More than 75% of the drug candidates are considered insoluble, limiting their oral absorption [[1], [2], [3]]. As a promising technique, amorphous solid dispersion (ASD) has been extensively used in improving the oral bioavailability of insoluble drugs. ASD is a homogeneous system in which the amorphous drugs are dispersed in hydrophilic polymeric carriers in the molecular state [4,5]. The amorphous form can significantly improve the solubility of the insoluble drugs due to the high free energy compared with the crystalline counterpart [6]. Moreover, the hydrophilic matrix, such as water-soluble amorphous polymers, can provide a fast dissolution rate [7,8]. From the 1980s to the 2020s, given the solubility–dissolution dual superiority, dozens of products based on the solid dispersion technique were already on the market (Table 1).

Despite the numerous advantages of ASD, the solution stability problems caused by the dissolution of the amorphous form limit its further application [1,9]. In the dissolution process, ASD preparation first exceeds the crystalline solubility of the insoluble drug under a non-sink dissolution condition and yields a supersaturated solution [10]. The recrystallization (de-supersaturation) phenomenon tends to spontaneously proceed in the supersaturation system due to the limited solubility, thereby disrupting the bioavailability of the insoluble drugs [11,12]. Although adding crystallization inhibitors can partially solve this problem, the specific mechanism is still unclear [12]. Hence, the supersaturation maintenance mechanism is of significant interest to researchers.

In recent studies, liquid–liquid phase separation (LLPS) has been found to be closely related to supersaturation maintenance [4,13]. As the free drug concentration consistently rises, the original homogeneous system is transformed into a heterogeneous system composed of a supersaturated solution phase and a drug aggregation supercooled liquid phase [13]. This phenomenon is commonly called “oiling out” in pharmaceutical production, which is also termed LLPS [4,14]. LLPS occurs when the integration of the drug molecules into the lattice is inhibited or delayed by the nucleation barrier [15]. At this point, the peak of the supersaturation state (amorphous solubility) is reached [16]. Moreover, with the further improvement in the system's capability with regard to amorphous solubility of the active pharmaceutical ingredient, the LLPS drug aggregates (LLPS-DAs) are accordingly formed [17]. LLPS-DA nanodroplets can work as drug reservoirs to continuously replenish free drug molecules into the system when the free concentration is reduced due to drug absorption [10]. Meanwhile, the colloidal characteristic of LLPS-DA can also bring an absorption advantage of membrane flux [18].

Although some studies have shown the advantages of LLPS-DA, systematic and definitive studies on the in vitro–in vivo correlation are still lacking. An in-depth review of LLPS-DA was required to better understand the dissolution mechanism of ASD and further explore the mechanism of supersaturation maintenance. Hence, this study was performed to present a short review to introduce the formation theories, stability characteristics, and characterization methods of the LLPS-DA, discuss the frontiers and cross-field investigation methods of the phase separation phenomena, and highlight the in vivo advantages of oral administration.