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, DG 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 nonglass-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, c, 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, Dd, 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.

Recent Advances in Amorphous Solid Dispersions: Preformulation, Formulation Strategies, Technological Advancements and Characterization

“…Therefore, APIs with T m /T g ratios on the lower side are desirable for the formulation of ASDs [ 53 ]. Since the stability of ASDs also depends on external factors such as moisture uptake (hygroscopicity) and storage temperature, several theoretical approaches including ternary or quaternary phase models (Flory–Huggin’s theory [ 54 , 55 ], Perturbed-Chain Statistical Associating Fluid Theory, and other hybrid models) have been proposed in the literature [ 56 ].…”

Considerations in the formulation of amorphous solid dispersions by hot melt extrusion

“…During the first stage, an in-depth evaluation of physicochemical properties of the drug and potential polymers is performed. Then, in the second stage, excipients are assessed through solubility parameters, melting point depression and Flory-Huggins interaction parameter (45,46). This preliminary evaluation can be complemented with experimental tests, such as DSC, where depression of the melting point evaluated and, eventually, the interaction parameter can be calculated (37).…”

Drug-Carrier Miscibility in Solid Dispersions of Glibenclamide and a Novel Approach to Enhance Its Solubility Using an Effervescent Agent

“…The different ratios of drug carriers were taken, and the depression in melting point was determined by the DSC technique at the melting temperature of GLB. Gibb's free energy depends on the drug-carrier miscibility (x) and Gibb's free energy gives information about the stability of the drug-carrier mix at room temperature [24]. A graph was plotted between drug-carrier weight fraction and ∆G mix (Fig.…”