Polymorphism Control of Aripiprazole with Phenol-Based Deep Eutectic Solvents: Tuning via Molar Ratio and Solvent Removal Rate

Deep eutectic solvents (DES) have emerged as environmentally friendly alternatives to conventional crystallization media in pharmaceutical applications. In this work, a phenol-based DES, in which phenol acts as the volatile hydrogen bond donor, was employed to regulate the polymorphism of aripiprazole (APZ). The results demonstrated that DES composition strongly affected the polymorphic outcome of APZ: a 1:6 molar ratio predominantly produced form III, 1:7–1:8 ratios yielded form V, and 1:9–1:10 ratios led to form VII. However, this tunability was lost when the phenol removal rate increased under vacuum, where only a single polymorph was obtained, indicating that the nucleation pathway was restricted by rapid solvent loss. Conformational analysis revealed that an excess of hydrogen bond donors promoted stronger multidirectional coordination and steric filling effects, driving APZ to adopt a noncoplanar conformation. Moreover, the rapid removal of phenol drives the composition swiftly beyond the metastable regions, resulting in the exclusive formation of a single polymorph. The DES composition influenced the formation of rhombic and star-like crystal morphologies, whereas the phenol removal rate had minimal impact, indicating its primary role in nucleation rather than crystal growth. Overall, this study highlights DES as promising crystallization media for the effective control of drug polymorphism and morphology, providing new insights into their application in pharmaceutical crystallization design.