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Understanding the dissolution mechanisms of amorphous solid dispersions (ASDs) and being able to link enhanced drug exposure with process parameters are key when formulating poorly soluble compounds. Thus, in this study, ASDs composed by itraconazole (ITZ) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were formulated with different polymer grades and drug loads (DLs) and processed by spray drying with different atomization ratios and outlet temperatures. Their in vitro performance and the ability to form drug-rich colloids were then evaluated by a physiologically relevant dissolution method. In gastric media, drug release followed a diffusion-controlled mechanism and drug-rich colloids were not formed since the solubility of the amorphous API at pH 1.6 was not exceeded. After changing to intestinal media, the API followed a polymer dissolution-controlled release, where the polymer rapidly dissolved, promoting the immediate release of API and thus leading to liquid–liquid phase separation (LLPS) and consequent formation of drug-rich colloids. However, the release of API and polymer was not congruent, so API surface enrichment occurred, which limited the further dissolution of the polymer, leading to a drug-controlled release. ASDs formulated with M-grade showed the highest ability to maintain supersaturation and the lowest tendency for AAPS due to its good balance between acetyl and succinoyl groups, and thus strong interactions with both the hydrophobic drug and the aqueous dissolution medium. The ability to form colloids increased for low DL (15%) and high specific surface area due to the high amount of polymer released until the occurrence of API surface enrichment. Even though congruent release was not observed, all ASDs formed drug-rich colloids that were stable in the solution until the end of the dissolution study (4 h), maintaining the same size distribution (ca. 300 nm). Drug-rich colloids can, in vivo, act as a drug reservoir replenishing the drug while it permeates. Designing ASDs that are prone to form colloids can overcome the solubility constraints of Biopharmaceutics Classification System (BCS) II and IV drugs, posing as a reliable formulation strategy.