Predicting the Formation and Stability of Amorphous Small Molecule Binary Mixtures from Computationally Determined Flory−Huggins Interaction Parameter and Phase Diagram

Abstract

The Flory-Huggins interaction parameter has been shown to be useful in predicting the thermodynamic miscibility of a polymer and a small molecule in a binary mixture. In the present paper, this concept was extended and evaluated to determine whether or not the Flory-Huggins interaction parameter can be applied to small molecule binary mixtures and if this parameter can predict the phase stability of such amorphous binary mixtures. This study was based on the assumption that a thermodynamically miscible binary system is stable and cannot crystallize, and that phase separation is essential before the individual components can crystallize. The stabilization of a binary system is thought to derive from molecular interactions between components in a solid dispersion, which are characterized by the Flory-Huggins interaction parameter. Based on DSC experiments, drug molecules (39) in the present study were classified into three different categories according to their crystallization tendency; i.e., highly crystallizing, moderately crystallizing and noncrystallizing compounds. The Flory-Huggins interaction parameter was systematically calculated for each drug pair. The validity of this approach was empirically verified by hot-stage polarized light microscopy. If both compounds in the pair belonged to the category of highly crystallizing compound, the Flory-Huggins interaction predicted an amorphous or crystalline phase with approximately 88% (23 out of 26) confidence. If one or both compounds of the pair were either moderately crystallizing or noncrystallizing compounds, the binary mixture remained in the amorphous phase during the cooling phase regardless of the interaction parameter. The Flory-Huggins interaction parameter was found to be a reasonably good indicator for predicting the phase stability of small molecule binary mixtures. The method described can enable fast screening of the potential stabilizers needed to produce a stable amorphous binary mixture.

Construction and Validation of Binary Phase Diagram for Amorphous Solid Dispersion Using Flory–Huggins Theory

“…For example, elevation of glass transition temperature (T g ) of amorphous drug by incorporation of high-T g polymer has been shown to reduce molecular mobility (i.e., increased relaxation time) required for crystallization at a certain storage temperature (12). Specific intermolecular interactions between drug and polymer are also reported to stabilize the amorphous drug (13). Thermodynamic principles suggest reduction in chemical potential of drug on mixing with polymer, thus lowering the driving force for crystallization.…”

“…As the configurational entropy always favors mixing for all combinations and compositions, it is the enthalpic component of ΔG mix which determines whether or not mixing may be spontaneous. In the enthalpic component, the binary interaction parameter, χ d-p, is naturally expected to be critical for understanding as well as predicting the behavior of a drug-polymer binary system (13). A value of χ d-p ≤0, indicative of adhesive interaction between drug and polymer molecules, would facilitate mixing.…”

“…Semiempirical methods which have been used for the determination of χ d-p include the following: (A) a priori estimates using solubility parameters (17)(18)(19)(20) and (B) using melting point depression of drug in the presence of polymer for estimation of χ d-p (21,22). In addition, molecular dynamic simulation and determination of solubility of drug in low-molecular weight analog of polymer have also been used for the estimation of the interaction parameter (13,23).…”

Optimising Drug Solubilisation in Amorphous Polymer Dispersions: Rational Selection of Hot-melt Extrusion Processing Parameters

“…The use of Flory-Huggins lattice theory to construct a T-ϕ phase diagram thus determining drug-polymer solubility as a function of temperature has been well established in the current literature (13)(14)(15)(16)(17)(18)20,21). Accordingly, Gibb's free energy of mixing ΔG mix can be expressed as (22):…”

Investigation of the phase behavior of food-grade microemulsions by mesoscopic simulation

“…In the current simulation, the Flory-Huggins parameters ( ij ) were derived using the Blends module [29]. The Blends module calculates the ij parameters for molecules in a binary mixture by combining a modified Flory-Huggins model with molecular simulation techniques [30]. The calculated interaction parameters derived from the ij parameter at 298 K are presented in Table 1.…”