Modulating Milling-Induced Amorphization Propensity of Drug Crystals by Cocrystallization

Amorphization is a common phase transformation that occurs during stress-intensive processes, such as milling. This study aims to evaluate the impact of cocrystallization on the amorphization behavior of sulfamethazine (SMT) during cryo-milling using two SMT cocrystals: one with p-hydroxybenzoic acid (SMT-HBA) and the other with benzamide (SMT-BNZ). At short milling durations (t < 30 min), the rank order of amorphous generation was SMT-BNZ > SMT ≫ SMT-HBA. However, after 2 h of cryo-milling, this order shifted to SMT-HBA > SMT-BNZ > SMT. Both SMT and SMT-BNZ exhibited an earlier onset of amorphization than SMT-HBA. The delayed amorphization onset of SMT-HBA is attributed to its higher crystal lattice strength. The rank order of amorphization extent over longer milling (up to 2 h) aligns with the physical stability of the generated amorphous phase, as assessed using configurational entropy and structural relaxation times based on the Adam–Gibbs equation. The combination of a slow onset of amorphization and the slow crystallization of the generated amorphous phase in SMT-HBA explains the shift in the rank order of amorphization extent over the entire milling duration. Understanding the interplay between crystal lattice strength and amorphous stability in stress-induced amorphization offers valuable guidance for mitigating the stress sensitivity of certain drugs through cocrystallization.