Category: Formulation and Quality
Purpose: In amorphous solid dispersions (ASDs), the drug is in a high energy state compared to its crystalline counterparts and thus, ASDs can be used to generate supersaturation in the GI tract, which can potentially increase bioavailability. However, amorphous solid dispersions at high drug loading levels often exhibit a significantly lower release rate due to phase separation in the gel phase during dissolution. This phase separation is moisture induced as moisture sorption leads to increased mobility and decreased solubility. Ternary phase diagrams can be used to describe the thermodynamics of moisture absorbed ASD systems of varying drug loading levels. Here, we construct a water-drug-polymer ternary phase diagram and apply it for the first time, to the best of our knowledge, to interpret the relationship between observed drug release rate and the evolution of phase separation morphology during dissolution of ritonavir (RTV)–PVP ASDs at varying drug loading levels. We also show that the locus of binodal can be used to understand the critical moisture sorption for phase separation to occur at different drug loadings, and the locus of spinodal can provide insight into the phase separation morphology.
Methods: Water-RTV-PVP ternary phase diagram was constructed based on Flory Huggin’s lattice model. The RTV-PVP and water-RTV interaction parameters were computed from moisture sorption data and water-PVP interaction parameter was obtained from literature. Gordon-Taylor equation was used to compute the vitrification line.
Rotating disk dissolution (RDD) studies of RTV-PVP solvent cast films were performed with varying drug loading levels (5%-60%) and both drug and polymer release were measured. Briefly, RTV and PVP were dissolved in ethanol, poured into a special two piece dish and then oven dried for a total of 24 hours at 60 °C. Disk samples of 12 mm diameter were prepared by punching from the ASD film, casting in paraffin-bee’s wax mixture with one surface exposed, then loading it into a custom rotating disk apparatus. After loading, samples were lowered into a phosphate buffer medium (pH 2.2) and rotated at 50 rpm. At selected time points, 1 ml of sample was withdrawn for analysis of RTV and PVP concentrations. RTV concentration was obtained by HPLC and PVP concentration was obtained from absorption at 500 nm after mixing with the triiodide reagent. To prevent crystallization during storage, PVP samples were analyzed immediately and RTV samples were diluted with organic solvent before analysis by HPLC.
The evolution of phase separation morphology during dissolution was probed by removing the films from the RDD apparatus and imaging under confocal fluorescence microscope. To compare phase development during dissolution with that during hydration (without erosion), RTV-PVP ASD films were placed in 98% RH environment generated using saturated potassium sulfate solution and the films were imaged by confocal fluorescence microscopy at selected time points.
Results: The ternary phase diagram (Figure 1) revealed that the spinodal and binodal occur at < 5% moisture gain for 20% drug loading level. This is much lower than the critical moisture content for glassy-rubbery transition, based on the vitrification line. Thus, the relative position of the spinodal and the vitrification line suggested that spinodal decomposition is likely during hydration (for > 10% drug loading). Confocal images confirmed that strand-like structures characteristic of spinodal decomposition formed only after crossing the vitrification line and underwent continuous to discrete transition during the coarsening stage.
Rotating disk dissolution data showed that the drug release was fastest at an intermediate drug loading level of 20%. Below this loading level, polymer and drug released congruently, whereas above this loading level, polymer released preferentially (Figure 2). Polarized light microscopy showed that after the dissolution study, no crystals were present. Amorphous phase separation was present at all drug loading levels tested, including at low drug loadings where congruent release was observed. The confocal images revealed that there was a change in phase separation morphology at around 20% drug loading. At low drug loading levels, the hydrophobic domains were discrete domains whereas at high drug loading levels, hydrophobic domains were continuous (Figure 3).
Conclusion: For RTV-PVP ASD, at low drug loadings, the eroding layer consists of drug-discrete phase and as the polymer matrix erodes, the drug-rich droplets are released. At high drug loading, phase separation leads to drug continuous morphology, leading to the formation of drug continuous scaffold due to preferential release of polymer rich phase. Further, as RTV-PVP undergoes phase separation by spinodal decomposition, the transition from drug discrete to drug continuous occurs at the percolation threshold for spinodal decomposition which is around 20%. Thus, ternary phase diagram should also provide insight into mechanisms of phase separation and release in other ASDs.