Crystallization of lipidated dexamethasone prodrugs: the linker matters.

Hydrophobic prodrug-based microcrystalline suspensions are widely employed in long-acting injectable formulations owing to their high drug loading, minimal excipient requirements, and sustained release profiles. However, the extent to which the molecular structure-particularly linker chemistry-governs prodrug crystallization remains poorly understood. Here, we address this question by comparing two dexamethasone prodrugs with identical hydrophobic chains but distinct linkages: palmityl ketal dexamethasone (PKD) and palmityl ester dexamethasone (DXP). Using an antisolvent assembly approach in combination with multimodal characterization, we show that PKD readily forms well-defined microcrystals, whereas DXP predominantly yields amorphous aggregates. Structural analyses reveal that the ketal linker in PKD, featuring gem-dimethyl substitution, imposes conformational constraints and promotes persistent intermolecular hydrogen bonding, thereby enabling the formation of extended, ordered networks during assembly. In contrast, the hydrogen-bonding motif observed for DXP at the single-crystal level depends on specific geometries that are not readily preserved during assembly, resulting in disordered packing and amorphization. These findings identify linker geometry and conformational rigidity as key determinants of crystallization behavior and provide molecular-level design principles for long-acting injectable microcrystalline prodrug formulations.