From prediction to performance: In silico-supported formulation of amorphous solid dispersions for PROTAC NX-2127

The oral delivery of PROTACs is frequently limited by poor aqueous solubility and low membrane permeability, whereas early formulation development is often constrained by limited drug substance availability. To address these challenges, this study established a material-sparing workflow integrating in silico prediction with in vitro screening to efficiently support formulation development of the model PROTAC NX-2127. Following physicochemical characterization confirming the amorphous nature and thermal stability of NX-2127, COSMOquick calculations served as an initial tool to prioritize polymer candidates, while miniaturized supersaturation assay enabled their final selection for amorphous solid dispersions (ASDs). Soluplus® and Eudragit® EPO exhibited superior supersaturation-inducing and -maintaining properties and were selected for ASD preparation via vacuum compression molding (VCM). To further enhance dissolution, ionic crosslinking within the EPO-based ASD was induced by incorporating tartaric acid (TA), yielding a ternary EPO/TA-ASD. This formulation delivered a pronounced enhancement in non-sink dissolution, resulting in a 546-fold increase in drug release in phosphate buffer (pH 6.8) compared to the neat compound at the endpoint of the dissolution assay at 270 min. These findings were consistently reflected in the biorelevant biphasic dissolution system (BiPHa+), where the EPO/TAASD exhibited the highest performance and further improved partitioning into the absorption compartment. Overall, this study demonstrates that while in silico prediction represents a valuable tool for supporting early formulation development, experimental in vitro screening remains indispensable for reliable polymer selection. The combination of both approaches enabled the rational design of ASD formulations and led to substantial gains in dissolution performance of poorly soluble PROTACs.