Elucidating the effect of crystallization on drug release from amorphous solid dispersions in soluble and insoluble...

The development of amorphous solid dispersions (ASDs) is one way to overcome the bioavailability challenges of poorly water-soluble active pharmaceutical ingredients (APIs). An important consideration with ASD systems is that crystallization can occur during preparation, storage, and dissolution, thus reducing their bioavailability advantage. Currently, it is unclear whether the dissolution characteristics of the polymer carrier affects the dissolution performance of ASDs with intrinsic crystallization. Our aim was to differentiate the impact of a minor amount of intrinsic crystallinity (up to 10%) within soluble and insoluble carriers on ASD performance, using the area under the curve (AUC) values of non-sink dissolution profiles as a measure of dissolution performance that can inform in vivo bioavailability. In order to discern such differences, itraconazole (ITZ) ASDs were prepared by Hot Melt Extrusion (HME) with 50% (w/w) drug loading. PVP K12 and HPMCAS were used as the soluble and insoluble carriers in pH 1.2 dissolution media, respectively. Dissolution was also conducted in pH 6.8 buffer, wherein HPMCAS becomes soluble, to cross-validate experimental observations. Crystalline content was determined by differential scanning calorimetry (DSC) prior to dissolution. Soluble polymers differed from insoluble polymers in that crystals formed during processing and storage were released during dissolution which can undergo further growth causing a sharp decline in drug concentration in the dissolution medium. This led to a significant decrease in the AUC for soluble ASDs containing intrinsic crystallinity. In contrast, insoluble polymer carriers did not release the intrinsically formed crystals and the impact of subsequent crystal growth on dissolution performance was minimal for insoluble ASD systems. Furthermore, physical mixtures with spiked crystallinity were only found to reflect the dissolution performance of soluble ASDs exhibiting intrinsic crystallinity. Thus, in considering the impact of intrinsic crystallinity on ASD performance, the nature of the polymeric carrier in terms of solubility characteristics needs to be taken into account as there is significantly more variation in AUC with soluble carriers than insoluble carriers exhibiting intrinsic crystallinity.