Modelling phase separation in amorphous solid dispersions

Abstract

Much work has been devoted to analysing thermodynamic models for solid dispersions with a view to identifying regions in the phase diagram where amorphous phase separation or drug recrystallization can occur. However, detailed partial differential equation non-equilibrium models that track the evolution of solid dispersions in time and space are lacking. Hence theoretical predictions for the timescale over which phase separation occurs in a solid dispersion are not available. In this paper, we address some of these deficiencies by (i) constructing a general multicomponent diffusion model for a dissolving solid dispersion; (ii) specializing the model to a binary drug/polymer system in storage; (iii) deriving an effective concentration dependent drug diffusion coefficient for the binary system, thereby obtaining a theoretical prediction for the timescale over which phase separation occurs; and (iv) presenting a detailed numerical investigation of the HPMCAS/Felodipine system assuming a Flory-Huggins activity coefficient. The numerical simulations exhibit numerous interesting phenomena, such as the formation of polymer droplets and strings, Ostwald ripening/coarsening, phase inversion, and dropletto-string transitions.

Recent Advances in Understanding the Micro- and Nanoscale Phenomena of Amorphous Solid Dispersions

“…For binary systems, the model enables the use of a single interaction parameter for estimating phase behavior over the entire composition range. Flory–Huggins theory has even been used to assess the time scale of phase separation in ASD systems . Yet, the assumptions associated with this theory hinder its application for ASDs.…”

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

“…Through this approach, the binodal curve (critical positions between one phase and AAPS) for FD-PVPK15-water ternary system was defined at temperatures 59 °C, 54 °C, 49 °C and 47 °C containing FD of 35%, 40%, 45% and 50% w / w respectively (Table 2). Recently, a very detailed illustration for the formation of AAPS in binary drug-polymer ASD has been reported where the drug-rich and polymer-rich domains at various time scales can be modelled [57]. In conclusion, two T g systems were shown in black lines in Figure 5 when a suitable annealing temperature was selected, whilst one T g systems can be observed at higher annealing temperature.…”

“…More importantly, the Flory–Huggins interaction parameter χ12false(Φ1, T) across the entire temperature and composition range was successfully obtained through carefully designed experiments and a more complex modelling. With the χ12false(Φ1, T) derived from this combinational approach, the understanding of the aFD-PVPK15 binary system can be further enhanced, e.g., the modelling for kinetics of phase behaviors in none-equilibrium ASDs where the time associated to the demixing may be predicted [57]. Thus, a comprehensive predictive tool encompassing both thermodynamic and kinetic aspects of physical stability may be subsequently obtained in the future.…”

Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

“…Similarly, important tool such as Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) modelling has also been used for the quantitative analysis of these systems [84]. Other hybrid models for drug-polymer binary systems and the subsequent extension of ternary or quaternary systems have been reported for the design and understanding of ASD formulations [85][86][87][88]. The combination of these insightful thermodynamic and kinetic models will certainly provide a more informative guide for the AAPS process in presence of moisture/solvent and therefore a better understanding of the ASD stability during its preparation and storage.…”