likely affected by kinetics as well. Another goal of this study was to find the correlation between the glass-forming ability (GFA) and fragility. FDTg was shown to correlate with GFA, presumably because both were determined on the balance of thermodynamic and kinetic factors. This correlation suggests that fragile glass has low GFA. Furthermore, the relevance of fragility to isothermal crystallization is discussed. Compounds with small FDTg and FDTf tended to exhibit pressure-controlled crystallization, for which better storage stability can be expected relative to temperature-controlled compounds. Fragility was shown to be a useful parameter practically as well as scientifically.

Molecular relaxations in supercooled liquid and glassy states of amorphous gambogic acid: Dielectric spectroscopy, calorimetry, and theoretical approach

“…Interestingly, the heating rate exponentially varies with both T g and 1000/T g . The Arrhenius form of h is consistent with many studies [31][32][33][34][35][36]. The linear relationship between log 10 h and T g can also be found in Ref.…”

Studying the Impact of Modified Saccharides on the Molecular Dynamics and Crystallization Tendencies of Model API Nifedipine

“…One can mention herein that there are theoretical and experimental studies that try to link fragility and the physical stability of glass forming liquids. 71,72 However, in our case we did not find any clear relationship between fragility and physical stability. What is more, fragility does not change enough to make any credible discussion about the role of this parameter in controlling and delaying the crystallization process.…”

Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs

“…93 The kinetic behavior of a supercooled liquid can also be estimated by examining the sensitivity of the liquid structure to temperature change, known as "fragility" of the liquid, which is closely linked to its GFA. 94 It has been observed that strong "liquids" are good glass formers having higher viscosity at T m and resistant to structural changes. Fragile liquids, on the other hand, are weak glass formers, exhibiting lower viscosity at T m and allowing larger structural changes with change in temperature.…”