Amorphous solid dispersions (ASDs) can potentially enhance the bioavailability of poorly water-soluble drugs by generating supersaturation in the GI tract. However, relaxation by crystallization or phase separation can occur during dissolution, not only in the solution phase but also in the ASD matrix, potentially resulting in the reduction in the bioavailability advantage. Although drug loading is known to affect the degree of supersaturation in the ASD matrix, its influence on the interplay between the polymer and drug release has not been fully explored. Here, we delineate the effect of drug loading levels on drug release rate and polymer erosion rate from ASDs.
Rotating disk dissolution (RDD) was used to study the release rate of ASDs under sink conditions. ASDs with different drug loadings were prepared by solvent casting. Briefly, model drug indomethacin (IND) and model water soluble polymer PVP-K90 were dissolved in ethanol, poured into a Teflon dish, degassed for 30 min, and then oven dried for a total of 24 hr 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 6.7) and rotated at 50 rpm. At selected time points, 1 ml of sample was withdrawn for analysis of IND and PVP concentrations. IND concentration was obtained from UV absorption and PVP concentration was obtained from absorption at 500 nm after mixing with the triiodide reagent. Sink condition was ensured by replacing media volumes as necessary. At the end of the dissolution, ASD samples were removed and viewed under PLM for the presence of crystals.
For IND-PVP ASD, higher loadings did not result in higher drug release rates and intermediate loading level led to the fastest drug release (Figure 1). The polymer release data showed that samples with higher drug loading experienced reduced polymer release even after normalizing to polymer weight fraction (Figure 2), suggesting that the overall erosion rate has been reduced. In addition, weight fraction of drug release relative to total amount of ASD released (ie. IND/(IND+PVP), Figure 3) was linear up to critical drug loading level and started to deviate negatively, suggesting erosion mediated release at early times and preferential polymer release at late times. Samples viewed under PLM did not show crystallization but change in opacity suggested phase separation in the samples. Thus, the preferential polymer release and lack of crystals suggest that the polymer-rich phase eroded preferentially. Overall, the combination of preferential polymer release at higher loadings and reduced overall erosion rate led to highest release rate being observed for an intermediate drug loading level.
Along different stages of ASD development, changes in drug loading level may be needed. Our results suggest that their effect on release profile should be carefully considered, as different drug loading levels can affect drug release rates to different extent.