Selective formation of coamorphous systems with enzalutamide: Benzene rings as key structural features

Enzalutamide (ENZ), a non-steroidal antiandrogen used in the treatment of metastatic castration-resistant prostate cancer, exhibits poor aqueous solubility and bioavailability. Coamorphous systems, formed between an active pharmaceutical ingredient (API) and a low-molecular-weight coformer, offer a promising strategy to enhance solubility and dissolution. Here, we systematically screened a range of small organic acids and amino acids as coformers for coamorphous system formation with ENZ. Interestingly, full coamorphous systems formed exclusively with coformers containing a benzene ring, including benzoic acid, salicylic acid, 2-aminobenzoic acid, 2,5-dihydroxybenzoic acid (25H), L-phenylalanine, and L-tryptophan. Crystal structure analysis revealed that ENZ is stabilized in its crystalline state through strong π–π stacking, but these interactions are weakened or disrupted upon amorphization. Coamorphization is facilitated by coformers that can stabilize the amorphous phase through molecular complementarity and favorable packing. FTIR indicated limited new strong interactions, suggesting stabilization mainly via molecular mixing and weak π–π contacts. Thermal analysis confirmed single-phase systems with distinct T_g values, and stability studies revealed that the ENZ–25H system remained amorphous for nearly four months, outperforming others. Dissolution testing demonstrated up to a 3.6-fold increase in intrinsic dissolution rate compared with crystalline ENZ. These results identify aromaticity as a critical structural feature for coamorphous formation with ENZ and provide a rational basis for coformer selection for this drug and, by extension, other aromatic-rich, poorly soluble APIs.