A New Method of Constructing a Drug–Polymer Temperature–Composition Phase Diagram Using Hot-Melt Extrusion

Abstract

Current experimental methodologies used to determine the thermodynamic solubility of an API within a polymer typically involves establishing the dissolution/melting end point of the crystalline API within a physical mixture or through the use of the glass transition temperature measurement of a demixed amorphous solid dispersion. The measurable "equilibrium" points for solubility are normally well above the glass transition temperature of the system, meaning extrapolation is required to predict the drug solubility at pharmaceutically relevant temperatures. In this manuscript, we argue that the presence of highly viscous polymers in these systems results in experimental data that exhibits an under or overestimated value relative to the true thermodynamic solubility. In previous work, we demonstrated the effects of experimental conditions and their impact on measured and predicted thermodynamic solubility points. In light of current understanding, we have developed a new method to limit error associated with viscosity effects for application in small-scale hot-melt extrusion (HME). In this study, HME was used to generate an intermediate (multiphase) system containing crystalline drug, amorphous drug/polymer-rich regions as well as drug that was molecularly dispersed in polymer. An extended annealing method was used together with high-speed differential scanning calorimetry to accurately determine the upper and lower boundaries of the thermodynamic solubility of a model drug-polymer system (felodipine and Soluplus). Compared to our previously published data, the current results confirmed our hypothesis that the prediction of the liquid-solid curve using dynamic determination of dissolution/melting end point of the crystalline API physical mixture presents an underestimation relative to the thermodynamic solubility point. With this proposed method, we were able to experimentally measure the upper and lower boundaries of the liquid-solid curve for the model system. The relationship between inverse temperature and drug-polymer solubility parameter (χ) remained linear at lower drug loadings. Significantly higher solubility and miscibility between the felodipine-Soluplus system were derived from the new χ values.

Analytical and Computational Methods for the Estimation of Drug-Polymer Solubility and Miscibility in Solid Dispersions Development

“…Schematic drawing of methods for the determination of drug solubility in the polymer, described in the references [13], [42], and [43] is given in Figure 1. Tian et al [44] recently proposed an improved method for the determination of equilibrium drug solubility within the polymeric matrix and the determination of the solid-liquid transition curve. In this method, a mixture of drug and polymer is firstly undergone to hot-melt extrusion and then subject to isothermal annealing at elevated temperatures (above T g of polymer and below the melting temperature ( T m ) of the drug) during 24 h. High-speed DSC (Hyper DSC) analysis with a heating rate of 200 °C/min is used to detect the presence of undissolved drug crystals remained after sample annealing.…”

“…This method should provide a more reliable determination of drug solubility within the polymer as long annealing process provides sufficient time for dissolution of drug crystals and overcoming of high polymer viscosity, which can delay completion of drug dissolution. High heating rate after sample annealing provides greater sensitivity to detect melting endotherm of remaining drug crystals, compared to usual DSC heating rates (1–10 °C/min), with the lower possibility that drug crystal will dissolve during DSC scan, leading to overestimation of drug equilibrium solubility in the polymer [44].…”

The Investigation of Flory–Huggins Interaction Parameters for Amorphous Solid Dispersion Across the Entire Temperature and Composition Range

“…However, as we already discussed that the level of FD-PVPK15 intermolecular interaction had significantly changed when the FD content was lower than 70% w / w . Therefore, the enhanced FD-PVPK15 intermolecular interactions were not captured in the high temperature dissolution/melting experiments (ideal mixing); hence, an underestimation on the extrapolated solubility value was expected [13].…”

“…Currently, two types of experimental methodologies are widely reported to determine the solubility limits of small molecule drug within the polymer matrix (phase diagram) [13]. One method is based on the detection of glass transition temperature after demixing of supersaturated ASD samples (high drug loadings) [14], the other is through measurement of the dissolution/melting of the crystalline drug within a polymer physic mixture [15,16].…”

“…One method is based on the detection of glass transition temperature after demixing of supersaturated ASD samples (high drug loadings) [14], the other is through measurement of the dissolution/melting of the crystalline drug within a polymer physic mixture [15,16]. However, due to the presence of high viscosity of the polymer in these testing samples, these two approaches provide overestimated or underestimated values on the solubility of the drug within the polymer [13,17]. Both the demixing method and the dissolution/melting method can only be used to physically measure the “equilibrium point” by using high drug loadings at high temperatures (e.g., higher than 70% w / w in the case of the felodipine and PVPK15 system).…”