Application of Thermodynamic Phase Diagrams and Gibbs Free Energy of Mixing for Screening of Polymers for Their Use in Amorphous Solid Dispersion Formulation of a Non-Glass-Forming Drug

Abstract

The objective of the present investigations was to assess the use of thermodynamic phase diagrams and the Gibbs free energy of mixing, ΔG_mix, for the screening of the polymeric carriers by determining the ideal drug-loading for an amorphous solid dispersion formulation and optimum processing temperature for the hot-melt extrusion of a non-glass-forming drug. Mefenamic acid (MFA) was used as a model non-glass-forming drug and four chemically distinct polymers with close values of the solubility parameters, viz. Kollidon® VA64, Soluplus®, Pluronic® F68, and Eudragit® EPO, were used as carriers. The thermodynamic phase diagrams were constructed using the melting point depression data, Flory-Huggins theory, and Gordan-Taylor equation. The Gibbs free energy of mixing was estimated using the values of the drug-polymer interaction parameter, χ, and Flory-Huggins theory. The rank order miscibility of MFA in the four polymeric carriers estimated based on the difference in the values of their solubility parameters, Δδ, did not correlate well with the thermodynamic phase diagrams and Gibbs free energy plots. The study highlights the limitation of using the solubility parameter method in screening the polymeric carriers for poorly glass-forming drugs and reiterates the applicability of thermodynamic phase diagrams and Gibbs free energy plots in determining the ideal drug-loading and optimum processing temperature for hot-melt extrusion.

Keywords: Amorphous solid dispersions; Drug-polymer interaction parameter; Flory-Huggins theory; Gibbs free energy of mixing; Melting point depression; Solid-liquid equilibrium; Solubility parameters; Thermodynamic phase diagrams.